Regulatory submission: NDA submitted September 2025

“AbbVie (NYSE: ABBV) today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tavapadon, a novel selective dopamine D1/D5 receptor partial agonist that was studied as a once daily oral treatment for Parkinson's disease.” (opens the source at this quote in a new tab)
“The submission is based on results from the TEMPO clinical development program that evaluated the efficacy, safety and tolerability of tavapadon across a broad Parkinson's disease population.” (opens the source at this quote in a new tab)
“The submission is also based on an interim data cut from TEMPO-4, an open-label extension (OLE) trial to assess the long-term clinical benefit of tavapadon.” (opens the source at this quote in a new tab)

“In September 2025, AbbVie announced the submission of a New Drug Application (NDA) to the U.S. FDA for tavapadon, a novel selective dopamine D1/D5 receptor partial agonist, for the treatment of Parkinson's disease.” (opens the source at this quote in a new tab)

Launch: Expected by Citi analysts in the third quarter of 2026

“AbbVie did not respond to a Reuters request for comment on the drug’s launch and pricing.” (opens the source at this quote in a new tab)
“Citi analysts had previously said the launch was expected in the third quarter of 2026, but that uptake was likely to be gradual as negotiations progressed on the drug’s Medicare coverage.” (opens the source at this quote in a new tab)

“COMING SOON” (opens the source at this quote in a new tab)
“Learn more right at launch about JUVMO and stay current with product updates when you sign up below.” (opens the source at this quote in a new tab)

FDA approval: September 2026

Field	Quoted record
Drug name	“Juvmo”
Active ingredient	“tavapadon”
Approval date	“9/25/2026”
FDA-approved use on approval date	“To treat Parkinson’s disease in adults”

“JUVMO™ (tavapadon) tablets, for oral use” (opens the prescribing information at this quote)
“Initial U.S. Approval: 2026” (opens the prescribing information at this quote)

Planned submission timing stated at the final Phase 3 readout

“AbbVie is on track to submit the New Drug Application (NDA) to the U.S. Food & Drug Administration (FDA) in 2025.” (opens the source at this quote in a new tab)

“A New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in 2025, with a decision expected in 2026.” (opens the source at this quote in a new tab)

Development history: discovery at Pfizer and transfer to Cerevel Therapeutics

“Pfizer is contributing a portfolio of pre-commercial neuroscience assets to Cerevel, which include three clinical-stage compounds and several pre-clinical compounds designed to target a broad range of CNS disorders including Parkinson’s, Alzheimer’s, epilepsy, schizophrenia and addiction.” (opens the source at this quote in a new tab)
“The most advanced assets in the portfolio are a D1 partial agonist which will likely enter Phase III in 2019 to treat the symptoms of Parkinson’s disease, and a Phase II ready selective GABA 2/3 agonist which will initially be studied for epilepsy.” (opens the source at this quote in a new tab)

“In August 2018, we entered into the Pfizer License Agreement pursuant to which we were granted an exclusive, sublicensable, worldwide license under certain Pfizer patent rights, and a non-exclusive, sublicensable, worldwide license under certain Pfizer know-how, to develop, manufacture and commercialize certain compounds and products” (opens the source at this quote in a new tab)
“We are also required to pay Pfizer tiered royalties on the aggregate net sales during each calendar year, determined on a product-by-product basis with respect to products under the Pfizer License Agreement, at percentages ranging from the low-single digits to mid-teens” (opens the source at this quote in a new tab)
“We initiated a registration-directed Phase 3 program for tavapadon beginning in January 2020, which includes two trials as monotherapy in early-stage Parkinson’s, known as TEMPO-1 and TEMPO-2, one trial as adjunctive therapy in late-stage Parkinson’s, known as TEMPO-3, and an open-label extension trial, known as TEMPO-4.” (opens the source at this quote in a new tab)

“It was initially developed by Pfizer and outlicensed to Cerevel Therapeutics, which was eventually acquired by AbbVie.” (opens the source at this quote in a new tab)

Development history: early-phase trials under Pfizer, including a terminated Phase 2 trial in advanced disease

“While this study suggested that tavapadon was generally well tolerated and provided motor benefit for the treatment of early-stage PD, enrollment was terminated early in this study due to its link to a concurrent phase 2 trial of tavapadon in advanced PD (NCT02687542) that failed to meet a prespecified efficacy threshold in an interim futility analysis” (opens the source at this quote in a new tab)

Development history: acquisition of Cerevel Therapeutics by AbbVie

“AbbVie (NYSE: ABBV) today announced that it has completed its acquisition of Cerevel Therapeutics (NASDAQ: CERE). With the completion of the acquisition, Cerevel is now part of AbbVie.” (opens the source at this quote in a new tab)
“Tavapadon, a first-in-class dopamine D1/D5 selective partial agonist for the management of Parkinson's disease, is currently in Phase 3 studies and has potential for both monotherapy and adjunctive treatment.” (opens the source at this quote in a new tab)
“AbbVie has acquired all outstanding Cerevel common stock for $45 .00 per share.” (opens the source at this quote in a new tab)

Development funding agreements with milestone and royalty repayment on approval

“Under the agreements, Cerevel Therapeutics received funding to support development of tavapadon and agreed to repay regulatory milestones, sales milestones and royalties contingent upon approval of tavapadon by the U.S. FDA.” (opens the source at this quote in a new tab)
“In all circumstances, total repayments under the funding agreements will not exceed $ 531 million in aggregate.” (opens the source at this quote in a new tab)

FDA expedited program designations

No evidence found.

Manufacturer: AbbVie

“Marketed by: AbbVie Inc. North Chicago, IL 60064 U.S.A.” (opens the prescribing information at this quote)
“JUVMO and its design are trademarks of Cerevel Therapeutics, LLC, an AbbVie company.” (opens the prescribing information at this quote)

Brand name, generic name, and established pharmacologic class

“JUVMO™ (tavapadon) tablets, for oral use” (opens the prescribing information at this quote)
“JUVMO is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease in adults.” (opens the prescribing information at this quote)
“The active ingredient of JUVMO is tavapadon, a non-ergot dopamine agonist.” (opens the prescribing information at this quote)

Chemical name, formula, and molecular weight

“The chemical name is (S)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl) pyridin-2-yl]oxy}phenyl)pyrimidine- 2,4(1H,3H)-dione.” (opens the prescribing information at this quote)
“Its molecular formula is C19H16F3N3O3 and its molecular weight is 391.35 Daltons.” (opens the prescribing information at this quote)
“Tavapadon is a white to pale-yellow solid that is practically insoluble in water.” (opens the prescribing information at this quote)

Development codes

“One such noncatechol compound, tavapadon (also known as PF-06649751 and CVL-751), originally developed by Pfizer and later Cerevel Therapeutics (now part of AbbVie), recently showed promise for symptom relief in Parkinson’s disease, meeting the primary end point in a phase III study.” (opens the source at this quote in a new tab)

Therapeutic class: selective dopamine D1/D5 receptor partial agonist

“Tavapadon is the first and only D1/D5 partial agonist under investigation as a once-daily treatment for Parkinson's disease.” (opens the source at this quote in a new tab)

“Tavapadon, a highly selective partial agonist at D1 and D5 receptors, is being investigated for early through advanced PD” (opens the source at this quote in a new tab)

Tablet strengths and descriptions

“Tablets: 0.25 mg, 1 mg, 5 mg, 10 mg, and 15 mg (3)” (opens the prescribing information at this quote)
“Each film-coated tablet contains 0.25 mg, 1 mg, 5 mg, 10 mg, or 15 mg tavapadon.” (opens the prescribing information at this quote)

Tablet descriptions by strength

Strength	Quoted description
0.25 mg	“Round, orange, film-coated”
1 mg	“Rectangle, orange, film-coated”
5 mg	“Diamond, purple, film-coated”
10 mg	“Oval, purple, film-coated”
15 mg	“Rectangle, purple, film-coated”

Inactive ingredients

“0.25 mg and 1 mg tablets: Lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, talc, titanium dioxide, and yellow iron oxide.” (opens the prescribing information at this quote)
“5 mg, 10 mg, and 15 mg tablets: Carmine, FD&C Blue No. 2, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, talc, and titanium dioxide.” (opens the prescribing information at this quote)

Storage and handling

“Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].” (opens the prescribing information at this quote)

Bioequivalence of the 15 mg tablet and three 5 mg tablets

“The primary purpose of the study is to evaluate the bioequivalence (BE) of tavapadon 15 milligram (mg) tablet to 3x5 mg tablets in participants with Parkinson's disease.” (opens the source at this quote in a new tab)

Relative bioavailability of clinical and commercial tablets

“A Phase 1, Two Part, Randomized, Single and Multiple Dose Crossover Study to Assess the Relative Bioavailability Between Tavapadon Clinical and Commercial Tablets” (opens the source at this quote in a new tab)

Reported list price of tavapadon, attributed to a William Blair analyst and to ICER public meeting slides; no AbbVie price statement published

“Matt Phipps notes that Juvmo carries a list price of $4,900 per 30-day supply, or $58,800 annually.” (opens the source at this quote in a new tab)

Drug	Quoted estimate	Quoted annual cost used in model
Tavapadon	“Reported WAC”	“$58,800”

Launch pricing not disclosed at approval

“AbbVie did not respond to a Reuters request for comment on the drug’s launch and pricing.” (opens the source at this quote in a new tab)

Placeholder annual price and comparator annual drug costs used in the ICER evidence report

“Because tavapadon had not yet received regulatory approval, a placeholder price of $15,000 per year (as reported by IPD Analytics) was used as the intervention acquisition cost in both models. In Model 1, levodopa was costed at the median generic wholesale acquisition cost (WAC) from RED BOOK ($289 per year), consistent with ICER Reference Case guidance for generic agents. In Model 2, the dopamine agonist comparator used a market-basket approach: market-share weights were derived from a 2024 Merative MarketScan Medicare Supplemental analysis restricted to the three most-dispensed agents and normalized to 100% (ropinirole 51.9%, pramipexole 41.6%, rotigotine 6.4%), and annual WAC for each agent was sourced from RED BOOK (with the SSR Health net price applied for rotigotine), yielding a weighted-average annual dopamine agonist cost of $3,588.” (opens the source at this quote in a new tab)

Branded and generic Parkinson's disease comparators: United States National Average Drug Acquisition Cost, week of 23 September 2026

Product and strength	Quoted record description	Quoted acquisition cost per unit	Quoted pricing unit
Opicapone 50 mg capsule	“ONGENTYS 50 MG CAPSULE”	“24.76028”	“EA”
Safinamide 100 mg tablet	“XADAGO 100 MG TABLET”	“36.32581”	“EA”
Carbidopa-levodopa extended-release 36.25 mg-145 mg capsule	“RYTARY ER 36.25 MG-145 MG CAP”	“3.97630”	“EA”
Pramipexole 1 mg tablet (generic)	“PRAMIPEXOLE 1 MG TABLET”	“0.06192”	“EA”
Ropinirole 3 mg tablet (generic)	“ROPINIROLE HCL 3 MG TABLET”	“0.07680”	“EA”
Carbidopa-levodopa 25-100 mg tablet (generic)	“CARBIDOPA-LEVODOPA 25-100 TAB”	“0.07589”	“EA”

Rotigotine, monoamine oxidase B inhibitor, catechol-O-methyltransferase inhibitor, and amantadine comparators: United States National Average Drug Acquisition Cost, week of 23 September 2026

Product and strength	Quoted record description	Quoted acquisition cost per unit	Quoted pricing unit
Rotigotine 2 mg/24 hours transdermal patch (Neupro)	“NEUPRO 2 MG”/ “24 HR PATCH”	“28.26022”	“EA”
Rasagiline 1 mg tablet (generic)	“RASAGILINE MESYLATE 1 MG TAB”	“0.92551”	“EA”
Selegiline 5 mg capsule (generic)	“SELEGILINE HCL 5 MG CAPSULE”	“0.75631”	“EA”
Entacapone 200 mg tablet (generic)	“ENTACAPONE 200 MG TABLET”	“0.32457”	“EA”
Carbidopa-levodopa-entacapone 25-100-200 mg tablet (generic)	“CARBIDOPA-LEVODOPA-ENTACAPONE 25-100-200 MG TAB”	“0.69542”	“EA”
Amantadine 100 mg capsule (generic)	“AMANTADINE 100 MG CAPSULE”	“0.14251”	“EA”

Gocovri and Nourianz: wholesale acquisition cost filings with the California Department of Health Care Access and Information

Product and package	Quoted manufacturer	Quoted drug product description	Quoted WAC effective date	Quoted WAC increase amount (USD)	Quoted WAC after increase (USD)
Gocovri (amantadine extended-release) 137 mg, 60 capsules	“Adamas Pharmaceuticals, Inc.”	“Gocovri Oral Capsule Extended Release 24 Hour 137 MG Package Size 60 Package Quantity 1”	“01/01/2023”	“149.67”	“3142.96”
Nourianz (istradefylline) 20 mg, 90 tablets	“Kyowa Kirin, Inc.”	“Nourianz Oral Tablet 20 MG, 90 Each, Bottle”	“01/05/2024”	“270.39”	“5678.15”
Nourianz (istradefylline) 40 mg, 90 tablets	“Kyowa Kirin, Inc.”	“Nourianz Oral Tablet 40 MG, 90 Each, Bottle”	“01/05/2024”	“270.39”	“5678.15”

Branded Parkinson's disease adjunctive therapies: Medicare Part D spending, 2024

Brand (generic)	Quoted total spending, 2024 (USD)	Quoted beneficiaries, 2024	Quoted average spending per dosage unit, 2024 (USD)	Quoted average spending per beneficiary, 2024 (USD)
Ongentys (opicapone)	“15354274.26”	“3276”	“21.749437532”	“4686.8969048”
Xadago (safinamide)	“7677985.91”	“759”	“37.323213575”	“10115.923465”
Nourianz (istradefylline)	“50721486.03”	“3610”	“62.728700759”	“14050.273139”
Neupro (rotigotine)	“90068151.36”	“14920”	“27.60090549”	“6036.7393673”
Gocovri (amantadine extended-release)	“99842781.69”	“4906”	“55.422069989”	“20351.15811”
Inbrija (inhaled levodopa)	“27688440.22”	“2431”	“20.495381225”	“11389.732711”
Rytary (carbidopa-levodopa extended-release)	“271784313.29”	“34890”	“4.2578095671”	“7789.7481596”

Monoamine oxidase B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine products: Medicare Part D beneficiaries, claims, and spending per dosage unit, 2024

Brand name in the record (generic)	Quoted beneficiaries, 2024	Quoted claims, 2024	Quoted average spending per dosage unit, 2024 (USD)
Rasagiline Mesylate (rasagiline, generic)	“31737”	“146909”	“3.2972061315”
Selegiline HCl (selegiline, generic)	“11299”	“50495”	“0.9994398084”
Xadago (safinamide)	“759”	“4385”	“37.323213575”
Entacapone (entacapone, generic)	“26289”	“128596”	“0.9670266984”
Carbidopa-Levodopa-Entacapone (carbidopa, levodopa, and entacapone, generic)	“9136”	“50738”	“1.3434262576”
Ongentys (opicapone)	“3276”	“16686”	“21.749437532”
Amantadine (amantadine, generic)	“104318”	“526882”	“0.5229425868”
Gocovri (amantadine extended-release)	“4906”	“30705”	“55.422069989”

Out-of-pocket costs of Parkinson's disease medications after generic entry, United States commercial claims

“We identified 186,144 patients with epilepsy, 54,676 with MS, 45,909 with PD, 169,127 with PN, and 60,861 with dementia/Alzheimer.” (opens the source at this quote in a new tab)
“Decreases ranging from 48% to 80% in annual OOP costs of duloxetine, pregabalin, rasagiline, rivastigmine, and memantine were observed in the years after generic introduction.” (opens the source at this quote in a new tab)

Established pharmacologic class in the prescribing information

“JUVMO is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease in adults.” (opens the prescribing information at this quote)

Classification among dopamine agonists by receptor selectivity

“Tavapadon is a novel selective long-acting dopamine D1/D5 receptor partial agonist suitable for once daily oral administration” (opens the source at this quote in a new tab)

AHFS classification

No evidence found.

FDA-approved indication

“JUVMO is indicated for the treatment of Parkinson’s disease (PD) in adults.” (opens the prescribing information at this quote)

Populations in which efficacy was established: without and with concomitant levodopa

“The efficacy of JUVMO for the treatment of PD in adults not on concomitant levodopa was established in two 27-week randomized, multicenter, double-blind, placebo-controlled studies, Study 1 (NCT04201093) and Study 2 (NCT04223193).” (opens the prescribing information at this quote)
“The efficacy of JUVMO for the treatment of PD as adjunctive therapy to levodopa was established in a 27-week, double-blind, randomized, placebo-controlled, parallel-group, flexible-dose trial, Study 3 (NCT04542499).” (opens the prescribing information at this quote)

Pediatric use not established

“Safety and effectiveness in pediatric patients have not been established.” (opens the prescribing information at this quote)

Mechanism of action in the prescribing information

“Tavapadon is a selective partial agonist at the dopamine D1 and D5 receptor subtypes (D1/D5).” (opens the prescribing information at this quote)

Receptor binding affinity and selectivity

“Tavapadon is a highly selective partial agonist at D1 and D5 dopamine receptors,” (opens the source at this quote in a new tab)
“with little to no functional activity at D2, D3, or D4 receptors in vitro (unpublished data).” (opens the source at this quote in a new tab)
“Assays measuring the displacement of radioligand binding in cell lines expressing recombinant human dopamine receptors have shown that tavapadon has a high affinity for both D1 (Ki = 9 nM) and D5 (Ki = 13 nM) (unpublished data).” (opens the source at this quote in a new tab)
“Conversely, tavapadon had a low affinity at D2 (Ki ≥ 6210 nM), D3 (Ki ≥ 6720 nM), and D4 (Ki ≥ 4870 nM) (unpublished data).” (opens the source at this quote in a new tab)

Intrinsic activity and potency at D1 and D5 receptors

“In vitro assays of functional activity have confirmed that tavapadon acts as a partial agonist by binding at D1 and D5 receptors, corresponding to 65% and 81% of dopamine’s intrinsic activity, respectively, and inducing functional receptor activation, with half-maximal effective concentration (EC50) values of 19 nM and 17 nM (unpublished data).” (opens the source at this quote in a new tab)

Striatal direct pathway as the site of D1/D5 receptor action

“D1/D5 receptors coupled to stimulatory Gs/Golf are predominantly expressed on medium spiny neurons (MSNs) of the direct pathway, which projects to striatal nuclei that directly regulate motor output” (opens the source at this quote in a new tab)
“Conversely, the D2/D3 receptors coupled to inhibitory Gi/Go are expressed primarily on indirect pathway MSNs, which regulate motor output via multisynaptic connections to the basal ganglia” (opens the source at this quote in a new tab)

Non-catechol structure and reduced receptor desensitization

“Computational modeling of binding interactions between D1 dopamine receptors and a non-catechol-based D1/D5-selective agonist similar to tavapadon (PF-6142) showed no direct binding to transmembrane 3 amine and aspartate residues and reduced association with serine residues in transmembrane 5, instead binding to extracellular domains of the receptor” (opens the source at this quote in a new tab)
“Live-cell fluorescence imaging experiments demonstrated that PF-6142 was able to activate functional downstream signaling cascades with reduced recruitment of β-arrestin when compared to dopamine, largely preventing receptor desensitization” (opens the source at this quote in a new tab)

Receptor internalization and binding kinetics in vitro

“Tavapadon and apomorphine did not induce significant D1R internalization, whereas pronounced internalization was observed with A77636, dopamine, and dihydrexidine.” (opens the source at this quote in a new tab)
“GIRK response deactivation time courses upon agonist washout were longer for A77636 and tavapadon compared to dopamine, dihydrexidine, and apomorphine.” (opens the source at this quote in a new tab)
“Tavapadon and apomorphine were partial agonists in both assays, whereas A77636 and dihydrexidine showed efficacies similar to dopamine.” (opens the source at this quote in a new tab)

G protein subtype selectivity: Gαolf and Gαs

“In contrast, the non-catechol agonist tavapadon acted as a full agonist at Gαolf and a partial agonist at Gαs.” (opens the source at this quote in a new tab)
“In the brain, Gαolf is predominantly found in the striatum whereas Gαs is expressed elsewhere.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“At the maximum recommended JUVMO dosage of 15 mg once daily, a mean increase in the QTc interval >20 ms is unlikely.” (opens the prescribing information at this quote)

QTc interval in the Phase 1 studies in Parkinson's disease

“There appeared to be a small dose-related increase in QT interval corrected for heart rate using Fridericia’s formula (QTcF) at the 2, 4, and 8 h post dose time points.” (opens the source at this quote in a new tab)
“The greatest increase from baseline in mean QTcF at any time point for any dose group was 11.7 ms.” (opens the source at this quote in a new tab)
“Despite these observations in the SAD study, no QTcF prolongation was observed in the MAD study, where higher PF-06649751 exposures were achieved, and no subject had a QTcF ≥ 500 ms or an increase of QTcF ≥ 60 ms.” (opens the source at this quote in a new tab)

Blood pressure effects in the Phase 3 trials

“In the TEMPO-1, tavapadon resulted in BP reductions during the initial titration, with a mean (standard deviation [SD]) reduction of −6.7 (7.31) mmHg in supine diastolic BP with tavapadon versus a mean increase of 0.1 (7.45) mmHg with placebo at week 27.” (opens the source at this quote in a new tab)
“The mean (SD) reduction in supine systolic BP at week 27 was −12.0 (13.17) mmHg with tavapadon and −1.7 (12.25) mmHg with placebo.” (opens the source at this quote in a new tab)
“These changes decreased gradually during treatment with tavapadon.” (opens the source at this quote in a new tab)

Cardiovascular effects in early-phase trials

“tavapadon produced only modest dose-related changes in cardiovascular measures that were not clinically meaningful” (opens the source at this quote in a new tab)
“Tavapadon produced consistent but mild decreases in systolic and diastolic blood pressure, increases in heart rate, and modest changes in other cardiovascular parameters.” (opens the source at this quote in a new tab)

Onset and duration of motor effect after single doses

“On the first day of treatment with 9.0 mg of tavapadon, patients showed a significant reduction in motor symptoms compared with placebo starting one hour after drug administration, as measured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III)” (opens the source at this quote in a new tab)
“Importantly, these improvements were sustained for at least 12 hours after treatment, providing further support for a once-daily dosing regimen” (opens the source at this quote in a new tab)

Nonhuman primate model: motor effect, dyskinesia, and receptor occupancy

“Here, we demonstrate, in a clinically translatable nonhuman primate model of parkinsonian motor symptoms, that treatment with the partial D1 receptor agonist CVL-751, formerly known as PF-06649751, is just as effective as L-DOPA in enabling movement and reducing disability.” (opens the source at this quote in a new tab)
“Importantly, CVL-751 efficacy is observed with less of the concomitant dyskinesia side effect associated with L-DOPA treatment.” (opens the source at this quote in a new tab)

“The peak receptor occupancy at D1 receptors was estimated to be 48% following the administration of 0.1 mg/kg of tavapadon, a dose that led to motor improvements comparable to those seen following levodopa administration” (opens the source at this quote in a new tab)
“Motor improvements following tavapadon administration were sustained for more than twice as long as those seen following treatment with levodopa, supporting potential sustained motor benefit with tavapadon” (opens the source at this quote in a new tab)

Striatal and cortical electrophysiology in mice

“In contrast to its effect in the mPFC, 1 μM tavapadon significantly potentiated the IPSC in the SNr (123.1% of baseline, p < 0.05).” (opens the source at this quote in a new tab)
“However, perfusing 1 μM tavapadon did not enhance the cortical EPSC amplitude (Figures 5B and 5C).” (opens the source at this quote in a new tab)

Absorption and dose proportionality

“Following oral administration of JUVMO, tavapadon is absorbed with peak plasma concentrations (Cmax) at approximately 2 to 4 hours.” (opens the prescribing information at this quote)
“Tavapadon displays dose-proportional pharmacokinetics within the maintenance dose range of 5 mg to 15 mg.” (opens the prescribing information at this quote)

Effect of food

“When JUVMO was administered with a high-fat/high-calorie meal, the food effect was not significant (AUCτ and Cmax were increased by approximately 10% and 12%, respectively, with no effect on median time to Cmax).” (opens the prescribing information at this quote)
“JUVMO was administered without regard to food in clinical efficacy studies.” (opens the prescribing information at this quote)

Distribution

“Tavapadon plasma protein binding is 93% (primarily albumin).” (opens the prescribing information at this quote)
“The apparent volume of distribution of tavapadon is 63.5 L.” (opens the prescribing information at this quote)

Metabolism, excretion, and half-life

“Tavapadon and its major inactive metabolite M4 are primarily metabolized by CYP3A.” (opens the prescribing information at this quote)
“The AUC ratio of M4 to tavapadon is approximately 1.4.” (opens the prescribing information at this quote)
“Unchanged tavapadon was a minor component in both urine and feces (less than 1%). Metabolite M4 accounted for less than 5% of the administered dose in both urine and feces.” (opens the prescribing information at this quote)
“The mean elimination half-life of tavapadon is approximately 25.5 hours.” (opens the prescribing information at this quote)

Phase 1 pharmacokinetics in Parkinson's disease: single and multiple doses

“Following administration of single oral doses of PF-06649751 from 0.75 mg to 9 mg under fasted conditions, PF-06649751 Cmax occurred at approximately 3.0–4.0 h post dose (Supplementary Fig. 1 top panel and Supplementary Table 3).” (opens the source at this quote in a new tab)
“On day 22 (steady-state), following administration of multiple oral doses of PF-06649751 from 5 mg to 25 mg, mean Cmax for PF-06649751 occurred at approximately 2.0–4.0 h post dose.” (opens the source at this quote in a new tab)
“On the basis of average values in Parkinson’s disease subjects with motor fluctuations (cohort 4 vs cohort 6), the increase in AUCtau was less than dose proportional between 15 mg and 25 mg.” (opens the source at this quote in a new tab)
“The mean apparent clearance values ranged from 2.4 L/h to 3.5 L/h.” (opens the source at this quote in a new tab)

Half-life relative to levodopa and other dopamine agonists

“The half-life of tavapadon is approximately 24 hours” (opens the source at this quote in a new tab)
“which is substantially longer than that of levodopa or standard formulations of many D2/D3-selective DAs” (opens the source at this quote in a new tab)

Mass balance study

“An Open-label Trial to Evaluate the Absorption, Metabolism, and Excretion of a Single Dose of [14C]-Tavapadon in Healthy Adult Male Subjects at Steady State” (opens the source at this quote in a new tab)

Summary of warnings and precautions in the prescribing information highlights

“May cause hypotension/orthostatic hypotension. (5.1)” (opens the prescribing information at this quote)
“May cause problems with impulse control or compulsive behaviors. Consider dose reductions or stopping JUVMO. (5.2)” (opens the prescribing information at this quote)
“May cause hallucinations and psychotic-like behavior. The risk of hallucinations may be increased when co-administered with strong CYP3A inhibitors during the maintenance phase. (5.3)” (opens the prescribing information at this quote)
“May cause dyskinesia or exacerbate pre-existing dyskinesia. (5.4)” (opens the prescribing information at this quote)

Contraindications

“CONTRAINDICATIONS None.” (opens the prescribing information at this quote)

Hypotension and orthostatic hypotension

“Patients with PD may have an impaired capacity to respond to an orthostatic challenge. In clinical studies and clinical experience, dopaminergic medications appear to impair the systemic regulation of blood pressure, resulting in hypotension and/or orthostatic hypotension, especially during dose escalation. For these reasons, patients with PD being treated with JUVMO should be monitored for signs and symptoms of hypotension/orthostatic hypotension especially during dose escalation, and should be informed of this risk.” (opens the prescribing information at this quote)
“In Study 1 and Study 2 in patients with PD who were not taking levodopa [see Clinical Studies (14.1)], orthostatic hypotension was reported in 5% of patients treated with JUVMO compared to 1% of patients who received placebo. Hypotension was reported in 4% of patients treated with JUVMO tablets compared to 1% on placebo.” (opens the prescribing information at this quote)
“In Study 3 in patients taking JUVMO as adjunctive therapy to fixed dose levodopa [see Clinical Studies (14.2)], orthostatic hypotension was reported in 8% of patients treated with JUVMO compared to 2% of patients on placebo. Hypotension was reported in 4% of patients treated with JUVMO compared to 0.4% on placebo.” (opens the prescribing information at this quote)

Impulse control and compulsive behaviors

“Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and are generally used for the treatment of PD, including JUVMO.” (opens the prescribing information at this quote)
“In Study 1 and Study 2, impulse control disorders were reported in 1% of patients treated with JUVMO compared to no patients on placebo. In Study 3, impulse control disorders were reported in 2% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“Consider reducing the dose or discontinuing JUVMO if a patient develops such urges.” (opens the prescribing information at this quote)

Hallucinations and psychotic-like behavior

“In Study 1 and Study 2, hallucination was reported in 3% of patients treated with JUVMO compared to no patients on placebo. In Study 3, when added as an adjunct to a fixed dose of levodopa, hallucination was reported in 7% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“Age appears to increase the risk of hallucinations in patients taking JUVMO. In Study 1 and Study 2, among patients 65 years of age and older, hallucination was reported in 4% of patients treated with JUVMO compared to no patients on placebo. In Study 3, among patients 65 years of age and older, hallucination was reported in 9% of patients treated with JUVMO compared to 1% of patients on placebo.” (opens the prescribing information at this quote)
“The risk of hallucination may be increased when JUVMO is co-administered with strong CYP3A inhibitors during the maintenance phase [see Dosage and Administration (2.2)].” (opens the prescribing information at this quote)

Drug-disease interaction: major psychotic disorder

“Consider the risks and benefits prior to initiating treatment with JUVMO in patients with a major psychotic disorder because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of PD. Consider stopping JUVMO if hallucinations or psychotic-like behaviors occur.” (opens the prescribing information at this quote)

Dyskinesia

“JUVMO may cause or exacerbate pre-existing dyskinesia. In Study 1 and Study 2, 0.6% of patients with PD treated with JUVMO reported dyskinesia compared with no patients on placebo. In Study 3, 10.0% of patients treated with JUVMO reported dyskinesia compared to 2% on placebo. Consider decreasing the dosage of JUVMO or other dopaminergic medications if dyskinesia occurs.” (opens the prescribing information at this quote)

Clinical trial safety database

“The safety of JUVMO was evaluated in 1,279 patients with PD who received at least one dose of JUVMO. Of the patients with PD who received JUVMO, 870 were treated for at least 6 months and 630 were treated for at least 1 year.” (opens the prescribing information at this quote)

Adverse reactions without concomitant levodopa: most common reactions and discontinuations

“In Study 1 and Study 2 combined (n=833 total patients), the most common adverse reactions that occurred in ≥ 5% of patients treated with JUVMO were nausea, headache, dizziness, fatigue, dysgeusia, vomiting, dry mouth, and anxiety. Adverse reactions led to discontinuation of JUVMO in 100 of 505 patients (20%). Of the 100 patients receiving JUVMO who discontinued because of an adverse reaction, 85 (85%) did so during the titration and/or adjustment phases. The most common adverse reactions leading to discontinuation in patients taking JUVMO were nausea, dizziness, headache, and vomiting.” (opens the prescribing information at this quote)

Adverse reactions in at least 3% of participants and at least 2% more than placebo, Studies 1 and 2 (without concomitant levodopa)

Adverse reaction	Juvmo (N=505), %	Placebo (N=328), %
Nausea	“27”	“2”
Headache (multiple related terms)	“17”	“5”
Dizziness	“14”	“4”
Fatigue (includes asthenia)	“10”	“3”
Dysgeusia	“8”	“0”
Vomiting	“7”	“<1”
Dry mouth	“5”	“<1”
Anxiety	“5”	“2”
Hypotension	“4”	“1”
Dyspepsia	“4”	“1”
Abnormal dreams	“4”	“<1”
Orthostatic hypotension	“4”	“<1”
Hallucination (multiple related terms)	“3”	“0”
Gastroesophageal reflux disease	“3”	“<1”
Constipation	“3”	“1”

Adverse reactions with concomitant levodopa: most common reactions and discontinuations

“Patients in Study 3 were on a fixed dose of levodopa and were titrated to JUVMO 15 mg once daily unless prevented by intolerance, resulting in maintenance doses between 5 mg and 15 mg (n=251), compared to placebo (n=254). The most common adverse reactions that occurred in ≥ 5% of patients treated with JUVMO were nausea, dyskinesia, dizziness, headache, hallucinations, and orthostatic hypotension. Adverse reactions led to discontinuation of JUVMO in 43 of 251 patients (17%). Of the 43 patients receiving JUVMO who discontinued because of an adverse reaction, 38 (88%) did so during the titration and adjustment phases. The most common adverse reactions leading to discontinuation included nausea, dyskinesia, visual hallucination, and dizziness.” (opens the prescribing information at this quote)

Adverse reactions in at least 3% of participants and at least 2% more than placebo, Study 3 (with concomitant levodopa)

Adverse reaction	Juvmo (N=251), %	Placebo (N=254), %
Nausea	“14”	“4”
Dyskinesia	“10”	“2”
Dizziness	“8”	“3”
Headache (multiple related terms)	“7”	“3”
Hallucination (multiple related terms)	“7”	“1”
Orthostatic hypotension	“6”	“1”
Hypotension	“4”	“<1”
Abdominal pain	“3”	“<1”
Asthenia	“3”	“0”

Nonclinical carcinogenicity findings

“In the 26-week study, mice had an increased incidence of hepatocellular adenomas at 100 mg/kg/day. In the 2-year study in rats, female rats exhibited an increase in pancreatic and whole body adenocarcinoma at the high dose 120 mg/kg/day. Tavapadon exposure at this dose was 14-fold greater than the exposure at the MRHD.” (opens the prescribing information at this quote)
“The endocrine mechanism involved in the production of these tumors (prolactin reduction) in rats is not considered relevant to humans.” (opens the prescribing information at this quote)
“Tavapadon was not mutagenic or clastogenic in in vitro (bacterial mutagenicity and micronucleus TK6 cells) and in vivo (rat peripheral blood micronucleus) assays.” (opens the prescribing information at this quote)

Pregnancy

“There are no adequate data on the developmental risk associated with the use of JUVMO in pregnant women. In animal studies, administration of tavapadon during organogenesis (rats and rabbits) did not result in adverse developmental effects at exposures greater than those used clinically (see Data). Following administration of tavapadon throughout pregnancy and lactation (rats), there were adverse effects on postnatal growth at exposures 7 times those used clinically (see Data).” (opens the prescribing information at this quote)

Lactation

“There are no data on the presence of tavapadon in human milk, the effects of tavapadon on the breastfed infant, or the effects of tavapadon on milk production. Tavapadon was present in the milk when administered to lactating rats.” (opens the prescribing information at this quote)

Pediatric use

“Safety and effectiveness in pediatric patients have not been established.” (opens the prescribing information at this quote)

Geriatric use and risk of hallucinations

“Of the 1,279 patients who received JUVMO in clinical studies, 691 (54%) were ≥ 65 years of age and 166 (13%) were ≥ 75 years of age. Patients aged 65 years and older who are treated with JUVMO are at an increased risk of hallucinations [see Warnings and Precautions (5.3)].” (opens the prescribing information at this quote)

Renal and hepatic impairment, age, sex, body weight, and race

“No clinically significant differences in pharmacokinetics of tavapadon were observed based on age (21 years to 79 years), sex, body weight (56 kg to 119 kg), race, severe renal impairment not requiring dialysis (eGFR < 30 mL/min estimated by CKD-EPI equation), mild hepatic impairment (Child-Pugh Class A), or moderate hepatic impairment (Child-Pugh Class B).” (opens the prescribing information at this quote)
“The effects of renal impairment in patients with eGFR < 15 mL/min or on dialysis and severe hepatic impairment (Child-Pugh Class C) on tavapadon pharmacokinetics have not been studied.” (opens the prescribing information at this quote)

Dedicated hepatic impairment study

“The primary purpose of the study is to assess the effect of hepatic impairment on the PK of tavapadon following administration of a single oral dose in participants with mild and moderate hepatic impairment relative to age, body weight, and sex-matched participants with normal hepatic function.” (opens the source at this quote in a new tab)

Dedicated renal impairment study

“The primary purpose is to assess the effect of renal impairment on the PK of tavapadon following administration of a single oral dose in participants with severe renal impairment relative to age, body weight, and sex-matched participants with normal renal function.” (opens the source at this quote in a new tab)

CYP3A inhibitors and inducers: prescribing information summary

“Avoid concomitant use of strong or moderate CYP3A inhibitors during titration and strong CYP3A inducers during titration and maintenance of JUVMO. (2.2, 7.1)” (opens the prescribing information at this quote)
“Strong and moderate CYP3A inhibitors: Decrease dosing frequency. (2.2, 7.1)” (opens the prescribing information at this quote)
“Strong CYP3A inducers: Concomitant use is not recommended. (2.3, 7.1)” (opens the prescribing information at this quote)
“Moderate CYP3A inducers (long-term): Increase dosing frequency. (2.3, 7.1)” (opens the prescribing information at this quote)

Strong and moderate CYP3A inhibitors: mechanism and clinical effect

“Tavapadon is CYP3A substrate. Concomitant use of strong and moderate CYP3A inhibitors increase the exposure of tavapadon, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].” (opens the prescribing information at this quote)
“Concomitant use of strong CYP3A inhibitors may increase the risk of hallucinations [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].” (opens the prescribing information at this quote)

Strong CYP3A inhibitor: itraconazole

“Concomitant administration of itraconazole (200 mg daily for 14 days), a strong CYP3A inhibitor, with JUVMO increased tavapadon AUCτ and Cmax by 5-fold and 4-fold, respectively.” (opens the prescribing information at this quote)

“The purpose of this study is to evaluate the impact of CYP3A4 inhibitor, itraconazole, on plasma concentration of PF-06649751 in healthy subjects” (opens the source at this quote in a new tab)

Moderate CYP3A inhibitor: fluconazole (model-predicted)

“Concomitant administration of fluconazole (200 mg daily), a moderate CYP3A inhibitor, with 15 mg JUVMO at steady-state is predicted to increase the AUCτ and Cmax of tavapadon by approximately 2.6-fold and 2.3-fold, respectively.” (opens the prescribing information at this quote)

Strong and moderate CYP3A inducers: mechanism and clinical effect

“Tavapadon is CYP3A substrate. Concomitant use of strong or moderate CYP3A inducer decreases the exposure of tavapadon which may result in reduced JUVMO efficacy [see Clinical Pharmacology (12.3)].” (opens the prescribing information at this quote)

Strong CYP3A inducer: carbamazepine

“Concomitant administration of carbamazepine (300 mg twice daily), a strong CYP3A inducer, with JUVMO decreased tavapadon AUCτ and Cmax by 63% and 49%, respectively [see Dosage and Administration (2.3), Drug Interactions (7.1)].” (opens the prescribing information at this quote)

“The primary purpose of this study is to evaluate the effect of carbamazepine, a strong CYP3A4 inducer, on the steady-state pharmacokinetics (PK) of tavapadon in healthy adult participants.” (opens the source at this quote in a new tab)

Moderate CYP3A inducer: efavirenz (model-predicted)

“Concomitant administration of efavirenz (600 mg), a moderate CYP3A inducer, with 15 mg JUVMO is predicted to decrease the AUCτ and Cmax of tavapadon by 70% and 58%, respectively.” (opens the prescribing information at this quote)

In vitro substrate profile for enzymes and transporters

“Cytochrome P450 (CYP450) Enzymes: Tavapadon and M4 are substrates of CYP3A, but are not substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.” (opens the prescribing information at this quote)
“Transporter Systems: Tavapadon is a substrate for P-gp and BCRP, but is not expected to result in clinically significant drug interactions.” (opens the prescribing information at this quote)

Counseling on herbal products and changes in concomitant medications

“Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines, dietary supplements, and herbal products (e.g., St. John’s Wort), and if there is a change (e.g., discontinuing) in their medication [see Dosage and Administration (2.2, 2.3), Drug Interactions (7.1, 7.2)].” (opens the prescribing information at this quote)

Predicted clinically relevant interactions

“Tavapadon is predicted to cause clinically relevant induction of CYP3A, inhibition of CYP2C8, and BCRP [see Drug Interactions (7.2)].” (opens the prescribing information at this quote)

CYP3A substrates

“Consider a dose modification of sensitive CYP3A substrates or CYP3A substrates where minimal concentration changes may lead to loss of efficacy, as clinically appropriate, when initiating or discontinuing JUVMO.” (opens the prescribing information at this quote)
“JUVMO is an inducer of CYP3A [see Clinical Pharmacology (12.3)]. Concomitant use of JUVMO may decrease the concentrations of CYP3A substrates.” (opens the prescribing information at this quote)

CYP2C8 substrates

“Consider a dosage reduction of sensitive CYP2C8 substrates or CYP2C8 substrates where minimal concentration changes may increase the risk of severe adverse reactions, as clinically appropriate, when concomitantly used with JUVMO.” (opens the prescribing information at this quote)
“JUVMO is an inhibitor of CYP2C8 [see Clinical Pharmacology (12.3)]. Concomitant use of JUVMO may increase the plasma concentrations of CYP2C8 substrates.” (opens the prescribing information at this quote)

BCRP substrates

“Consider a dosage reduction of BCRP substrates, as clinically appropriate, when concomitantly used with JUVMO.” (opens the prescribing information at this quote)
“JUVMO is an inhibitor of efflux transporter BCRP [see Clinical Pharmacology (12.3)]. Concomitant use of JUVMO may increase the exposure of BCRP substrates.” (opens the prescribing information at this quote)

In vitro inhibition and induction profile

“Tavapadon is a time-dependent inhibitor of CYP2C8. Tavapadon and M4 did not demonstrate time-dependent inhibition of CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4.” (opens the prescribing information at this quote)
“Tavapadon and M4 are inducers of CYP3A, but are not inducers of CYP1A2 or CYP2B6.” (opens the prescribing information at this quote)
“UDP-Glucuronosyltransferase (UGT): Tavapadon is an inhibitor of UGT1A9 but is not expected to result in clinically significant drug interactions.” (opens the prescribing information at this quote)
“Tavapadon inhibits BCRP, but not P-gp, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3.” (opens the prescribing information at this quote)

Recommended maintenance and maximum dosage

“Recommended maintenance dosage is 5 mg orally once daily. The dosage may be increased to a maximum of 15 mg once daily based on tolerability and clinical response. (2.1)” (opens the prescribing information at this quote)

Titration schedule

Treatment days	Quoted dosage
Days 1 to 4	“0.25 mg once daily”
Days 5 to 8	“0.5 mg once daily”
Days 9 to 12	“0.75 mg once daily”
Days 13 to 16	“1 mg once daily”
Days 17 to 20	“1.5 mg once daily”
Days 21 to 24	“2.25 mg once daily”
Days 25 to 40	“3 mg once daily”
Maintenance, day 41 and thereafter	“5 mg once daily”
Maximum dosage	“15 mg once daily”

Dose escalation above 5 mg and titration interval

“If needed, based on tolerability and clinical response, the maintenance dose may be increased in increments of 5 mg approximately every 15 days to the maximum recommended daily dosage.” (opens the prescribing information at this quote)
“Dose and titration should be guided by tolerability and clinical response. If required, longer intervals between dose adjustment can be used.” (opens the prescribing information at this quote)

Dosage modification when initiating a CYP3A inhibitor during maintenance

Current maintenance dosage	Strong CYP3A inhibitor	Moderate CYP3A inhibitor
5 mg once daily	“5 mg every 7 days”	“5 mg every 3 days”
10 mg once daily	“10 mg every 7 days”	“10 mg every 3 days”
15 mg once daily	“15 mg every 7 days”	“15 mg every 3 days”

CYP3A inhibitors during titration and after discontinuation

“Avoid concomitant use of strong or moderate CYP3A inhibitors during titration of JUVMO.” (opens the prescribing information at this quote)
“Upon discontinuation of the strong or moderate CYP3A inhibitor, resume the JUVMO maintenance dosage that was used prior to the initiation of the CYP3A inhibitor. Monitor patients for clinical response and tolerability.” (opens the prescribing information at this quote)

Dosage for patients already on long-term moderate CYP3A inducers

Treatment days	Quoted dosage
Days 1 to 4	“0.25 mg twice daily”
Days 5 to 8	“0.5 mg twice daily”
Days 9 to 12	“0.75 mg twice daily”
Days 13 to 16	“1 mg twice daily”
Days 17 to 20	“1.5 mg twice daily”
Days 21 to 24	“2.25 mg twice daily”
Days 25 to 40	“3 mg twice daily”
Maintenance, day 41 and thereafter	“5 mg twice daily”
Maximum dosage	“45 mg daily”

Moderate CYP3A inducers started during maintenance, and strong CYP3A inducers

“Avoid concomitant use of strong CYP3A inducers during titration and maintenance of JUVMO.” (opens the prescribing information at this quote)
“Days 1 to 7 of concomitant use: continue the current maintenance dosage of JUVMO (5 mg, 10 mg, or 15 mg once daily).” (opens the prescribing information at this quote)
“Day 8 and thereafter during concomitant use: increase the frequency of the maintenance dosage of JUVMO to twice daily. If needed, based on clinical response and tolerability, the maintenance dosage can be increased to three times daily.” (opens the prescribing information at this quote)
“Upon discontinuation of moderate CYP3A inducers, gradually reduce the JUVMO dosage to once daily. Monitor patients for clinical response and tolerability.” (opens the prescribing information at this quote)

Renal and hepatic impairment dosing

“No clinically significant differences in pharmacokinetics of tavapadon were observed based on age (21 years to 79 years), sex, body weight (56 kg to 119 kg), race, severe renal impairment not requiring dialysis (eGFR < 30 mL/min estimated by CKD-EPI equation), mild hepatic impairment (Child-Pugh Class A), or moderate hepatic impairment (Child-Pugh Class B).” (opens the prescribing information at this quote)

Oral once-daily administration with or without food

“Administer JUVMO orally once daily with or without food.” (opens the prescribing information at this quote)
“JUVMO was administered without regard to food in clinical efficacy studies.” (opens the prescribing information at this quote)

Titration pack

“The JUVMO titration pack is recommended for patients initiating therapy with JUVMO to provide doses consistent with the recommended titration schedule to reach the 5 mg maintenance dosage [see How Supplied/Storage and Handling (16.1)].” (opens the prescribing information at this quote)
“Use one JUVMO titration pack for the morning dose and the second JUVMO titration pack for the evening dose.” (opens the prescribing information at this quote)

Missed dose

“If a dose of JUVMO is missed, take it as soon as remembered on the same day, but do not double the dose. Do not take a missed dose on the following day. Skip the missed dose and resume the regular dosing schedule.” (opens the prescribing information at this quote)

Patient counseling on orthostatic symptoms during initiation and dose increases

“Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time. Instruct patients to rise slowly after sitting or lying down while using JUVMO [see Warnings and Precautions (5.1)].” (opens the prescribing information at this quote)

Marketer and trademark holder

“Marketed by: AbbVie Inc. North Chicago, IL 60064 U.S.A.” (opens the prescribing information at this quote)
“JUVMO and its design are trademarks of Cerevel Therapeutics, LLC, an AbbVie company.” (opens the prescribing information at this quote)

Package configurations and National Drug Codes

Presentation	Quoted package configuration	Quoted NDC
5 mg tablets	“Bottle of 30”	“0074-6105-30”
10 mg tablets	“Bottle of 30”	“0074-6210-30”
15 mg tablets	“Bottle of 30”	“0074-6315-30”
Titration pack (0.25 mg and 1 mg tablets)	“Each carton contains 6 weekly blister cards containing the following total number of tablets:”	“0074-6090-40”

Prescriber website before launch

“Get ready for something new from AbbVie Inc.” (opens the source at this quote in a new tab)
“Learn more right at launch about JUVMO and stay current with product updates when you sign up below.” (opens the source at this quote in a new tab)

Expanded access program

“This is an expanded access program (EAP) for eligible participants. This program is designed to provide access to tavapadon prior to approval by the local regulatory agency. Availability will depend on territory eligibility.” (opens the source at this quote in a new tab)

Patent protection

“For tavapadon, the applicable patents and pending patent applications are directed to tavapadon, compositions of matter and certain methods of treatment, including methods of treating Parkinson’s disease and apathy in Alzheimer’s disease, and, excluding any patent term adjustments or extensions, have a statutory expiration date in 2034.” (opens the source at this quote in a new tab)

Security interest held by development funding investors

“In conjunction with the funding agreements, AbbVie also assumed security agreements entered into by Cerevel Therapeutics prior to the acquisition pursuant to which Cerevel Therapeutics granted the funding investors a security interest in the assets material to the development and commercialization of tavapadon in the United States.” (opens the source at this quote in a new tab)

Monotherapy trials: concomitant MAO-B inhibitor permitted

“not receiving medications to treat Parkinson’s disease (e.g., levodopa) other than concomitant stable dose of an MAO-B inhibitor.” (opens the prescribing information at this quote)

“TEMPO-1 and -2 enrolled patients with early Parkinson's disease (with or without an MAO-B inhibitor) and TEMPO-3 enrolled patients who are on fixed-dose levodopa and had motor fluctuations.” (opens the source at this quote in a new tab)

Adjunctive trial: fixed background levodopa

“minimum stable dose of levodopa of 400 mg per day divided at least 3 or 4 times daily depending on dose formulation; and a good response to levodopa in the judgement of the investigator.” (opens the prescribing information at this quote)
“In this trial, 507 patients were randomized 1:1 to receive JUVMO 5 mg to 15 mg (N = 252) or placebo (N = 255) once daily as adjunctive therapy to the pre-study levodopa dose. No changes in levodopa were allowed during study participation.” (opens the prescribing information at this quote)

Adjusting other dopaminergic medications for dyskinesia

“Consider decreasing the dosage of JUVMO or other dopaminergic medications if dyskinesia occurs.” (opens the prescribing information at this quote)

Antipsychotic medications in patients with Parkinson's disease

“In addition, certain medications used to treat psychosis may exacerbate the symptoms of PD.” (opens the prescribing information at this quote)

Anticipated role alongside existing therapies for advanced disease

“Tavapadon's efficacy and safety-tolerability profile could enable its utility in early Parkinson's disease, becoming a near-term complementary asset to AbbVie's existing symptomatic therapies for advanced Parkinson's disease.” (opens the source at this quote in a new tab)

Product-specific effect on quality measures

No evidence found.

American Academy of Neurology measure: assessment of impulse control disorders in patients taking Parkinson's disease medications

“Percentage of all patients with a diagnosis of PD currently taking dopaminergic medications who were assessed for impulse control disorder once during the measurement period” (opens the source at this quote in a new tab)
“Parkinson’s disease medications include any preparation containing levodopa, dopamine agonists, amantadine, MAOB inhibitors” (opens the source at this quote in a new tab)
“Impulse control disorders (ICDs), including pathological gambling, compulsive shopping, compulsive sexual behaviors, and binge eating occur in approximately 14-17% of people with PD. ICDs occur mainly with dopaminergic medications, especially the dopamine agonists.” (opens the source at this quote in a new tab)

American Academy of Neurology measure: assessment of dopaminergic medication-related motor complications

“Percentage of all patients diagnosed with PD who were assessed for dopaminergic medication-related motor complications once during the measurement period” (opens the source at this quote in a new tab)
“In a 2013 study by Baek et al. reviewing compliance with quality measure recommendations, it was noted provider compliance rate for every visit for Parkinson’s disease medication-related motor complications (e.g., wearing off, dyskinesia, or off-time) was 23.5%.” (opens the source at this quote in a new tab)

Merit-based Incentive Payment System 2026 measure: cognitive assessment in Parkinson's disease

“Percentage of all patients with a diagnosis of Parkinson’s disease (PD) who were assessed for cognitive impairment or dysfunction once during the measurement period.” (opens the source at this quote in a new tab)

Merit-based Incentive Payment System 2026 measure: rehabilitative therapy referral in Parkinson's disease

“Percentage of all patients with a diagnosis of Parkinson’s Disease (PD) who were referred to physical, occupational, speech, or recreational therapy once during the measurement period.” (opens the source at this quote in a new tab)

Cardiovascular effects of tavapadon and other oral or transdermal dopamine agonists

Drug	Quoted route	Quoted mechanism	Quoted cardiovascular effect	Quoted status
Tavapadon	“Oral”	“D1/D5 partial agonist”	“Supine SBP reduction of −12 mmHg (versus 1.7 PBO); OH 6.5% versus 1.1% PBO (TEMPO-1); standing SBP drop of −8.6 mmHg (versus −0.8 PBO); OH 6% versus 1.2% PBO (TEMPO-3).”	“NDA filed (expected US approval in 2026)”
Pramipexole	“Oral”	“Non-ergot D2/D3 (D3 preferring)”	“OH: OR 1.65 (NS versus PBO); standing SBP −3 to 5 mmHg in PD.”	“Launched”
Ropinirole	“Oral”	“Non-ergot D2-like (D3>D2>>D4)”	“OH: OR 6.46 versus PBO; standing SBP −6 mmHg; HR +2–4 bpm in PD.”	“Launched”
Rotigotine	“Transdermal patch”	“Non-ergot nonselective DA agonist (D1, D2, D3)”	“OH ~18% in early PD versus PBO. Reduces nocturnal hypertension.”	“Launched”

Hypotension risk in relation to intrinsic activity

“Dopaminergic receptor agonism generally lowers blood pressure, with the magnitude of hypotension tracking with intrinsic activity: full orthosteric agonists (bromocriptine, ropirinole, apomorphine) carry the highest risk of orthostatic hypotension, and partial agonists (tavapadon) produce attenuated but clinically relevant hypotension.” (opens the source at this quote in a new tab)

Receptor mode of action of dopamine agonists used or in development for Parkinson's disease

Drug	Quoted mode of action	Quoted indication	Quoted phase of development
Pramipexole	“D2 agonist”	“PD motor symptoms and motor fluctuations”	“In clinical use”
Ropinirole	“D2 agonist”	“PD motor symptoms and motor fluctuations”	“In clinical use”
Rotigotine	“D2 > D1 agonist”	“PD motor symptoms and motor fluctuations”	“In clinical use”
Apomorphine continuous subcutaneous infusion	“D1 and D2 agonist”	“Motor fluctuations”	“In clinical use”
Tavapadon	“Selective D1 partial agonist”	“PD motor symptoms and motor fluctuations”	“Phase 3 completed”

Comparison with levodopa and D2/D3 agonists: mechanism, metabolism, half-life, and dosing frequency

Parameter	Tavapadon	Levodopa	D2/D3 agonists (e.g., pramipexole)
Mechanism of action	“Selective partial D1/D5 dopamine agonist”	“Non-selective dopamine precursor”	“D2/D3 full agonist”
Metabolism pathway	“Primarily CYP3A4”	“MAO-B and COMT”	“Various hepatic pathways”
Half-life	“~24 h”	“~60–90 min”	“5–12 h”
Dosing frequency	“Once daily”	“2–6 times daily”	“1–3 times daily”
Common side effects	“Nausea, headache, dizziness”	“Dyskinesias, severe on-off motor fluctuations”	“Impulsive behavior problems (e.g., gambling, hypersexual)”

Rationale for D1/D5 selectivity relative to D2/D3 agonists

“Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors.” (opens the source at this quote in a new tab)
“A commonly reported AE associated with currently used D2/D3 DAs is the risk of ICDs” (opens the source at this quote in a new tab)
“ICDs are reported in 17% of patients with PD taking D2/D3 DAs, a significantly greater rate of ICDs than observed with patients with PD not taking D2/D3 DAs (7%)” (opens the source at this quote in a new tab)

Pramipexole: receptor pharmacology, dosing frequency, half-life, and sleep-related warning

“Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.” (opens the source at this quote in a new tab)
“Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days.” (opens the source at this quote in a new tab)
“Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers.” (opens the source at this quote in a new tab)
“Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents.” (opens the source at this quote in a new tab)

Ropinirole: receptor pharmacology, dosing frequency, half-life, and sleep-related warning

“Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain.” (opens the source at this quote in a new tab)
“The recommended starting dose of REQUIP for Parkinson’s disease is 0.25 mg 3 times daily.” (opens the source at this quote in a new tab)
“The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours.” (opens the source at this quote in a new tab)
“Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents.” (opens the source at this quote in a new tab)

Rotigotine: receptor pharmacology, dosing frequency, half-life, and sleep-related warning

“Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain.” (opens the source at this quote in a new tab)
“NEUPRO should be applied once daily to clean, dry, and intact skin on the abdomen, thigh, hip, flank, shoulder, or upper arm.” (opens the source at this quote in a new tab)
“After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours.” (opens the source at this quote in a new tab)
“Falling asleep during activities of daily living, including the operation of motor vehicles, and somnolence may occur. (5.2)” (opens the source at this quote in a new tab)

Tavapadon warnings and precautions for comparison with other dopamine agonists

“5.1 Hypotension/Orthostatic Hypotension 5.2 Impulse Control/Compulsive Behaviors 5.3 Hallucinations and Psychotic-like Behavior 5.4 Dyskinesia” (opens the prescribing information at this quote)
“The mean elimination half-life of tavapadon is approximately 25.5 hours.” (opens the prescribing information at this quote)

Receptor selectivity and adverse effects of tavapadon compared with D2 agonists in a commentary

“Among the currently marketed antiparkinsonian medications, L-DOPA (decarboxylated into dopamine) and apomorphine (a mixed D1/D2 agonist) are the only drugs that stimulate both receptor subtypes simultaneously. Conversely, all other antiparkinsonian dopamine agonists (eg, pramipexole, ropinirole, rotigotine, and others) are D2-selective, and no selective D1 agonists are available, highlighting a gap in our understanding of dopaminergic mechanisms and possibly in management of patients with Parkinson’s disease.” (opens the source at this quote in a new tab)
“The proportion of nausea and orthostatic hypotension in TEMPO-2 does not suggest a better profile on these peripheral side-effects than D2 agonists.” (opens the source at this quote in a new tab)
“The same applies to dyskinesia. Its incidence was low in TEMPO-2, comparable to D2 agonist trials, as expected in a short-term trial in levodopa-naive patients.” (opens the source at this quote in a new tab)
“On the other hand, somnolence was not a concern in TEMPO-2, as changes in Epworth Sleep Scale scores did not differ between groups, whereas sleepiness induced by D2 agonists is easily detected in small and short trials, even at low doses.” (opens the source at this quote in a new tab)

Clinical and pathological definition of Parkinson's disease

“Parkinson’s disease (PD) is a complex age-related neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits.” (opens the source at this quote in a new tab)
“Pathologically, PD is defined by loss of dopaminergic neurons in the substantia nigra pars compacta (SN) located in the midbrain and associated with Lewy bodies, which are cytoplasmic inclusions that include insoluble alpha-synuclein aggregates.” (opens the source at this quote in a new tab)
“The clinical diagnosis of PD is based primarily on motor features, such as a slowly progressive asymmetric resting tremor, cogwheel rigidity and bradykinesia, although non-motor features, which include anosmia, constipation, depression and REM sleep behavior disorder, can develop years before motor deficits.” (opens the source at this quote in a new tab)

Parkinsonism as the core clinical feature

“Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity.” (opens the source at this quote in a new tab)
“Parkinsonism is defined as bradykinesia, in combination with either rest tremor, rigidity, or both. These features must be clearly demonstrable and not attributable to confounding factors.” (opens the source at this quote in a new tab)
“Bradykinesia is defined as slowness of movement AND decrement in amplitude or speed (or progressive hesitations/halts) as movements are continued.” (opens the source at this quote in a new tab)
“Although bradykinesia also occurs in voice, face, and axial/gait domains, limb bradykinesia must be documented to establish a diagnosis of PD.” (opens the source at this quote in a new tab)
“Rest tremor refers to a 4- to 6-Hz tremor in the fully resting limb, which is suppressed during movement initiation.” (opens the source at this quote in a new tab)
“Although postural instability is a feature of parkinsonism, it is not part of the MDS-PD criteria for parkinsonism caused by PD.” (opens the source at this quote in a new tab)
“This is reflected in a new diagnostic classification, prodromal PD, which is considered to be a true stage of PD (ie, prodromal PD is PD).” (opens the source at this quote in a new tab)

Parkinson's disease among the parkinsonian disorders

“Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy.” (opens the source at this quote in a new tab)
“PD is but one of a host of parkinsonian disorders” (opens the source at this quote in a new tab)

Clinical indicators of advanced Parkinson's disease

“Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care.” (opens the source at this quote in a new tab)
“Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living.” (opens the source at this quote in a new tab)

Age as a risk factor

“Indeed, the single greatest risk factor for PD is advanced age” (opens the source at this quote in a new tab)

Multifactorial etiology and heritability

“Most PD cases likely have a multifactorial etiology, resulting from the combined effects of environmental and genetic factors.” (opens the source at this quote in a new tab)
“Although identifiable mutations in certain genes cause PD in around 5–10% of cases, these mutations are absent in most people with PD.” (opens the source at this quote in a new tab)
“A study comparing concordance rates in monozygotic and dizygotic twins estimated the heritability of PD to be only 30%, suggesting that the majority of PD risk is related to environmental and behavioral factors” (opens the source at this quote in a new tab)

Genetic etiology: LRRK2 and GBA variants

“Mutations in the LRRK2 gene are associated with autosomal dominant PD with incomplete penetrance (about 25% for the G2019S mutation, but much higher for the R144G mutation), and are present in about 1 to 2 percent of all PD patients and 5% in familial PD, but higher in some populations such as patients of Ashkenazi Jewish ancestry and in North African Berbers” (opens the source at this quote in a new tab)
“Carriers of a GBA mutation have an approximately 4-fold increased risk of PD, although the risk varies with different GBA mutations.” (opens the source at this quote in a new tab)

Genetic etiology: causal and risk variants across ancestries

“We analysed genome and exome sequencing and genotyping data of 99,783 individuals, including 58,559 individuals with PD and 41,224 controls, from eleven different genetically inferred ancestries” (opens the source at this quote in a new tab)
“Overall, ~2% (1217/58559) of individuals with Parkinson’s disease carried a causal variant, with substantial variations across ancestries ranging from ~0·5% (10/2844 and 3/550) in African and African-Admixed to ~7% (92/1347) in Middle Eastern and >10% (251/2343) Ashkenazi Jewish ancestries.” (opens the source at this quote in a new tab)
“Risk variants in GBA1 and LRRK2 were identified in 11·8% (6893/58559) of individuals with Parkinson’s disease and 8·7% (3578/41224) of controls.” (opens the source at this quote in a new tab)

Genetic etiology: monogenic forms and polygenic risk

“In most populations, 3–5% of Parkinson’s disease is explained by genetic causes linked to known Parkinson’s disease genes, thus representing monogenic Parkinson’s disease, whereas 90 genetic risk variants collectively explain 16–36% of the heritable risk of non-monogenic Parkinson’s disease.” (opens the source at this quote in a new tab)
“Mutations in PRKN and PINK1 are the major causes of autosomal recessive and early-onset Parkinson’s disease, with the frequent PRKN mutations accounting for up to 77% of cases of juvenile Parkinson’s disease (age of onset being younger than 20 years) and 10–20% of young-onset Parkinson’s disease.” (opens the source at this quote in a new tab)
“pathogenic GBA variants occurred in 8·5% of people with Parkinson’s disease in a multi-ethnic sample of more than 1100 individuals.” (opens the source at this quote in a new tab)

Genetic etiology: proportion of genetic cases by age at onset

“Young-onset Parkinson disease is commonly defined by an age of onset <45 years and >10% of those individuals have a genetic basis, and the proportion of genetically defined cases rises to >40% of those with disease onset before 30 years of age” (opens the source at this quote in a new tab)

Environmental etiology: pesticides and other exposures

“In studies spanning many decades in numerous populations worldwide, pesticide exposure, farm work or rural residence have been associated with an increased PD risk” (opens the source at this quote in a new tab)
“Occupational exposure as well as “passive” exposure due to residence near to pesticide treated fields is associated with a greater risk of PD.” (opens the source at this quote in a new tab)
“Pesticides associated with PD, including paraquat, rotenone, 2,4-D and several dithiocarbamates and organochlorines, cause experimental parkinsonism in laboratory studies, supporting the possibility that these associations reflect causal effects” (opens the source at this quote in a new tab)

Factors associated with lower risk: tobacco and caffeine

“The most consistent association is a reduced risk of PD in cigarette smokers and, in a few studies, other tobacco users” (opens the source at this quote in a new tab)
“Coffee drinking and caffeine use are also associated with a lower risk of PD” (opens the source at this quote in a new tab)

Family history, constipation, non-smoking, and other associated factors

“Additional causal associations include having a relative with Parkinson’s disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson’s disease.” (opens the source at this quote in a new tab)
“Negative associations with the risk of developing Parkinson’s disease include smoking, coffee drinking, anti-inflammatory drug use, high plasma urate levels, or physical activity.” (opens the source at this quote in a new tab)

Incidence in North America among adults aged 45 and 65 years and older

“The cohorts contained data on 6.7 million person-years of adults ages 45 and older, and 9.3 million person-years of adults ages 65 and older.” (opens the source at this quote in a new tab)
“Our estimates of age-sex-adjusted incidence of PD ranged from 108 to 212 per 100,000 among persons ages 65 and older, and from 47 to 77 per 100,00 among persons ages 45 and older.” (opens the source at this quote in a new tab)
“PD incidence increased with age and was higher among males.” (opens the source at this quote in a new tab)

Estimated number of new diagnoses per year in North America

“We established a range of total incident PD diagnoses in North America of approximately 60,000 to 95,000 among adults ages 45 and older.” (opens the source at this quote in a new tab)
“Using the Medicare administrative database alone for this same time period suggests an incident rate of PD of nearly 90,000 per annum just for those 65 and older.” (opens the source at this quote in a new tab)
“Nevertheless, this contrasts sharply with the estimate of 40,000-60,000 new cases per annum that has been cited previously for PD incidence” (opens the source at this quote in a new tab)

Incidence by sex among adults aged 65 years and older

“Age standardized PD incidence estimates for ages 65 and older ranged from 108 to 212 per 100, 000 person-years, from 162 to 277 among males, and from 66 to 161 among females.” (opens the source at this quote in a new tab)
“As shown in Fig. 1, incidence estimates were higher in males as compared to females at all ages in the datasets which allowed sex-based comparisons into the 8th decade” (opens the source at this quote in a new tab)

Incidence by age

“As examined in persons aged 65 and older, PD incidence estimates increased with age in the decades 65–74 years, 75–84 years in every study sample.” (opens the source at this quote in a new tab)
“PD incidence among males rose first, most sharply between ages 64 and 74 in the fourstudy cohorts.” (opens the source at this quote in a new tab)

Variation in incidence by case ascertainment method

“The Ontario Health care and Medicare program datasets produced incidence rates that were 1.5–2.0 times higher than found in among Kaiser Permanente Northern California members or the HAAS and Rochester Epidemiology Project cohorts.” (opens the source at this quote in a new tab)
“The HAAS, REP, and KPNC studies, which produced lower incidence estimates, required high levels of clinical evidence and diagnosis by an expert clinician (a neurologist or movement disorders neurologist), even after screening, similar to the diagnostic protocols used for entry into a PD research study or clinical trial.” (opens the source at this quote in a new tab)

Geographic variation in incidence among Medicare beneficiaries

“A clustering of counties with a higher incidence of PD was observed at the juxtaposition of the Midwestern and Southern regions of the United States.” (opens the source at this quote in a new tab)
“Lower incidence areas included the Mountain West region, the western Midwest, and the far Northwest.” (opens the source at this quote in a new tab)

United States prevalence among adults aged 45 years and older, with projections to 2030

“Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537–614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections.” (opens the source at this quote in a new tab)

United States prevalence by sex

“For females, the prevalence was 488 (444–543), and for males 667 (612–732).” (opens the source at this quote in a new tab)
“The estimates were higher in men than in women and rose with age in both sexes.” (opens the source at this quote in a new tab)

Regional variation in North American prevalence

“We find this suggestive that—even within North America—the prevalence of PD that has come to medical attention does vary by region.” (opens the source at this quote in a new tab)
“As previously mentioned, analysis of the Medicare nationwide database found a higher prevalence in Whites and Hispanics than in Black or Asian individuals.” (opens the source at this quote in a new tab)

Prevalence by age

“In a meta-analysis of four North American populations, prevalence increased from less than 1 percent of men and women aged 45–54 years to 4 percent of men and 2 percent of women aged 85 or older” (opens the source at this quote in a new tab)

Diagnosed prevalence in the United States, 2017, with projection to 2037

“We estimated that 1.04 million individuals in the U.S. have been diagnosed with PD in 2017, with about 919,000 (89%) eligible for Medicare (91% age ≥65; 9% <65).” (opens the source at this quote in a new tab)
“PD was more prevalent in the ≥65 population (16.9 cases vs. 0.7 per 1,000 population), and more prevalent in men (595,000 males vs. 443,000 females).” (opens the source at this quote in a new tab)
“Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037.” (opens the source at this quote in a new tab)

Global prevalence, 1990 to 2016

“In 2016, 6·1 million (95% UI 5·0–7·3) individuals worldwide had Parkinson's disease, of whom 2·9 million (47·5%) were women and 3·2 million (52·5%) were men.” (opens the source at this quote in a new tab)
“The number of individuals with Parkinson's disease in 2016 was 2·4 times higher than in 1990 (2·5 million, 95% UI 2·0–3·0).” (opens the source at this quote in a new tab)
“Neurological disorders are now the leading source of disability in the world, and Parkinson's disease is the fastest growing of these disorders.” (opens the source at this quote in a new tab)

Global prevalence projected to 2050

“25.2 (95% uncertainty interval 21.7 to 30.1) million people were projected to be living with Parkinson’s disease worldwide in 2050, representing a 112% (95% uncertainty interval 71% to 152%) increase from 2021.” (opens the source at this quote in a new tab)
“Population ageing (89%) was predicted to be the primary contributor to the growth in cases from 2021 to 2050, followed by population growth (20%) and changes in prevalence (3%).” (opens the source at this quote in a new tab)
“The regions with the highest increase in all age prevalence were estimated to be North Africa and the Middle East (145%, 99% to 190%), South Asia (135%, 122% to 194%), and South East Asia (131%, 89% to 151%), whereas Australasia (39%, 22% to 62%) and high income North America (18%, 10% to 50%) were forecasted to have the lowest rise.” (opens the source at this quote in a new tab)

Prodromal phase before motor diagnosis

“Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible.” (opens the source at this quote in a new tab)
“we proposed that early PD should be divided into three stages: preclinical PD” (opens the source at this quote in a new tab)
“(neurodegenerative processes have commenced, but there are no evident symptoms or signs); prodromal PD (symptoms and signs are present, but are yet insufficient to define disease); and clinical PD (i.e., diagnosis of PD based on presence of classical motor signs).” (opens the source at this quote in a new tab)
“The speed of progression from prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level.” (opens the source at this quote in a new tab)
“Polysomnogram-proven RBD: Prospective studies show that more than 75% will develop disease” (opens the source at this quote in a new tab)
“Some studies in cohorts (e.g., RBD cohorts) have clearly documented prodromal durations of >20 years in duration.” (opens the source at this quote in a new tab)
“Based upon an overall assessment of the literature, we posited an average prodromal period of 10 years, but this was extremely subjective; the true value may differ considerably.” (opens the source at this quote in a new tab)

Postural instability, dependency, dementia, and death in population-based incidence cohorts

“In 883 population‐based incident patients, median age at motor symptom onset was 69.2 years. Median time to postural instability and functional dependency was 7.4 years. Dementia affected 49.6% by 10 years and 54.7% had died by 12 years (median survival 9.4 years).” (opens the source at this quote in a new tab)
“In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early.” (opens the source at this quote in a new tab)

Mortality relative to people without Parkinson's disease

“Eighty-eight studies were included in the review with variable study methods and quality.” (opens the source at this quote in a new tab)
“Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity.” (opens the source at this quote in a new tab)
“Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5.” (opens the source at this quote in a new tab)
“The overall mortality ratio in the inception cohorts (9 studies; 1,801 patients; median follow-up duration, 9 years) was 1.52 (95% CI, 1.25-1.78), but heterogeneity was high” (opens the source at this quote in a new tab)
“Most of the heterogeneity was because of a single study (Hoehn, 1967)” (opens the source at this quote in a new tab)
“and when this study was removed, the overall mortality ratio was 1.41 (95% CI, 1.28-1.55) with low heterogeneity” (opens the source at this quote in a new tab)
“The non-inception cohorts (33 studies; 27,480 patients; median follow-up duration, 7 years) had mortality ratios ranging from 0.90 to 3.79, with major heterogeneity” (opens the source at this quote in a new tab)
“A funnel plot (Supplemental Data Figure 1) did not show any evidence of publication bias or other small-study effect (Egger’s test, P = 0.87).” (opens the source at this quote in a new tab)
“Univariable metaregression of sex on these data showed no significant differences between males and females (P = 0.17).” (opens the source at this quote in a new tab)
“Most mortality ratios lay between 1.2 and 2.4, but, because of the major heterogeneity in the included studies, calculation of an overall measure was inappropriate.” (opens the source at this quote in a new tab)
“Forty-five studies (27,458 patients) reported survival proportion at specific times” (opens the source at this quote in a new tab)
“The regression coefficient was –0.045 (95% CI, –0.056-0.033).” (opens the source at this quote in a new tab)
“On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity.” (opens the source at this quote in a new tab)
“Eighteen studies reported median survival, 5 inception and 13 non-inception cohorts (Supplemental Data Table 6), which ranged from 6 to 22 years.” (opens the source at this quote in a new tab)
“Meta-analysis of 10 studies (1,306 patients) reporting the mean disease duration at death (Fig. 4) showed major heterogeneity” (opens the source at this quote in a new tab)
“In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years.” (opens the source at this quote in a new tab)
“Increasing age and presence of dementia were most commonly associated with increased mortality.” (opens the source at this quote in a new tab)
“Treatment also may alter prognosis over time, but we did not find any robust evidence that L-dopa has reduced mortality, and we are not aware of data to suggest that any other treatments alter survival.” (opens the source at this quote in a new tab)
“Only 5 studies met all 4 quality criteria.” (opens the source at this quote in a new tab)
“Most of the studies in this review were from Europe or North America, so generalizability to other geographical areas may be limited.” (opens the source at this quote in a new tab)

Independent predictors of mortality across cohort studies

“Twenty-one studies reported independent predictors of mortality” (opens the source at this quote in a new tab)
“Several studies did not report negative findings, so quantitative analysis of these data was not possible.” (opens the source at this quote in a new tab)

Prognostic factor	Studies finding the factor independently associated with increased mortality / studies that examined the association
Increasing age, at onset or at recruitment	“15/17”
Presence of dementia	“9/13”
Male sex	“6/17”
Higher Hoehn and Yahr stage	“5/8”
Postural instability and gait difficulty phenotype, prominent bradykinesia, or lack of tremor	“4/8”
Higher parkinsonian impairment score	“3/6”
Presence of psychosis or hallucinations	“2/4”
Presence of extensor plantar response	“2/2”

Mortality and causes of death over 15 and 20 years in a levodopa-era incident cohort

“The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms.” (opens the source at this quote in a new tab)
“Eighty-two deaths were observed but only 44 were expected.” (opens the source at this quote in a new tab)
“The excess of observed deaths was 86% (SMR, 1.86; 95% confidence interval [CI], 1.48–2.31; P < 0.001).” (opens the source at this quote in a new tab)
“The mean age of death was 75.5 years (SD = 8.1): 74.8 years (SD=7.9) for men and 76.4 (SD = 8.3) for women.” (opens the source at this quote in a new tab)
“Overall, the median time from onset of disease to death was 12.2 years (95% CI, 10.3–14.0 years).” (opens the source at this quote in a new tab)
“For men, the median survival was 11.9 years (95% CI, 9.7–14.0 years), and for women 12.9 years (95% CI, 9.6–16.1 years).” (opens the source at this quote in a new tab)
“The difference in survival between men and women and the difference between randomization groups was not statistically significant.” (opens the source at this quote in a new tab)
“Patients randomly assigned to L-dopa survived for a median of 13.1 years (95% CI, 10.5–15.6 years), whereas patients randomly assigned to bromocriptine survived for a median of 11.6 years (95% CI, 8.7–14.4 years).” (opens the source at this quote in a new tab)
“Variables that were statistically significant univariately to predict death by 15 years were older age at onset (P < 0.001), Hoehn and Yahr Stage 3 at baseline (P < 0.003), rapid prestudy disease progression rate (P < 0.005), imbalance at baseline (P < 0.03), dementia at baseline (P < 0.05), increased tremor score at baseline (P < 0.02), dementia noted within 15 years (P < 0.001), and imbalance developing within the 15 years (P < 0.001).” (opens the source at this quote in a new tab)
“In multivariate analysis, the variables were the older the age of onset and the higher the risk of mortality (P < 0.001), increasing by approximately 15% per year of age.” (opens the source at this quote in a new tab)
“Imbalance noted within 15 years increased the risk of death almost threefold (P < 0.03).” (opens the source at this quote in a new tab)
“pneumonia being the most common cause (22 of 82, 27%) with a SMR >10.” (opens the source at this quote in a new tab)
“Parkinson’s disease was considered to have contributed to the deaths of 43 patients (52%) because of pneumonia, inanition, pulmonary embolism, suicide, and patients who were Stage 5 who had cardiovascular or cerebrovascular events but who were considered unsuitable for rehabilitation.” (opens the source at this quote in a new tab)
“Significantly lower than expected death rates were observed from carcinoma (12 vs. 24.2 expected; SMR, 0.50; 95% CI, 0.26–0.87).” (opens the source at this quote in a new tab)
“Deaths due to cardiovascular disease (15 vs. 13.5 expected) were not significantly increased.” (opens the source at this quote in a new tab)
“In this study, the SMR is 1.58 at 10 years and 1.86 at 15 years” (opens the source at this quote in a new tab)

“After 20 years follow-up of newly diagnosed patients with Parkinson’s disease (PD), 100 of 136 (74%) have died.” (opens the source at this quote in a new tab)
“The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1.” (opens the source at this quote in a new tab)
“In the first 3 years, five died compared with an expected 9.2 deaths (SMR = 0.5, 95% CI 0.2–1.1).” (opens the source at this quote in a new tab)
“Between 3 and 20 years, 95 died compared with an expected 38.7 deaths (SMR = 2.5, 95% CI = 2.0–3.0).” (opens the source at this quote in a new tab)
“The SMR was similar for the periods 3 to 5, 5 to 10, 10 to 15, and 15 to 20 years (chi-square test statistic for between period differences = 2.6 for 3 degrees of freedom, P = 0.5) but showed a trend to increase with duration of disease compared to the age matched Australian population after falling in the early years of treatment: SMR = 0.5 at 0 to 3 years, 1.8 at 3 to 5 years, 2.3 at 5 to 10 years, 2.7 at 10 to 15 years and 3.1 at 15 to 20 years.” (opens the source at this quote in a new tab)
“The mean age at death was 76 years (SD = 7.5), 75 years for men and 78 years for women after a mean of 121 and 132 months from entry to the study, respectively.” (opens the source at this quote in a new tab)
“The median time from historical onset of disease to death was 12.4 years.” (opens the source at this quote in a new tab)
“Pneumonia was the most common cause of death, 26 of 103 (25%), generally occurring in Hoehn and Yahr stage 5.” (opens the source at this quote in a new tab)
“PD was considered to have been a significant contributor to the death of 55 of 103 (54%).” (opens the source at this quote in a new tab)
“Once dementia was diagnosed (excluding those diagnosed at baseline), the median survival was 54 months.” (opens the source at this quote in a new tab)
“Although dementia was predictive of death (P = 0.001) univariately, it is so strongly associated with increasing age as to render it insignificant when age is corrected for multivariately.” (opens the source at this quote in a new tab)

Six-year survival among United States Medicare beneficiaries with incident Parkinson's disease

“Retrospective cohort study of 138,000 Medicare beneficiaries with incident PD were identified in 2002 and followed through 2008.” (opens the source at this quote in a new tab)
“Thirty-five percent of PD cases lived more than six years.” (opens the source at this quote in a new tab)
“Sex and race significantly predicted survival: female (HR 0.74, 0.73– 0.75), Hispanic (HR 0.72, 0.65–0.80) and Asian (HR 0.86, 0.82–0.91) cases had a lower adjusted risk of death than white males.” (opens the source at this quote in a new tab)
“Dementia/cognitive impairment, diagnosed in 69.6% of cases, most often in Blacks (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR 1.72, 1.69–1.75).” (opens the source at this quote in a new tab)

Trends in Parkinson's disease mortality in the United States, 1999 to 2019

“Analyses focused on the data from 479,059 deaths due to PD from 1999 to 2019.” (opens the source at this quote in a new tab)
“The age-adjusted mortality from PD increased from 5.4 (95% confidence interval [CI] 5.3–5.5) per 100,000 population in 1999 to 8.8 (95% CI, 8.7–8.9) per 100,000 population in 2019, with an average annual percent change of 2.4%” (opens the source at this quote in a new tab)
“Age-adjusted PD mortality rates were twice as high in men as in women and were greater in White individuals than those from other racial/ethnic groups.” (opens the source at this quote in a new tab)
“Between 1999 and 2019, the number of deaths from PD in the US population was more than doubled, from 14,593 to 35,311” (opens the source at this quote in a new tab)
“The state-level estimates of the increases ranged from 3.1 to 8.4 per 100,000 in 1999 to 4.6 to 11.7 per 100,000 in 2019” (opens the source at this quote in a new tab)
“Death resulting from PD was ascertained by its designation as the underlying cause of death in death certificates with codes G20 to G21 of the ICD-10, which was implemented in 1999.” (opens the source at this quote in a new tab)
“Thus, in our study, only PD as the underlying cause of death was counted.” (opens the source at this quote in a new tab)

Group	Deaths, 1999	Death rate per 100,000 (95% CI), 1999	Deaths, 2019	Death rate per 100,000 (95% CI), 2019	Average annual percent change (95% CI), 1999 to 2019
All ages, crude rate	“14,593”	“5.2 (5.1–5.3)”	“35,311”	“10.8 (10.6–10.9)”	“3.6 (3.0–4.2)”
All ages, age-adjusted rate	Not applicable	“5.4 (5.3–5.5)”	Not applicable	“8.8 (8.7–8.9)”	“2.4 (1.8–3.0)”
Aged 64 years or younger, crude rate	“295”	“0.1 (0.1–0.1)”	“876”	“0.3 (0.3–0.3)”	“5.0 (3.4–6.6)”
Aged 65 to 74 years, crude rate	“2,020”	“11.0 (10.5–11.4)”	“5,276”	“16.8 (16.3–17.2)”	“1.9 (1.4–2.5)”
Aged 75 to 84 years, crude rate	“7,110”	“58.2 (56.8–59.5)”	“14,902”	“93.3 (91.8–94.8)”	“2.2 (1.8–2.5)”
Aged 85 years or older, crude rate	“5,168”	“124.4 (121.0–127.8)”	“14,257”	“215.9 (212.3–219.4)”	“2.7 (2.0–3.5)”
Men, age-adjusted rate	“8,262”	“8.4 (8.2–8.6)”	“21,592”	“13.1 (13.0–13.3)”	“2.2 (1.7–2.7)”
Women, age-adjusted rate	“6,331”	“3.7 (3.6–3.8)”	“13,719”	“5.8 (5.7–5.9)”	“2.1 (1.7–2.5)”
Hispanic, age-adjusted rate	“389”	“3.5 (3.2–3.9)”	“2,126”	“6.5 (6.2–6.8)”	“3.0 (2.7–3.3)”
Non-Hispanic White, age-adjusted rate	“13,475”	“5.8 (5.7–5.9)”	“30,307”	“9.7 (9.6–9.8)”	“2.5 (1.9–3.1)”
Non-Hispanic Black, age-adjusted rate	“502”	“2.4 (2.2–2.6)”	“1,655”	“4.7 (4.5–5.0)”	“3.5 (2.7–4.3)”
Non-Hispanic, other, age-adjusted rate	“200”	“3.4 (2.9–3.8)”	“1,182”	“5.6 (5.3–6.0)”	“2.5 (1.7–3.4)”
Large central metropolitan, age-adjusted rate	“3,894”	“5.1 (5.0–5.3)”	“8,907”	“8.2 (8.1–8.4)”	“2.4 (1.7–3.1)”
Large fringe metropolitan, age-adjusted rate	“3,400”	“5.7 (5.5–5.9)”	“9,008”	“9.2 (9.0–9.4)”	“2.4 (1.7–3.2)”
Medium metropolitan, age-adjusted rate	“3,136”	“5.6 (5.4–5.8)”	“7,768”	“9.0 (8.8–9.2)”	“2.4 (1.5–3.2)”
Small metropolitan, age-adjusted rate	“1,592”	“6.0 (5.7–6.2)”	“3,707”	“9.3 (9.0–9.6)”	“2.3 (2.0–2.7)”
Micropolitan, age-adjusted rate	“1,510”	“5.3 (5.0–5.5)”	“3,464”	“9.1 (8.8–9.5)”	“2.5 (2.1–2.9)”
Noncore, age-adjusted rate	“1,061”	“4.4 (4.2–4.7)”	“2,457”	“8.3 (8.0–8.7)”	“2.9 (2.4–3.4)”

Global deaths and disability-adjusted life-years

“Parkinson's disease caused 3·2 million (95% UI 2·6–4·0) DALYs and 211 296 deaths (95% UI 167 771–265 160) in 2016.” (opens the source at this quote in a new tab)
“From 1990 to 2016, age-standardised prevalence, DALY rates, and death rates increased for all global burden of disease regions except for southern Latin America, eastern Europe, and Oceania.” (opens the source at this quote in a new tab)

Motor complications and survival in a population-based cohort

“At 13 years, 61 of 141 patients were alive.” (opens the source at this quote in a new tab)
“Both early motor fluctuations and levodopa‐induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years).” (opens the source at this quote in a new tab)

Nigral dopaminergic neuron loss and Lewy pathology

“The neuropathological hallmarks of PD are the degeneration of dopaminergic neurons in the SN and intraneuronal protein aggregates called Lewy bodies and Lewy neurites” (opens the source at this quote in a new tab)
“It was long considered that 50–70% of SN dopaminergic neurons have died by the time that clinical motor symptoms become evident” (opens the source at this quote in a new tab)
“However, more recent work suggests that the loss of dopaminergic terminals in the basal ganglia, as opposed to loss of the neurons in the SN, is crucial for onset of motor symptoms” (opens the source at this quote in a new tab)

Time course of nigrostriatal degeneration after diagnosis

“Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis.” (opens the source at this quote in a new tab)
“In the substantia nigra pars compacta, there was a 50–90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter.” (opens the source at this quote in a new tab)
“Quantitative analyses revealed a 35–75% loss of tyrosine hydroxylase and dopamine transporter optical fibre density at Years 1–3 after diagnosis, ∼70–90% reduction by Year 5, and relatively little change thereafter.” (opens the source at this quote in a new tab)

Non-dopaminergic involvement

“However, PD is characterized by more widespread pathology in other brain regions and involves non-dopaminergic neurons as well.” (opens the source at this quote in a new tab)

“The loss of pigmentation correlates with neuronal loss of dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus ceruleus.” (opens the source at this quote in a new tab)
“The concept of as a “parkinsonism-plus” disorder has become increasingly muddled as it clear that most patients with PD also have nonparkinsonian clinical features, such as autonomic dysfunction, sleep disorders, and eventually dementia” (opens the source at this quote in a new tab)

Spread of alpha-synuclein pathology and Braak staging

“In a series of seminal studies, Heiko Braak and colleagues proposed that there are six stages of Lewy pathology in PD” (opens the source at this quote in a new tab)
“They suggested that in the first stages the Lewy pathology is limited to the dorsal motor nucleus of the vagal nerve, located on the medulla oblongata and the origin of the nerve fibers innervating the gut and other visceral organs, and the olfactory bulb and closely associated olfactory nucleus.” (opens the source at this quote in a new tab)
“The Braak staging model is based on post-mortem observations, and it has not been possible to obtain definitive proof that pathology spreads in accordance with the Braak stages” (opens the source at this quote in a new tab)
“Because these pathogenic alpha-synuclein assemblies can be transported intra-axonally to interconnected nuclei, prion-like behavior of alpha-synuclein assemblies might explain how Lewy pathology propagates from one brain region to another” (opens the source at this quote in a new tab)

Cellular mechanisms shared by genetic and environmental causes

“Environmental and genetic factors influence PD pathogenesis by impacting similar pathways, including mitochondrial function, oxidative stress, alpha-synuclein aggregation, and clearance pathways for abnormal proteins.” (opens the source at this quote in a new tab)

Striatal direct and indirect pathways and D1 and D2 dopamine receptors

“Dopamine has opponent affects on the function of these pathways due to the segregation of the D1- and D2-dopamine receptors in the spiny projection neurons giving rise to the direct and indirect pathways.” (opens the source at this quote in a new tab)
“The direct pathway originates from Drd1a-expressing SPNs that project to the GPi and SNr output nuclei.” (opens the source at this quote in a new tab)
“The indirect pathway originates from Drd2-expressing SPNs that project only to the external segment of the globus pallidus (GPe), which together with the subthalamic nucleus (STN) contain transynaptic circuits connecting to the basal output nuclei.” (opens the source at this quote in a new tab)
“Taken together these findings led to the proposal that in Parkinson’s disease the loss of striatal dopamine produces decreased activity in the direct striatonigral pathway and increased activity in the indirect pathway through the multisynaptic pathway through the GPe and STN to SNr.” (opens the source at this quote in a new tab)
“Imbalance in activity between these pathways, with activity in the indirect pathway predominating over the disinhibition of direct pathway activity required for the generation of movements was proposed to produce bradykinetic symptoms of Parkinson’s disease.” (opens the source at this quote in a new tab)

Basal ganglia oscillatory activity in the off state and in levodopa-induced dyskinesia

“The parkinsonian off-state is characterized by enhanced beta-band activity (~20 Hz) in local field potential recordings from the basal ganglia, which is suppressed by dopaminergic medication or DBS in parallel with the clinical improvement of bradykinesia and rigidity” (opens the source at this quote in a new tab)
“By contrast, hyperkinesia — such as l-DOPA-induced dyskinesia in Parkinson disease — has been associated with increased theta-band activity in the same structures (4–12 Hz)” (opens the source at this quote in a new tab)

Striatal pathway alterations underlying levodopa-induced dyskinesia

“In Parkinson’s disease dopamine depletion in the striatum produces physiologic alterations in both pathways responsible for L-DOPA induced dyskinesias (LIDs)” (opens the source at this quote in a new tab)

Presynaptic and postsynaptic mechanisms of levodopa-induced motor complications

“The key cause is discontinuous drug delivery due to the short half-life of l-DOPA and the variability in its gastrointestinal absorption and blood–brain barrier transport” (opens the source at this quote in a new tab)
“Mechanisms underlying l‑DOPA‑induced dyskinesias include presynaptic and postsynaptic mechanisms: the loss of dopaminergic nigrostriatal terminals leads to reduced presynaptic dopamine storage capacity and dysregulated dopamine release, whereas discontinuous delivery of l‑DOPA results in pulsatile activation of postsynaptic dopamine receptors.” (opens the source at this quote in a new tab)

Movement Disorder Society clinical diagnostic criteria

“The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis.” (opens the source at this quote in a new tab)
“After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis).” (opens the source at this quote in a new tab)
“Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity).” (opens the source at this quote in a new tab)
“Clinically Established PD: Maximizing specificity, the category is anchored with the goal that the large majority (ie, at least 90%) will have PD.” (opens the source at this quote in a new tab)
“Clinically Probable PD: Balancing sensitivity and specificity, the category is anchored with the goal that at least 80% of patients diagnosed as probable PD truly have PD” (opens the source at this quote in a new tab)
“Diagnosis of clinically established PD requires: 1. Absence of absolute exclusion criteria 2. At least two supportive criteria 3. No red flags” (opens the source at this quote in a new tab)
“Diagnosis of clinically probable PD can be made in: 1. Absence of absolute exclusion criteria 2. Presence of red flags counterbalanced by supportive criteria, ie, if one red flag is present there must also be at least one supportive criterion; if two red flags, at least two supportive criteria are needed. If there are more than two red flags, clinically probable PD cannot be diagnosed.” (opens the source at this quote in a new tab)
“As outlined in our introductory manuscript, the MDS-PD criteria do not consider dementia as an exclusion criterion for PD, regardless of when it occurs in relation to parkinsonism onset.” (opens the source at this quote in a new tab)
“Full diagnostic certainty is impossible during life; between 75% and 95% of patients diagnosed with PD by experts have their diagnosis confirmed on autopsy.” (opens the source at this quote in a new tab)

Supportive criteria in the Movement Disorder Society clinical diagnostic criteria

“Clear and dramatic beneficial response to dopaminergic therapy. To meet this criterion, during initial treatment, patients should have returned to normal or near-normal level of function.” (opens the source at this quote in a new tab)
“Presence of levodopa-induced dyskinesia” (opens the source at this quote in a new tab)
“Rest tremor of a limb, documented on clinical examination (in the past, or on current examination)” (opens the source at this quote in a new tab)
“Positive results from at least one ancillary diagnostic test having a specificity greater than 80% for differential diagnosis of PD from other parkinsonian conditions.” (opens the source at this quote in a new tab)
“Such a marker must have been assessed as 80% or more specific in the differential diagnosis of parkinsonism (compared with gold-standard clinical or clinicopathologic diagnosis) in most studies.” (opens the source at this quote in a new tab)
“Olfactory loss (in the anosmic or clearly hyposmic range, adjusted for age and sex)” (opens the source at this quote in a new tab)
“Metaiodobenzylguanidine scintigraphy clearly documenting cardiac sympathetic denervation” (opens the source at this quote in a new tab)
“Note that although dopaminergic neuroimaging can help distinguish parkinsonism (ie, degeneration of the nigrostriatal system) from PD-mimics without parkinsonism (eg, essential tremor), it does not qualify as a criterion for the differentiation of PD from other parkinsonian conditions like atypical parkinsonian syndromes.” (opens the source at this quote in a new tab)

Absolute exclusion criteria in the Movement Disorder Society clinical diagnostic criteria

“A benchmark for an absolute exclusion was occurrence in less than 3% of true PD” (opens the source at this quote in a new tab)
“The presence of any of these features rules out PD” (opens the source at this quote in a new tab)
“Unequivocal cerebellar abnormalities on examination, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (eg, sustained gaze-evoked nystagmus, macro square wave jerks, hypermetric saccades)” (opens the source at this quote in a new tab)
“Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades” (opens the source at this quote in a new tab)
“Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria” (opens the source at this quote in a new tab)
“within the first 5 y of disease” (opens the source at this quote in a new tab)
“Other forms of dementia are not an exclusion criterion for PD.” (opens the source at this quote in a new tab)
“Parkinsonian features restricted to the lower limbs for more than 3 y” (opens the source at this quote in a new tab)
“Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism” (opens the source at this quote in a new tab)
“Absence of observable response to high-dose levodopa despite at least moderate severity of disease” (opens the source at this quote in a new tab)
“Unequivocal cortical sensory loss (ie, graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia” (opens the source at this quote in a new tab)
“Normal functional neuroimaging of the presynaptic dopaminergic system” (opens the source at this quote in a new tab)
“Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or the expert evaluating physician, based on the full diagnostic assessment, believes that an alternative syndrome is more likely than PD.” (opens the source at this quote in a new tab)

Red flags in the Movement Disorder Society clinical diagnostic criteria

“Red flags rule out probable PD diagnosis only when they cannot be counterbalanced by supportive criteria.” (opens the source at this quote in a new tab)
“Rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset” (opens the source at this quote in a new tab)
“A complete absence of progression of motor symptoms or signs over 5 or more years unless stability is related to treatment” (opens the source at this quote in a new tab)
“Early bulbar dysfunction, defined as one of severe dysphonia, dysarthria (speech unintelligible most of the time), or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within the first 5 y of disease.” (opens the source at this quote in a new tab)
“Inspiratory respiratory dysfunction defined as either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs” (opens the source at this quote in a new tab)
“Severe autonomic failure in the first 5 y of disease.” (opens the source at this quote in a new tab)
“orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, in the absence of dehydration, medication, or other diseases that could plausibly explain autonomic dysfunction” (opens the source at this quote in a new tab)
“Severe urinary incontinence or urinary retention in the first 5 y of disease (excluding longstanding low-volume stress incontinence in women), which is not simply functional incontinence (ie, inability to get to the bathroom in a reasonable time).” (opens the source at this quote in a new tab)
“Recurrent (>1/y) falls because of impaired balance within 3 y of onset.” (opens the source at this quote in a new tab)
“The presence of disproportionate anterocollis (dystonic in nature) or contractures of hand or feet within the first 10 y.” (opens the source at this quote in a new tab)
“Absence of any of the common nonmotor features of disease despite 5 y disease duration.” (opens the source at this quote in a new tab)
“Otherwise unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry in the more affected limb, and isolated extensor plantar response).” (opens the source at this quote in a new tab)
“Bilateral symmetric parkinsonism throughout the disease course. The patient or caregiver reports bilateral symptom onset with no side predominance, and no side predominance is observed on objective examination.” (opens the source at this quote in a new tab)

Validation of the criteria against expert clinical diagnosis

“From 8 centers, we recruited 626 parkinsonism patients (434 PD, 192 non-PD).” (opens the source at this quote in a new tab)
“Of 434 patients diagnosed with PD, 94.5% met the International Parkinson and Movement Disorder Society criteria for probable PD (5.5% false-negative rate). Of 192 non-PD patients, 88.5% were identified as non-PD by the criteria (11.5% false-positive rate). The overall accuracy for probable PD was 92.6%.” (opens the source at this quote in a new tab)
“In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001).” (opens the source at this quote in a new tab)
“In the non-PD group, the commonest conditions were multiple system atrophy (38%), progressive supranuclear palsy (33%), and corticobasal syndrome (10%)” (opens the source at this quote in a new tab)
“In addition, 59.3% of PD patients met MDS criteria for clinically established PD. Only 1.6% of non-PD patients met clinically established criteria.” (opens the source at this quote in a new tab)
“Moreover, if optimal specificity is desired, the clinically established criteria had very high specificity (98.4%) with a reasonable sensitivity of 59%.” (opens the source at this quote in a new tab)

UK Brain Bank criteria sensitivity that differs between the abstract and the results

“In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001).” (opens the source at this quote in a new tab)
“89.4% of PD patients met UK Brain Bank criteria for PD (10.6% false-negatives, P = 0.008 to MDS criteria)” (opens the source at this quote in a new tab)

Overall accuracy of the criteria for probable PD that differs among the results, a post hoc analysis, and the discussion

“Combining all patients, the overall accuracy for probable PD was 92.6% compared with the gold standard, expert clinical diagnosis.” (opens the source at this quote in a new tab)
“removing this from the diagnostic criteria did not improve overall accuracy (91.3% without ancillary testing vs 92.7% with testing). Sensitivity dropped from 94.5% to 91.9%, whereas specificity rose modestly, from 88.5% to 90.1%.” (opens the source at this quote in a new tab)
“We found an overall accuracy/concordance rate of 92.4%, with sensitivity of 94.5% and specificity of 88.5%.” (opens the source at this quote in a new tab)

Proportion of PD participants meeting criteria for clinically established PD that differs between the results text and table 1

“In addition, 59.3% of PD patients met MDS criteria for clinically established PD. Only 1.6% of non-PD patients met clinically established criteria.” (opens the source at this quote in a new tab)

Table 1 characteristic	PD (n = 434)	Non-PD parkinsonism (n = 192)
Meets MDS probable criteria (%)	“94.5”	“11.5”
Meets MDS clinically established (%)	“60.4”	“1.6”

Validation of the criteria by disease duration, age, and sex

“Sensitivity was relatively similar (95.9% for > 5 years, 92.8% for < 5 years). However, specificity improved considerably with longer duration; 95.0% for duration ≥ 5 years, versus 86.8% for < 5 years.” (opens the source at this quote in a new tab)
“Sensitivity did not differ (93.4% young vs 95.4% old), but specificity was lower in older patients (93.8% vs 83.3%, P = 0.039).” (opens the source at this quote in a new tab)
“Accuracy was not significantly different in men versus women (sensitivity, 96.1% in men, 91.6% in women; P = 0.078; specificity, 86.0% in men vs 92.3% in women; P = 0.24).” (opens the source at this quote in a new tab)
“Therefore, we analyzed the effect of treating red flags as absolute exclusion criteria (and removing duration components) in cases with disease duration < 5 years. This yielded 95.4% specificity and 68.9% sensitivity compared with the gold standard, clinical diagnosis (by comparison, the existing clinically established category in this group had 98.7% specificity and 47.1% sensitivity).” (opens the source at this quote in a new tab)

Validation of the criteria: frequency of individual criteria items

“Supportive criteria were originally designed to have benchmark specificity ≥ 80%. Three of 4 criteria met this benchmark; dyskinesia occurred in 7% of non-PD patients, rest tremor in 13.6%, and excellent levodopa response in 19.9%.” (opens the source at this quote in a new tab)
“However, although positive ancillary testing differed between groups (P < 0.001) specificity of the ancillary testing criterion was low, at 61.7%.” (opens the source at this quote in a new tab)
“Absolute exclusions were originally designed with a benchmark specificity of >95%; all absolute exclusion criteria met this benchmark, with the highest single absolute exclusion (absent levodopa response) occurring in only 1.3% of PD-diagnosed cases.” (opens the source at this quote in a new tab)
“We found that 19.1% of PD patients had at least 1 red flag, compared with 84.1% of non-PD patients (P < 0.001; Table 4).” (opens the source at this quote in a new tab)
“Therefore, olfactory testing’s diagnostic utility remains unclear.” (opens the source at this quote in a new tab)

Criterion item	PD (n = 434), %	Non-PD parkinsonism (n = 192), %
Supportive criterion: excellent levodopa response	“73.4 (n = 364)”	“19.9 (n = 151)”
Supportive criterion: dyskinesia	“34.0 (n = 382)”	“7.0 (n = 157)”
Supportive criterion: asymmetric rest tremor	“56.5”	“13.6”
Supportive criterion: positive ancillary test	“67.6”	“38.3”
Supportive criterion: abnormal olfaction	“67.4”	“36.6”
Any absolute exclusion	“3.2”	“64.1”
Absolute exclusion: cerebellar abnormalities	“0.2”	“14.2”
Absolute exclusion: vertical supranuclear gaze palsy	“1.2”	“29.2”
Absolute exclusion: frontotemporal dementia	“0.2”	“1.1”
Absolute exclusion: leg-only parkinsonism	“0.5”	“2.6”
Absolute exclusion: dopamine blocker or depleter	“0.5”	“4.2”
Absolute exclusion: absent levodopa response	“1.3 (n = 393)”	“33.8 (n = 157)”
Absolute exclusion: cortical sensory loss	“0”	“13.1”
Absolute exclusion: normal dopamine imaging	“0 (n = 42)”	“13.0 (n = 23)”
Any red flag	“19.1”	“84.4”
Red flag 1: rapid progression of gait impairment	“1.4”	“22.7”
Red flag 2: absence of progression over 5 years	“1.2”	“0.6”
Red flag 3: severe bulbar dysfunction within 5 years	“0”	“18.0”
Red flag 4: inspiratory stridor	“0.2”	“9.0”
Red flag 5: severe autonomic failure within 5 years	“9.7”	“40.1”
Red flag 6: recurrent falls within 3 years	“3.7”	“51.3”
Red flag 7: anterocollis or contractures	“2.6”	“10.2”
Red flag 8: absent nonmotor features after 5 years	“1.6”	“1.6”
Red flag 9: pyramidal tract signs	“1.8”	“25.8”
Red flag 10: bilateral symmetric parkinsonism	“1.9”	“25.1”

Proportion of non-PD participants with any red flag that differs between the results text and table 4

“We found that 19.1% of PD patients had at least 1 red flag, compared with 84.1% of non-PD patients (P < 0.001; Table 4).” (opens the source at this quote in a new tab)

Table 4 item	PD (n = 434), %	Non-PD parkinsonism (n = 192), %
Any red flag	“19.1”	“84.4”

Validation of the criteria: study limitations

“First, it must be emphasized that this is not a clinicopathologic or clinicogenetic study. The gold standard used here is expert clinician diagnosis, using all modalities available to them in their clinical practice.” (opens the source at this quote in a new tab)
“Fourth, the overall occurrence of vascular parkinsonism and drug-induced parkinsonism was low (4.7% and 2.1%, respectively), perhaps reflective of the subspecialty centers in this study; in general neurology practice, these may be more common, and we cannot state how reliably the criteria exclude these diagnoses.” (opens the source at this quote in a new tab)
“Finally, this study did not include parkinsonism mimics or those with only a single parkinsonism sign (eg, isolated rest tremor), because all patients were required to fulfill the operational definition of parkinsonism for entry.” (opens the source at this quote in a new tab)

Autopsy validation of the criteria

“A recent autopsy validation of the clinically-probable PD criteria using the UK Brain Bank material in 141 PD and 126 non-PD parkinsonism found an overall accuracy of 92.5% for the final criteria evaluation at death and 89.5% for the criteria at initial clinical evaluation” (opens the source at this quote in a new tab)
“Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful.” (opens the source at this quote in a new tab)
“For practicing clinicians, a clinical diagnosis will remain the first step, aided by available imaging or laboratory tests depending on region and health care system” (opens the source at this quote in a new tab)

Accuracy of clinical diagnosis against neuropathology

“We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%-85.3%). Accuracy was 73.8% (95% CrI 67.8%-79.6%) for clinical diagnosis performed mainly by nonexperts.” (opens the source at this quote in a new tab)
“Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%-95.1%) of initial assessment to 83.9% (95% CrI 69.7%-92.6%) of refined diagnosis after follow-up.” (opens the source at this quote in a new tab)
“The accuracy did not significantly improve in the last 25 years, particularly in the early stages of disease, where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged.” (opens the source at this quote in a new tab)

Diagnostic delay and misclassification in early disease

“The earliest stages of Parkinson’s disease can be difficult to recognise, as reflected by the long delay (average 10 years) that typically separates the person’s first noticeable symptom from the timing of diagnosis.” (opens the source at this quote in a new tab)
“Diagnostic errors are common in daily practice. In clinical trials of early-stage Parkinson’s disease, up to 15% of people with the disease are diagnosed incorrectly” (opens the source at this quote in a new tab)

Clinical basis of diagnosis, levodopa response, and role of ancillary testing

“The diagnosis is clinically based; ancillary testing is reserved for people with an atypical presentation.” (opens the source at this quote in a new tab)
“In daily practice, Parkinson’s disease is a clinical diagnosis, and is based on history taking and neurological examination.” (opens the source at this quote in a new tab)
“if needed, the levodopa dose should be escalated to 1000 mg daily for 4 weeks before concluding that people with Parkinson’s disease are not responsive.” (opens the source at this quote in a new tab)
“Dopaminergic neuroimaging remains normal in conditions that mimic parkinsonism; note that dopaminergic neuroimaging does not distinguish Parkinson’s disease from the various forms of atypical parkinsonism; therefore, dopaminergic neuroimaging is not recommended for routine use in daily clinical practice” (opens the source at this quote in a new tab)

Dopamine transporter single-photon emission computed tomography

“As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (123I) single-photon emission computed tomography (SPECT) or DaTSCAN as a diagnostic tool has been a matter of debate for years.” (opens the source at this quote in a new tab)
“The performance of DaTSCAN is generally recommended in the follow-up of patients with a clinically uncertain diagnosis, especially in those with a suspected essential tremor, drug-induced parkinsonism, or vascular parkinsonism.” (opens the source at this quote in a new tab)
“To date, a specific nigrostriatal dopamine uptake pattern that would help differentiate PD from the most frequent atypical parkinsonisms is yet to be described.” (opens the source at this quote in a new tab)

Role of genetic testing in diagnosis

“Genetic forms only account for a small percentage of Parkinson disease cases in clinical practice, and, as of yet, genetic testing is not part of the routine diagnostic process, except in patients in whom there is a specific suspicion for a possible genetic cause (for example, suggestive family history, early onset (which is typical for several recessive genes) or specific clinical features, such as dystonia as a presenting symptom).” (opens the source at this quote in a new tab)
“Overall, the implications of genetic testing in clinical routine are limited by reduced penetrance and variable expressivity, and there is currently no impact of genetic findings on practical treatment decisions.” (opens the source at this quote in a new tab)

Alpha-synuclein seed amplification assay in cerebrospinal fluid

“This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019.” (opens the source at this quote in a new tab)
“Sensitivity for Parkinson’s disease was 87·7% (95% CI 84·9–90·5), and specificity for healthy controls was 96·3% (93·4–99·2).” (opens the source at this quote in a new tab)
“The sensitivity of the α-synuclein SAA in sporadic Parkinson’s disease with the typical olfactory deficit was 98·6% (96·4–99·4).” (opens the source at this quote in a new tab)
“Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD).” (opens the source at this quote in a new tab)

Research criteria for prodromal Parkinson's disease

“Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only.” (opens the source at this quote in a new tab)
“The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty.” (opens the source at this quote in a new tab)
“In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios.” (opens the source at this quote in a new tab)
“However, prodromal PD criteria cannot be met with only risk markers; some markers of ongoing neurodegeneration (i.e., prodromal markers) must also be present.” (opens the source at this quote in a new tab)
“Prodromal markers with combined minimum LR of at least +4 (i.e., approximating one strong or two combined moderate-strength markers) must also be present, to indicate that the neurodegenerative process has likely started.” (opens the source at this quote in a new tab)

“Diabetes, global cognitive deficit, physical inactivity, and low plasma urate levels in men enter the criteria as new markers.” (opens the source at this quote in a new tab)
“These studies show relatively high specificity and positive predictive values for conversion from probable prodromal PD to clinical PD, with variable sensitivity of detecting prodromal PD that depends on the depth of marker assessment and the time from marker assessments to PD diagnosis.” (opens the source at this quote in a new tab)
“Importantly, the presented criteria are still, at this stage, for research purposes only.” (opens the source at this quote in a new tab)

Likelihood ratios of risk and prodromal markers: 2015 research criteria

Marker type	Marker	Positive likelihood ratio	Negative likelihood ratio
Risk marker	Male sex	“1.2 (male)”	“0.8 (female)”
Risk marker	Regular pesticide exposure	“1.5”	Not applicable
Risk marker	Occupational solvent exposure	“1.5”	Not applicable
Risk marker	Nonuse of caffeine	“1.35”	“0.88”
Risk marker	Current smoker	Not applicable	“0.45”
Risk marker	Never smoker	“1.25”	Not applicable
Risk marker	Former smoker	Not applicable	“0.8”
Risk marker	Sibling with PD onset before age 50 years	“7.5”	Not applicable
Risk marker	Any other first-degree relative with PD	“2.5”	Not applicable
Risk marker	Known gene mutation	“see Supporting Table II”	Not applicable
Risk marker	Substantia nigra hyperechogenicity	“4.7”	“0.45”
Prodromal marker	Polysomnography-proven RBD	“130”	“0.62”
Prodromal marker	Positive RBD screening questionnaire with more than 80% specificity	“2.3”	“0.76”
Prodromal marker	Dopaminergic PET or SPECT clearly abnormal	“40”	“0.65”
Prodromal marker	Possible subthreshold parkinsonism (UPDRS above 3, excluding action tremor)	“10”	“0.70”
Prodromal marker	Abnormal quantitative motor testing	“3.5”	“0.60”
Prodromal marker	Olfactory loss	“4.0”	“0.43”
Prodromal marker	Constipation	“2.2”	“0.80”
Prodromal marker	Excessive daytime somnolence	“2.2”	“0.88”
Prodromal marker	Symptomatic hypotension	“2.1”	“0.87”
Prodromal marker	Severe erectile dysfunction	“2.0”	“0.90”
Prodromal marker	Urinary dysfunction	“1.9”	“0.90”
Prodromal marker	Depression with or without anxiety	“1.8”	“0.85”

Prior probability of prodromal Parkinson's disease by age

“Based on current knowledge, we combined estimates from these different sources together, adding subjective weighting and smoothing, to create an age-specific estimate of prodromal PD prevalence.” (opens the source at this quote in a new tab)

Age group, years	Prior probability, %	Minimum total likelihood ratio for probable prodromal PD
50 to 54	“0.4”	“1,000”
55 to 59	“0.75”	“515”
60 to 64	“1.25”	“300”
65 to 69	“2.0”	“180”
70 to 74	“2.5”	“155”
75 to 79	“3.5”	“110”
80 and over	“4.0”	“95”

Likelihood ratios of risk and prodromal markers: 2019 update

“Markers not included previously entered the revised criteria if evidence from 2 prospective studies was now available. The median positive likelihood ratio (LR+) and median negative likelihood ratio (LR−) of all available evidence of a respective marker was used as the revised predictive value.” (opens the source at this quote in a new tab)
“Abnormal dopaminergic PET/SPECT scan (43.3, previously 40.0) and olfactory loss (6.4, previous 4.0) have substantial increases in LR+ relative to their previous value, as new evidence is considered.” (opens the source at this quote in a new tab)
“Modest increases in LR+ are observed for possible RBD (questionnaire-based; LR+ = 2.8, previous = 2.3), constipation (2.5, previous = 2.2), excessive daytime somnolence (2.7, previous = 2.2), symptomatic hypotension (3.2, previous = 2.1), and erectile dysfunction (3.4, previous = 2.0).” (opens the source at this quote in a new tab)
“For risk markers of male sex, regular pesticide and occupational solvent exposure, and nonuse of caffeine, no new prospective evidence has, to our knowledge, been published that would have changed their LRs.” (opens the source at this quote in a new tab)
“Neurogenic OH is LR+ = 18.5, LR− = 0.88; symptomatic OH is LR+ = 3.2, LR− = 0.80.” (opens the source at this quote in a new tab)
“For instance, the cumulative PD risk of a GBA mutation carrier is ~18% at 65 years of age but only 2% in the general population.” (opens the source at this quote in a new tab)
“Using these risk values as estimates of sensitivity and specificity of the marker, the LR+ can be calculated (LR+ = 9).” (opens the source at this quote in a new tab)
“When a sibling or parent of an individual has been diagnosed with PD, an OR of 2–3.5 is estimated” (opens the source at this quote in a new tab)

Marker type	Marker	Positive likelihood ratio	Negative likelihood ratio
Risk marker	Male sex	“1.2 (male)”	“0.8 (female)”
Risk marker	Regular pesticide exposure	“1.5”	Not applicable
Risk marker	Occupational solvent exposure	“1.5”	Not applicable
Risk marker	Nonuse of caffeine	“1.35”	“0.88”
Risk marker	Current smoker	Not applicable	“0.51”
Risk marker	Never smoker	“1.2”	Not applicable
Risk marker	Former smoker	Not applicable	“0.91”
Risk marker	First-degree relative with PD	“2.5”	Not applicable
Risk marker	Known gene mutation with intermediate-strength penetrance	“LR+ dependent on age-related penetrance, see Table 2”	Not applicable
Risk marker	Polygenic risk score	“1.57 (highest quartile of PRS scores)”	“0.45 (lowest quartile)”
Risk marker	Substantia nigra hyperechogenicity	“3.4”	“0.38”
Risk marker	Diabetes mellitus (type II)	“1.5”	“0.97”
Risk marker	Physical inactivity	“1.3”	“0.91”
Risk marker	Low plasma urate levels	“1.8 (in men)”	“0.88 (in men)”
Prodromal marker	Polysomnography-proven RBD	“130”	“0.65”
Prodromal marker	Possible RBD (questionnaire)	“2.8”	“0.89”
Prodromal marker	Dopaminergic PET or SPECT clearly abnormal	“43.3”	“0.66”
Prodromal marker	Subthreshold parkinsonism	“9.6”	“0.55”
Prodromal marker	Abnormal quantitative motor testing	“3.5”	“0.60”
Prodromal marker	Olfactory loss	“6.4”	“0.40”
Prodromal marker	Constipation	“2.5”	“0.82”
Prodromal marker	Excessive daytime somnolence	“2.7”	“0.86”
Prodromal marker	Neurogenic orthostatic hypotension	“18.5”	“0.88”
Prodromal marker	Symptomatic orthostatic hypotension	“3.2”	“0.80”
Prodromal marker	Erectile dysfunction	“3.4 (in men)”	“0.87 (in men)”
Prodromal marker	Urinary dysfunction	“2.0”	“0.90”
Prodromal marker	Depression with or without anxiety	“1.6”	“0.88”
Prodromal marker	Global cognitive deficit	“1.8”	“0.88”

Likelihood ratios of intermediate-strength genetic variants by age: 2019 update

Age group, years	PD risk, noncarriers	PD risk, GBA mutation carriers	GBA positive likelihood ratio	PD risk, LRRK2 mutation carriers	LRRK2 positive likelihood ratio
50 to 54	“0.4%”	“8%”	“20.0”	“~1%”	“2.5”
55 to 59	“0.75%”	“11%”	“14.7”	“3%”	“4.0”
60 to 64	“1.25%”	“14%”	“11.2”	“7%”	“5.6”
65 to 69	“2.0%”	“18%”	“9.0”	“15%”	“7.5”
70 to 74	“2.5%”	“21%”	“8.4”	“29%”	“11.6”
75 to 79	“3.5%”	“25%”	“7.1”	“32%”	“9.1”
80 and over	“4%”	“30%”	“7.5”	“42%”	“10.5”

Limitations of the prodromal research criteria

“One of the most obvious limitations of these criteria is the quality of the underlying data; there are a limited number of prospective studies that have analyzed markers before patients develop PD. Because most studies have relatively few de novo PD patients, confidence intervals are wide.” (opens the source at this quote in a new tab)
“Another critical caveat is that markers cannot be combined if they are not independent.” (opens the source at this quote in a new tab)
“Regardless of these steps, some dependence remains possible, and so some patients determined as >80% likely prodromal PD (i.e., probable) might actually have a lower probability.” (opens the source at this quote in a new tab)

“First, the individual longitudinal studies have variable strengths and limitations” (opens the source at this quote in a new tab)
“yet the criteria largely do not weigh or prioritize evidence based on study characteristics nor do they consider the uncertainties of marker estimates.” (opens the source at this quote in a new tab)
“Thus, marker independence might be violated, and for certain marker constellations, prodromal PD probabilities would be either over- or underestimated.” (opens the source at this quote in a new tab)
“Third, LRs are applied equally to all individuals, but the LR of many single markers likely differs depending on ethnicity” (opens the source at this quote in a new tab)

Biological research frameworks: neuronal alpha-synuclein disease integrated staging system

“Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome.” (opens the source at this quote in a new tab)
“Neuronal α-synuclein disease is defined by the presence of n-αsyn (S) and stage-dependent evidence of dopaminergic neuronal dysfunction (D).” (opens the source at this quote in a new tab)
“Stages 0–1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B–6 require both S and D and stage-specific increases in functional impairment.” (opens the source at this quote in a new tab)
“However, at present, only a CSF α-synuclein seed amplification assay has undergone robust validation.” (opens the source at this quote in a new tab)
“This assay is positive in more than 95% of autopsy-confirmed cases of Parkinson’s disease or dementia with Lewy bodies” (opens the source at this quote in a new tab)
“A quantitative dopamine transporter SPECT biomarker, the specific binding ratio in the lowest putamen adjusted for age and sex, is used to categorise individuals with dopamine transporter deficit (D+) or without dopamine transporter deficit (D–).” (opens the source at this quote in a new tab)
“We have conceptualised functional impairment qualitatively as progressing along the continuum of slight, mild, moderate, and severe, and provide categorical descriptors of this progression (table 1).” (opens the source at this quote in a new tab)
“Although operational definitions of anchors for functional impairment for stages 3–6 are beyond the scope of this Position Paper, they are crucial for future versions of the NSD-ISS.” (opens the source at this quote in a new tab)
“However, MDS-UPDRS has limited sensitivity to detect changes in function in early disease stages and new scales and approaches need to be developed.” (opens the source at this quote in a new tab)
“Among individuals with clinically diagnosed sporadic Parkinson’s disease and with evidence of dopaminergic dysfunction, about 7% do not have n-αsyn, relevant genetic variants, or alternative known biology” (opens the source at this quote in a new tab)
“Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.” (opens the source at this quote in a new tab)

Biological research frameworks: SynNeurGe classification

“Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson’s disease.” (opens the source at this quote in a new tab)
“α-synuclein positivity, detected by use of these assays, has been found in multiple biological samples, with the highest sensitivities in skin and CSF (0·92 [95% CI 0·87–0·95] and 0·90 [0·86–0·93], respectively).” (opens the source at this quote in a new tab)
“The data suggest that only skin biopsies, with specific methods (appendix pp 6–8), provide adequate diagnostic sensitivity and specificity to distinguish between patients with Parkinson’s disease, people with rapid eye movement (REM)-sleep behaviour disorder as a presumed early clinical manifestation of Parkinson’s disease, and healthy controls to be considered useful for a biological classification.” (opens the source at this quote in a new tab)
“In our proposed criteria, evidence of any of the findings listed in table 2 is sufficient to define neurodegeneration in biologically suspected Parkinson’s disease (appendix pp 23–34).” (opens the source at this quote in a new tab)
“However, available methods have inadequate specificity to differentiate between people with Parkinson’s disease and those with other neurodegenerative forms of parkinsonism, and they focus on a limited number of neuroanatomical systems, chiefly the nigrostriatal dopaminergic projection.” (opens the source at this quote in a new tab)
“Reduced striatal uptake (typically asymmetric and with a caudal to rostral pattern) can be detected by use of molecular imaging markers for the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), or aromatic amino acid decarboxylase (F-dopa).” (opens the source at this quote in a new tab)
“Reduced tracer uptake on metaiodobenzylguanidine SPECT provides sufficient evidence of peripheral cardiac sympathetic denervation to define the presence of neurodegeneration in people with Parkinson’s disease.” (opens the source at this quote in a new tab)
“The first category includes the most likley fully penetrant variants: SNCA triplications, SNCA missense variants, and biallelic PRKN, PINK1, and PARK7 missense, nonsense, small indels, and copy number variants.” (opens the source at this quote in a new tab)
“The second category includes the genetic variants that confer a strong predisposition to Parkinson’s disease but with incomplete penetrance, such as SNCA duplications and variants in LRRK2, VPS35, and CHCHD2.” (opens the source at this quote in a new tab)
“The third category includes the genetic variants that result in intermediate and lower predispositions, including pathogenic GBA1 variants” (opens the source at this quote in a new tab)
“Biallelic variants in PRKN predispose to a Parkinson’s type synucleinopathy in approximately 20% of cases.” (opens the source at this quote in a new tab)
“No regulatory agencies, such as the US Food and Drug Administration, have formally approved the methods for defining the presence of pathological α-synuclein that we have endorsed.” (opens the source at this quote in a new tab)
“We emphasise the initial application of these criteria exclusively for research.” (opens the source at this quote in a new tab)

Motor symptoms: bradykinesia, rigidity, and rest tremor

“Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor.” (opens the source at this quote in a new tab)
“History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety).” (opens the source at this quote in a new tab)
“Examination typically demonstrates bradykinesia with tremor, rigidity, or both.” (opens the source at this quote in a new tab)
“Motor symptoms consist of movement and physical tasks: tremor, stiffness, slowness, and imbalance.” (opens the source at this quote in a new tab)
“Approximately 20% of individuals with Parkinson disease do not present with resting tremors.” (opens the source at this quote in a new tab)

Motor symptoms: clinical subtypes and rate of progression

“Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression.” (opens the source at this quote in a new tab)
“Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression.” (opens the source at this quote in a new tab)
“When individuals are categorized this way, the mild motor-predominant form is the most common (49%-53%), followed by the intermediate form (35%-39%).” (opens the source at this quote in a new tab)
“In a clinical-pathologic assessment of the 3 proposed subtypes, the diffuse malignant group had a mean (SD) time from diagnosis to first milestone (regular falls, wheelchair dependence, dementia, or residential/nursing home placement) of 3.5 (3.2) years, compared with 8.2 (5.3) years for the intermediate form and 14.3 (5.7) years for the mild motor-predominant form.” (opens the source at this quote in a new tab)
“Mean (SD) survival after diagnosis was 8.1 (5.4) years for the diffuse malignant group, 13.2 (6.7) years for the intermediate subtype, and 20.2 (7.8) years for the mild motor-predominant form.” (opens the source at this quote in a new tab)

Motor symptoms: postural instability and freezing of gait

“Some 359 patients developed sustained postural instability after baseline with median time to postural instability of 7.4 years (95% confidence interval [95% CI] 6.5–7.6) and 10‐year probability of postural instability was 69.2% (95% CI 63.8–74.5)” (opens the source at this quote in a new tab)

“The point prevalence of FOG at baseline was 27% (95% confidence interval (95%-CI) 22–33%).” (opens the source at this quote in a new tab)
“By study end, 63% (95%-CI 56–69%) of patients had developed FOG.” (opens the source at this quote in a new tab)
“The incidence rate of FOG was 124.2 (95%-CI 101.5–152.1) per 1000 person-years.” (opens the source at this quote in a new tab)
“Point prevalence rates increased during follow-up, reaching a peak after eight years of follow-up, where 75% of patients presented with FOG (Table 2).” (opens the source at this quote in a new tab)
“Of the 169 non-freezers at baseline, 82 (49%) developed incident FOG during follow-up.” (opens the source at this quote in a new tab)
“The incidence rate of FOG was 124 per 1000 person-years of observation, suggesting that more than 10% of patients develop FOG each year.” (opens the source at this quote in a new tab)

Assessment	Participants assessed, n	Freezing of gait, n (%, 95% CI)
Baseline	“232”	“63 (27, 22–33)”
4-year visit	“143”	“79 (55, 47–64)”
8-year visit	“89”	“67 (75, 65–84)”
9-year visit	“67”	“38 (57, 44–69)”
10-year visit	“47”	“27 (57, 42–72)”
11-year visit	“33”	“12 (36, 20–55)”
12-year visit	“19”	“12 (63, 38–84)”
12-year period prevalence	“232”	“145 (63, 56–69)”

Freezing of gait: motor fluctuations and levodopa dose as risk factors

“Thus, 232 patients whose PD diagnosis remained unchanged were eligible for this long-term study of FOG in PD.” (opens the source at this quote in a new tab)
“Mean (SD) age at motor onset was 64.9 (9.9) years and mean age at baseline was 73.5 (8.4) years.” (opens the source at this quote in a new tab)
“The majority of patients (75%) had mild to moderate disease (HY stage ≤3) at study entry.” (opens the source at this quote in a new tab)
“We found that higher doses of levodopa, but not dopamine agonists, at baseline were a significant predictor of new-onset FOG during follow-up in a dose-dependent fashion.” (opens the source at this quote in a new tab)
“For a 100 mg increase in levodopa dose at baseline, the risk of incident FOG during the 12-year study period increased with 30%.” (opens the source at this quote in a new tab)
“We found that non-freezers who presented with motor fluctuations at study entry were at more than 3-fold increased risk to develop incident FOG during the 12-year follow-up period as compared with patients without motor fluctuations at baseline.” (opens the source at this quote in a new tab)
“This finding also implies that motor fluctuations not only co-exist but may precede the onset of FOG in PD.” (opens the source at this quote in a new tab)
“In contrast, dyskinesias at baseline were associated with a statistically non-significant but still more than 60% reduced risk of incident FOG during follow-up.” (opens the source at this quote in a new tab)
“Finally, FOG was assessed by history using a single item derived from the UPDRS.” (opens the source at this quote in a new tab)

Baseline variable (participants without freezing of gait at baseline)	Odds ratio for incident freezing of gait (95% CI)	p-value
Age at onset, per 10 years increase	“1.33 (0.89–2.00)”	“0.161”
Disease duration, per 10 years increase	“1.07 (0.41–2.78)”	“0.888”
Female sex	“0.95 (0.52–1.74)”	“0.872”
UPDRS motor score, per 10 points increase	“1.32 (0.94–1.86)”	“0.115”
Psychosis	“5.97 (0.71–49.93)”	“0.099”
MMSE, per 5 points increase	“1.13 (0.80–1.61)”	“0.486”
Levodopa dose (levodopa-equivalent), per 100 mg increase	“1.30 (1.07–1.58)”	“0.009”
Dopamine agonist dose (levodopa-equivalent), per 100 mg increase	“1.13 (0.76–1.68)”	“0.558”
Dyskinesias	“0.39 (0.15–1.05)”	“0.062”
Motor fluctuations	“3.45 (1.08–11.02)”	“0.036”
Follow-up time, per year increase	“1.11 (1.02–1.22)”	“0.023”

Freezing of gait: clinical features associated with freezing of gait during 12 years of follow-up

Variable at each visit (all participants)	Odds ratio for freezing of gait (95% CI)	p-value
Age at onset, per 10 years increase	“1.32 (1.00–1.75)”	“0.052”
Disease duration, per 10 years increase	“1.38 (0.88–2.18)”	“0.158”
Female sex	“0.74 (0.49–1.13)”	“0.166”
UPDRS motor score, per 10 points increase	“1.46 (1.25–1.71)”	“<0.001”
Psychosis	“1.85 (1.12–3.05)”	“0.016”
MMSE, per 5 points increase	“0.94 (0.78–1.13)”	“0.521”
Levodopa dose (levodopa-equivalent), per 100 mg increase	“1.12 (1.03–1.21)”	“0.006”
Dopamine agonist dose (levodopa-equivalent), per 100 mg increase	“1.16 (0.87–1.55)”	“0.303”
Dyskinesias	“1.88 (1.14–3.09)”	“0.013”
Motor fluctuations	“1.68 (1.05–2.68)”	“0.030”

“Supplemental analysis in which the UPDRS motor score was replaced by subscores for tremor, rigidity, bradykinesia and PIGD, revealed that FOG was positively associated with PIGD severity (OR 6.30 per 10 points, p < 0.001).” (opens the source at this quote in a new tab)
“Other cardinal features were not associated with FOG over time.” (opens the source at this quote in a new tab)
“In line with this, we found that severity of PIGD symptoms and psychotic symptoms, features thought to relate to extrastriatal pathology, were independently associated with FOG during the 12-year study period.” (opens the source at this quote in a new tab)

Motor fluctuations: cumulative incidence in a population-based incident cohort

“Cumulative incidence of motor fluctuations and levodopa‐induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years.” (opens the source at this quote in a new tab)
“Eighty‐three patients developed MF, with a cumulative incidence of 54.3% and 100% at 5 and 10 years, respectively.” (opens the source at this quote in a new tab)
“Median time to MF was 4.7 years (Fig. 1).” (opens the source at this quote in a new tab)
“Early levodopa use did not predict motor complications.” (opens the source at this quote in a new tab)

“The 5-year cumulative incidence of any motor complications was 52.4%, with a corresponding incidence rate of 158 (95% CI 132–189) per 1000 person-years of observation.” (opens the source at this quote in a new tab)
“Motor fluctuations occurred in 42.9% and dyskinesias in 24.3%.” (opens the source at this quote in a new tab)
“For dyskinesias, the 5-year cumulative incidence was 24.3%, with a corresponding incidence rate of 59 (45–78) per 1000 person-years.” (opens the source at this quote in a new tab)

Motor complications: point prevalence and cumulative incidence by year of follow-up in drug-naive participants

“Of 212 patients included in the original cohort, five were not drug-naïve at baseline and further 18 rediagnosed during follow-up, leaving 189 patients eligible for this study.” (opens the source at this quote in a new tab)
“Point prevalence rates increased progressively, reaching 38.0% for any motor complications, 31.0% for motor fluctuations, and 12.7% for dyskinesias at 5 years of follow-up (Table 2).” (opens the source at this quote in a new tab)
“14.8% of the total population and 28.3% of those with motor complications experienced both motor fluctuations and dyskinesias.” (opens the source at this quote in a new tab)

Measure	1 year	2 years	3 years	4 years	5 years
Any motor complications: point prevalence, %	“10.9”	“13.6”	“22.8”	“23.2”	“38.0”
Any motor complications: cumulative incidence, %	“14.3”	“24.3”	“32.8”	“40.7”	“52.4”
Motor fluctuations: point prevalence, %	“7.7”	“10.2”	“18.1”	“17.1”	“31.0”
Motor fluctuations: cumulative incidence, %	“10.6”	“19.0”	“26.5”	“33.9”	“42.9”
Dyskinesias: point prevalence, %	“3.8”	“4.5”	“5.2”	“9.8”	“12.7”
Dyskinesias: cumulative incidence, %	“6.3”	“9.5”	“12.7”	“18.0”	“24.3”
Concomitant dyskinesias and motor fluctuations: point prevalence, %	“0.5”	“1.1”	“0.5”	“3.7”	“5.7”
Concomitant dyskinesias and motor fluctuations: cumulative incidence, %	“2.6”	“4.2”	“6.3”	“11.1”	“14.8”
Levodopa use, %	“41.5”	“56.8”	“67.1”	“78.7”	“84.2”
Dopamine agonist use, %	“44.8”	“47.7”	“48.6”	“53.7”	“53.8”
Other dopaminergic medications, %	“23.5”	“30.7”	“33.5”	“29.9”	“32.9”
Total levodopa equivalent dose (SD)	“252 (169)”	“333 (161)”	“424 (224)”	“514 (250)”	“587 (334)”

Motor complications: baseline risk factors and levodopa dose in drug-naive participants

“We found that lower age but not gender was a strong and independent predictor of motor fluctuations, with a nearly 6-fold increased risk in patients younger than 60 years compared to those aged 80 or older.” (opens the source at this quote in a new tab)
“For example, the cumulative 5-year incidence of motor fluctuations in patients aged >80 was 11% while it was 41% for patients aged 60–79 and 64% for patients below 60 years at baseline (Fig. 2a).” (opens the source at this quote in a new tab)
“In contrast, gender was the most important independent predictor of dyskinesias, with an almost 3-fold increased risk in females.” (opens the source at this quote in a new tab)
“We found that more severe parkinsonism at diagnosis (in the drug-naïve state) independently predicted early development of motor fluctuations and dyskinesias, suggesting that dopamine depletion is a principal underlying cause of both of these motor complications.” (opens the source at this quote in a new tab)
“A subgroup of patients (36/189) never used levodopa.” (opens the source at this quote in a new tab)
“Among these, only 5 (13.9%) experienced motor fluctuations, and 4 (11.1%) had dyskinesias.” (opens the source at this quote in a new tab)
“The corresponding rates in levodopa-treated patients were 49.7% and 27.5%, respectively.” (opens the source at this quote in a new tab)
“This implies that actual levodopa dose rather than initial treatment with levodopa is crucial for the development of motor complications.” (opens the source at this quote in a new tab)
“Overall, these data indicate that levodopa treatment in low doses should not be withheld in patients with early PD.” (opens the source at this quote in a new tab)

Outcome and factor (Cox regression)	Hazard ratio	95% CI	p-value
Any motor complications: age at diagnosis, per year	“0.97”	“0.95–0.99”	“p = 0.013”
Any motor complications: female gender	“1.84”	“1.23–2.77”	“p = 0.003”
Any motor complications: baseline UPDRS motor score, per unit	“1.04”	“1.01–1.06”	“p = 0.001”
Any motor complications: time since motor onset, per year	“0.97”	“0.86–1.09”	“p = 0.593”
Motor fluctuations: age, per year	“0.96”	“0.94–0.98”	“p = 0.001”
Motor fluctuations: baseline UPDRS motor score, per unit	“1.03”	“1.01–1.05”	“p = 0.016”
Motor fluctuations: female vs. male gender	“1.48”	“0.94–2.33”	“p = 0.087”
Motor fluctuations: time since motor onset, per year	“1.03”	“0.91–1.16”	“p = 0.675”
Dyskinesias: female gender	“2.73”	“1.49–4.98”	“p = 0.001”
Dyskinesias: baseline UPDRS motor score, per unit	“1.05”	“1.02–1.08”	“p = 0.001”
Dyskinesias: age, per year	“0.98”	“0.95–1.02”	“p = 0.262”
Dyskinesias: time since motor onset, per year	“0.91”	“0.75–1.10”	“p = 0.332”
Dyskinesias, model adding body weight: female gender	“2.34”	“1.21–4.53”	“p = 0.011”
Dyskinesias, model adding body weight: body weight, per kg	“0.99”	“0.96–1.01”	“p = 0.239”
Motor fluctuations: initial levodopa vs. initial dopamine agonist	“1.84”	“1.09–3.10”	“p = 0.023”
Dyskinesias: initial levodopa vs. initial dopamine agonist	“0.88”	“0.42–1.85”	“p = 0.744”
Motor fluctuations, model adding levodopa dose at onset: initial levodopa vs. initial dopamine agonist	“1.37”	“0.87–2.87”	“p = 0.137”
Motor fluctuations, model adding levodopa dose at onset: levodopa dose, per 100 mg	“1.13”	“1.01–1.26”	“p = 0.037”
Dyskinesias, model adding levodopa dose at onset: levodopa dose, per 100 mg	“1.28”	“1.16–1.42”	“p < 0.001”

Motor complications: severity and reversal on oral therapy within 5 years of diagnosis

“Motor fluctuations were predictable in the majority of patients, with no more than 5.1% experiencing unpredictable or sudden off periods, respectively, during follow-up.” (opens the source at this quote in a new tab)
“Few patients (≤5.1%) spent larger proportions (>25%) of their day in off.” (opens the source at this quote in a new tab)
“Similarly, few patients (≤3.8%) experienced dyskinesias larger proportions of their day and very few rated their dyskinesias as severe (≤0.6%) or painful (≤1.8%) within the first 5 years of diagnosis.” (opens the source at this quote in a new tab)
“Of 78 patients who had experienced motor fluctuations during follow-up, 29 did not so at study end, indicating reversal in 37%.” (opens the source at this quote in a new tab)
“Patients with persistent motor fluctuations were younger than those in whom motor fluctuations reversed on oral treatment (62.3 (SD 9.1) vs. 68.8 (SD 6.9) years, p = 0.001), but did not differ in gender, baseline motor severity, or LED at final visit (all p > 0.05).” (opens the source at this quote in a new tab)
“Nineteen of the 39 had no dyskinesias at final visit, indicating reversal in 49%.” (opens the source at this quote in a new tab)
“Patients whose dyskinesias reversed did not differ from those with persistent dyskinesias in terms of age, gender, baseline motor severity or LED at final visit (all p > 0.05).” (opens the source at this quote in a new tab)
“No patients were considered in need of advanced, device-aided therapies by their study neurologists during follow-up.” (opens the source at this quote in a new tab)
“A further caveat of our observation of substantial reversal is that follow-up was limited to the first 5 years of the disease, which may be regarded a relative limitation of our study given the slowly progressive nature of the disease.” (opens the source at this quote in a new tab)

Motor fluctuations: frequency by duration of levodopa therapy

“Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4–6 years of treatment.” (opens the source at this quote in a new tab)
“Long-term treatment beyond 9 years was associated with a substantially higher median fluctuation frequency of approximately 70%.” (opens the source at this quote in a new tab)

Motor complications: frequency and risk factors with chronic levodopa exposure

“Chronic exposure to l‑DOPA is associated with the development of motor complications in ~30% of patients with Parkinson disease after 2–3 years of exposure and >50% after >5 years. Major risk factors are high l‑DOPA dose, longer disease duration and younger age.” (opens the source at this quote in a new tab)

Motor fluctuations: OFF episodes

“As a patient's disease progresses, OFF episodes emerge due to a shorter duration of response to levodopa treatment.” (opens the source at this quote in a new tab)
“OFF episodes include both motor and nonmotor symptoms, are common, and can occur at any time.” (opens the source at this quote in a new tab)
“OFF episodes can be predictable or unpredictable, significantly impact patient quality of life and functionality, and place a burden on families.” (opens the source at this quote in a new tab)

Motor complications: onset of OFF periods and frequency and severity of dyskinesia

“Off periods improve with the next medication dose (Figure 3) and they can occur within 2 years of starting levodopa, but their prevalence increases over time.” (opens the source at this quote in a new tab)
“Off periods are associated with functional disability and can include motor and nonmotor symptoms.” (opens the source at this quote in a new tab)
“An estimated 40% of individuals with Parkinson disease experience dyskinesias after 4 to 6 years of levodopa treatment, typically at times of high levodopa concentrations (Figure 3).” (opens the source at this quote in a new tab)
“Dyskinesia onset is associated with longer duration of Parkinson disease and higher levodopa doses rather than the length of time a patient has taken levodopa.” (opens the source at this quote in a new tab)
“Although dyskinesia is severe in only 3% of individuals with Parkinson disease treated with levodopa (11% of individuals with dyskinesia), the presence of dyskinesia prompts medication changes in more than 60% of individuals with this feature” (opens the source at this quote in a new tab)

Motor fluctuations: early-morning OFF periods and associated non-motor symptoms

“We report data from a consecutive series of 320 patients with a mean age of 70.0 years (range: 42–90 years) and a mean disease duration of 7.0 years (range: 0–24 years).” (opens the source at this quote in a new tab)
“The results demonstrate that EMO periods are common and occur in 59.7% of subjects across all disease stages in line with other reports.” (opens the source at this quote in a new tab)
“However, importantly, in 88.0% of those, EMOs were found to be associated with NMS.” (opens the source at this quote in a new tab)
“with a mean disease duration of 8.0 years (range: 0–24) and a median H&Y stage of 3.0 (range: 1.0–5.0)” (opens the source at this quote in a new tab)
“129 patients (40.3%), mean age 70.7 years (range: 42–90), mean disease duration of 5.5 years (range: 0–20) and a median H&Y stage of 2.5 (range: 1.0–5.0) reported no EMO.” (opens the source at this quote in a new tab)
“The predominant NMS associated with EMO were urinary urgency, anxiety, dribbling of saliva, pain, low mood, limb paresthesia and dizziness.” (opens the source at this quote in a new tab)
“The most common NMS during EMO included urinary urgency (61.3% of all EMO positive cases), anxiety (49.7%), dribbling of saliva (46.6%), pain (46.6%), low mood (45.5%) or paresthesia (42.6%)” (opens the source at this quote in a new tab)
“In some patients these NMS were exclusive to the morning and did not reoccur throughout the day (pain in 23.4%, urgency in 23.3%, anxiety in 20.6%, dribbling of saliva in 18.6%).” (opens the source at this quote in a new tab)
“We found that the clinical characteristics of the EMO positive and the EMO negative group match quite closely in terms of age, but differ slightly in H&Y and noticeably in duration of disease, both being higher in the EMO positive group.” (opens the source at this quote in a new tab)
“This suggests that EMO is more likely to occur with advanced motor disease.” (opens the source at this quote in a new tab)
“An important issue was that prior to this study these NMS were never discussed by patients with any healthcare professionals although they were intrusive and have an adverse effect on QoL” (opens the source at this quote in a new tab)
“The definition of EMO and NMS were arbitrary and NMS were recorded in a retrospective fashion based on the recollection of patients.” (opens the source at this quote in a new tab)

Dyskinesia: cumulative incidence of levodopa-induced dyskinesia

“LID developed in 39 patients, with a cumulative incidence of 14.5% and 55.7% at 5 and 10 years, respectively.” (opens the source at this quote in a new tab)
“Median time to LID was 8.7 years (Fig. 1).” (opens the source at this quote in a new tab)
“Higher baseline UPDRS‐total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini‐mental State Examination and GBA mutations predicted levodopa‐induced dyskinesias.” (opens the source at this quote in a new tab)

“The median dyskinesia frequency was slightly less than 40% by 4–6 years of levodopa therapy among modern era patients.” (opens the source at this quote in a new tab)
“The available data, however, suggest that dyskinesias eventually develop in almost all patients, close to 90% in the series cited above.” (opens the source at this quote in a new tab)

Non-motor symptoms: overall prevalence and most frequent symptoms

“We found that 98.6% of patients with PD reported the presence of NMSs.” (opens the source at this quote in a new tab)
“The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%).” (opens the source at this quote in a new tab)
“Mean (SD) number of NMS per patient was 7.8 (4.9), ranging from 0 to 32.” (opens the source at this quote in a new tab)
“Frequency of NMS increased along with the disease duration and severity.” (opens the source at this quote in a new tab)
“We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson’s disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients’ quality of life (QoL).” (opens the source at this quote in a new tab)
“There were 647 (60.4%) males with a mean age of 66.8 (SD, 9.6) years, and 425 (39.6%) females with a mean age of 68.2 (SD, 9.1) years.” (opens the source at this quote in a new tab)
“Dopaminergic treatment was as follows: levodopa (N = 189 patients, 17.6%), dopamine agonists (N = 199 patients, 18.6%), or both (N = 577 patients, 53.8%).” (opens the source at this quote in a new tab)
“NMS in the psychiatric domain were the most frequent (67%).” (opens the source at this quote in a new tab)
“Pain, fatigue, and psychiatric NMSd were significantly more prevalent in women, namely 67.5, 65.9, and 73.9%, respectively, versus 56.6, 53.0, and 62.1% in men (Chi-square test, P < 0.0042, with Bonferroni’s correction).” (opens the source at this quote in a new tab)
“Eleven percent (N = 119) of patients with PD had MMSE score lower than 23.8.” (opens the source at this quote in a new tab)
“Cognitive impairment (MMSE ≤ 23.8) was associated with greater frequency of apathy, attention/memory, fatigue, psychiatric, and respiratory features (Fisher exact Test; P < 0.0001).” (opens the source at this quote in a new tab)
“When patients were asked about NMS at PD onset, joint/muscular pain (298; 27.8%), anxiety (272; 25.4%), fatigue (252; 23.5%), and depression (240; 22.4%) were the most frequently recalled.” (opens the source at this quote in a new tab)
“In particular, psychiatric NMS, mainly anxiety and depression, were reported by 61.1% of patients at HY stage 1, representing the most common NMS in early disease” (opens the source at this quote in a new tab)
“We acknowledge that our study has two major limitations: (1) lack of normal controls to assess differences with PD, (2) recruitment of patients mainly in early stages of disease, as revealed by the low mean score of the UPDRS-part III scale (mean = 24.2), the low median stage of the Hoehn and Yahr scale (2), and the relative short mean disease duration (5.1 years).” (opens the source at this quote in a new tab)

Non-motor symptoms: prevalence by domain and Hoehn and Yahr stage

Non-motor symptom domain	All stages (N = 1,072), n (%)	Hoehn and Yahr 1 (N = 167), n (%)	Hoehn and Yahr 1.5 to 2 (N = 515), n (%)	Hoehn and Yahr 2.5 to 3 (N = 325), n (%)	Hoehn and Yahr 4 to 5 (N = 49), n (%)
Gastrointestinal	“654 (61.0)”	“76 (45.5)”	“280 (54.4)”	“250 (76.9)”	“36 (73.5)”
Pain	“653 (60.9)”	“85 (50.9)”	“302 (58.6)”	“218 (67.1)”	“39 (79.6)”
Urinary	“614 (57.3)”	“72 (43.1)”	“266 (51.7)”	“222 (68.3)”	“44 (89.8)”
Cardiovascular	“158 (14.7)”	“22 (13.2)”	“70 (13.6)”	“53 (16.3)”	“11 (22.5)”
Sleep	“687 (64.1)”	“80 (47.9)”	“312 (60.6)”	“245 (75.4)”	“40 (81.6)”
Fatigue	“623 (58.1)”	“63 (37.7)”	“291 (56.5)”	“224 (68.9)”	“40 (81.6)”
Apathy	“328 (30.6)”	“41 (24.6)”	“138 (26.8)”	“119 (36.6)”	“24 (49.0)”
Attention/memory	“479 (44.7)”	“63 (37.7)”	“208 (40.4)”	“168 (51.7)”	“32 (65.3)”
Skin	“260 (24.3)”	“24 (14.4)”	“102 (19.8)”	“112 (34.5)”	“16 (32.7)”
Psychiatric	“716 (66.8)”	“102 (61.1)”	“326 (63.3)”	“238 (73.2)”	“41 (83.7)”
Respiratory	“191 (17.8)”	“16 (9.6)”	“80 (15.5)”	“74 (22.8)”	“15 (30.6)”
Miscellaneous	“515 (48.0)”	“62 (37.1)”	“247 (48.0)”	“168 (51.7)”	“29 (59.2)”

“Cochran-Armitage trend test <0.0045 (with Bonferroni’s correction) for all NMS except cardiovascular symptoms (P = 0.0774).” (opens the source at this quote in a new tab)
“Disease duration (mean ± SD) was significantly longer (T test; P < 0.0042, with Bonferroni’s correction) in patients with NMS than in patients without NMS related to the domains: skin disorders (7.4 ± 5.6 vs. 6.1 ± 4.8 years), urinary symptoms (7.1 ± 5.4 vs. 5.5 ± 4.2 years), fatigue (7.0 ± 5.3 vs. 5.7 ± 4.5 years), gastrointestinal (7.0 ± 5.3 vs. 5.6 ± 4.5 years), and sleep disturbances (7.0 ± 5 vs. 5.4 ± 4.6 years).” (opens the source at this quote in a new tab)
“With the exception of cardiovascular and miscellaneous domains, UPDRS motor score was higher in patients with NMSs (T test; P < 0.0001).” (opens the source at this quote in a new tab)
“it was 8 points higher for fatigue (mean UPDRS score 27.5 ± 13.6 vs. 19.6 ± 11.0), 6.5 points higher for apathy (28.7 ± 14.9 vs. 22.2 ± 11.8), and 6.4 points higher for attention/memory problems (27.7 ± 13.9 vs. 21.3 ± 11.8) and gastrointestinal symptoms (26.6 ± 13.8 vs. 20.3 ± 10.9).” (opens the source at this quote in a new tab)

Non-motor symptoms: prodromal onset and under-reporting

“Individuals diagnosed with Parkinson disease typically have gradual development of nonmotor symptoms for years before movement symptoms begin, but often they will not mention these symptoms unless specifically queried.” (opens the source at this quote in a new tab)
“These prodromal nonmotor features include rapid eye movement sleep behavior disorder, loss of smell, constipation, urinary dysfunction, orthostatic hypotension, excessive daytime sleepiness, and depression.” (opens the source at this quote in a new tab)
“Patients may not proactively volunteer nonmotor symptoms because they are embarrassed, appointment time is focused on motor symptoms, or they are unaware that the symptoms could be Parkinson disease related.” (opens the source at this quote in a new tab)

Non-motor symptoms: frequency by domain and change with disease progression

“Select nonmotor symptoms (hyposmia, rapid eye movement sleep behavior disorder, depression, constipation) start in prodromal Parkinson disease, but the nonmotor symptom burden increases as Parkinson disease progresses.” (opens the source at this quote in a new tab)
“Sensory symptoms include hyposmia (occurring in >90% of individuals with Parkinson disease), visual disturbances (22%-78%), and somatosensory dysfunction and pain (30%-85%).” (opens the source at this quote in a new tab)
“Autonomic symptoms include constipation, orthostatic hypotension, and urinary dysfunction (eg, nocturia, urgency, frequency), all increasing in frequency with disease progression.” (opens the source at this quote in a new tab)
“Neuropsychiatric symptoms include anxiety (60%), apathy (60%), and depression (35%).” (opens the source at this quote in a new tab)
“Psychosis occurs in approximately 40% of individuals with Parkinson disease, usually in later stages.” (opens the source at this quote in a new tab)
“An estimated 30% to 50% of individuals with Parkinson disease have rapid eye movement sleep behavior disorder.” (opens the source at this quote in a new tab)

Cognitive symptoms: mild cognitive impairment

“A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI.” (opens the source at this quote in a new tab)
“Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9).” (opens the source at this quote in a new tab)

Psychiatric symptoms: depression

“In the remaining 36 articles, the weighted prevalence of major depressive disorder was 17% of PD patients, that of minor depression 22% and dysthymia 13%.” (opens the source at this quote in a new tab)
“Clinically significant depressive symptoms, irrespective of the presence of a DSM defined depressive disorder, were present in 35%.” (opens the source at this quote in a new tab)

Psychiatric symptoms: depression prevalence by study setting and diagnostic method

Setting	Major depressive disorder: number of studies	Major depressive disorder: prevalence (%)	Clinically relevant depressive symptoms: number of studies	Clinically relevant depressive symptoms: prevalence (%)
General population	“4”	“8.1”	“5”	“10.8”
General practice	“0”	Not applicable	“2”	“42.3”
Outpatient setting	“11”	“24.0”	“25”	“40.4”
Inpatient setting	“1”	“21.7”	“3”	“54.3”
Nursing home	“0”	Not applicable	“1”	“32.7”

“For major depressive disorder, population studies report significantly lower prevalences than studies in outpatient samples” (opens the source at this quote in a new tab)
“Studies in hospital inpatient settings report significantly higher prevalences than studies in the population, general practices, outpatient settings, and nursing homes” (opens the source at this quote in a new tab)
“The reported prevalence of major depressive disorder in studies using a (semi) structured interview to establish DSM criteria ranges from 2.3% to 55.6% with a weighted mean of 19%.” (opens the source at this quote in a new tab)
“In studies using DSM criteria without a structured interview the prevalence rates of major depressive disorder ranges from 2.9% to 7.7% with a weighted mean of 7%.” (opens the source at this quote in a new tab)
“Clinically significant depressive symptoms were present in 2.7% to 57.8% with a weighted mean of 33% in studies using a (semi) structured interview, 7.3% to 47% with a weighted mean of 27% in studies using DSM criteria, and in 13% to 89% with a weighted mean of 42% in studies using a cut-off on a depression rating scale.” (opens the source at this quote in a new tab)
“Especially the fact that PD patients may be effectively treated with an antidepressant for their depressive disorder, and hence not be recognized as having suffered from depression, may lead to under-reporting in this review.” (opens the source at this quote in a new tab)

Psychiatric symptoms: anxiety

“The average point prevalence of anxiety disorders in PD was 31%, with nonepisodic anxiety being more prevalent than episodic anxiety.” (opens the source at this quote in a new tab)
“Based on anxiety rating scale cutoff scores, clinically significant anxiety symptoms were present in a weighted average of 25.7%.” (opens the source at this quote in a new tab)
“A total of 39 studies were in outpatient settings, often in movement disorder clinics, and 5 were population based.” (opens the source at this quote in a new tab)
“Of the 49 studies included in the qualitative synthesis, 45 met the cut-off score of 14 points on the QUADAS tool (92%).” (opens the source at this quote in a new tab)
“This is a substantial percentage that exceeds the average point prevalence of depressive disorders in PD (17%).” (opens the source at this quote in a new tab)
“A large community survey from the World Health Organization found a 12-month prevalence of 8.3% of any anxiety disorder.” (opens the source at this quote in a new tab)
“In addition, an extensive review of epidemiological surveys on anxiety disorders in the general population found a 12-month prevalence of panic disorder, with a range of 0.7% to 3.1%, GAD 0.2% to 4.3%, and social phobia 0.6% to 7.9%.” (opens the source at this quote in a new tab)
“Most of the studies were conducted at specialized movement disorder clinics where they may encounter more complex patients with a higher prevalence of anxiety disorders.” (opens the source at this quote in a new tab)
“However, studies have indicated that still more than half of clinically significant anxiety cases are not recognized by clinicians, and therefore anxiety is undertreated both in PD and in the general elderly population.” (opens the source at this quote in a new tab)

Psychiatric symptoms: anxiety disorder prevalence by DSM subtype

Anxiety disorder	Number of studies	Total participants with Parkinson's disease	Range, %	Weighted prevalence, %
Any anxiety disorder	“13”	“2399”	“24.5–46.7”	“31.0”
Generalized anxiety disorder	“14”	“2080”	“2.6–52.5”	“14.1”
Panic disorder	“13”	“2040”	“2.3–30.0”	“6.8”
Agoraphobia	“7”	“1684”	“1.6–15.5”	“8.6”
Social phobia	“11”	“1823”	“6.8–50.0”	“13.8”
Other phobia	“4”	“705”	“2.4–16.7”	“13.0”
Obsessive-compulsive disorder	“9”	“1270”	“0.3–13.3”	“2.6”
Anxiety not otherwise specified	“4”	“766”	“2.4–22.0”	“13.3”
Two or more comorbid anxiety disorders, among participants diagnosed with anxiety	“4”	“1337”	“23.7–37.0”	“31.1”
Clinically relevant anxiety symptoms by rating scale cutoff	“27”	“7212”	“6.9–55.0”	“25.7”

Psychiatric symptoms: psychosis

“By study's end, 137 patients (60%) had developed hallucinations or delusions.” (opens the source at this quote in a new tab)
“The incidence rate of PDP was 79.7 per 1000 person-years.” (opens the source at this quote in a new tab)
“Higher age at onset, higher baseline levodopa-equivalent doses, probable rapid eye movement (REM) sleep behavior disorder at baseline, and follow-up time were independent risk factors of incident PDP.” (opens the source at this quote in a new tab)

Psychiatric symptoms: impulse control disorders

“An ICD was identified in 13.6% of patients (gambling in 5.0%, compulsive sexual behavior in 3.5%, compulsive buying in 5.7%, and binge-eating disorder in 4.3%), and 3.9% had 2 or more ICDs.” (opens the source at this quote in a new tab)
“Impulse control disorders were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08-3.54; P < .001).” (opens the source at this quote in a new tab)

Autonomic symptoms: orthostatic hypotension

“The combined prevalence of orthostatic hypotension (OH) was 33% (95%CI, 28–37%), with high heterogeneity among studies (I2 = 96%).” (opens the source at this quote in a new tab)
“Based on 10 studies, the pooled prevalence of symptomatic orthostatic hypotension was 20% (95% CI: 13–29%; I2 = 90%).” (opens the source at this quote in a new tab)

Autonomic symptoms: constipation in established and prodromal Parkinson's disease

“The prevalence of constipation in patients with established PD ranges from 50 to 80%” (opens the source at this quote in a new tab)
“Seventeen studies comprising 3,024,193 participants (case-control = 1,636,831; cohort = 1,387,362) were eligible for inclusion.” (opens the source at this quote in a new tab)
“The pooled OR for the association between constipation and PD was 2.36 (95% confidence interval: 1.93–2.88), although strong heterogeneity was observed (I2 = 90%, p < 0.01).” (opens the source at this quote in a new tab)
“The pooled prevalence of constipation in the prodromal PD group was 20% (95% CI: 0.09–0.34), while that in the control group was 11% (95% CI: 0.04–0.20)” (opens the source at this quote in a new tab)

Autonomic symptoms: constipation and Parkinson's disease risk by study subgroup

Subgroup	Number of studies	Pooled estimate (95% CI)	I2 (%)
Study design: case-control	“11”	“2.21 [1.72–2.83]”	“86”
Study design: cohort	“6”	“2.57 [2.17–3.05]”	“48”
Location: United States	“5”	“2.78 [1.57–4.92]”	“92”
Location: Europe	“6”	“2.10 [1.44–3.06]”	“68”
Location: China	“3”	“2.24 [2.03–2.49]”	“0.0”
Location: other	“3”	“2.75 [1.14–6.63]”	“85”
Prodromal duration: 10 years or more	“11”	“2.06 [1.61–2.63]”	“87”
Prodromal duration: 5 to 10 years	“3”	“2.43 [1.97–3.00]”	“54”
Prodromal duration: 5 years or less	“3”	“5.00 [3.59–6.97]”	“0.0”
Diagnosis of constipation: frequency of bowel movement	“5”	“3.60 [2.24–5.78]”	“81”
Diagnosis of constipation: medical record	“7”	“2.20 [1.77–2.74]”	“68”
Diagnosis of constipation: other	“5”	“1.80 [1.36–2.38]”	“78”

“Taken together, these results suggest that differences in disease duration are another major source of heterogeneity in studies of constipation and PD risk.” (opens the source at this quote in a new tab)
“The variety of definitions for constipation in different countries and territories may have affected our results.” (opens the source at this quote in a new tab)

Bulbar symptoms: oropharyngeal dysphagia

“The 10 studies with subjective outcomes were statistically heterogeneous (p < 0.001), with prevalence rates ranging from 16% to 55%, giving a pooled prevalence estimate with random effect analysis of 35% (95% CI 28–41).” (opens the source at this quote in a new tab)
“The four studies with objective measurements were statistically homogeneous (p = 0.23), with prevalence rates between 72% and 87%, giving a pooled prevalence estimate of 82% (95% CI 77–87).” (opens the source at this quote in a new tab)
“In controls the pooled subjective prevalence was 9% (95% CI 2–17), while the pooled objective prevalence was 23% (95% CI 13–32).” (opens the source at this quote in a new tab)
“The pooled relative risk was 3.2 for both subjective outcomes (95% CI 2.32–4.41) and objective outcomes (95% CI 2.08–4.98).” (opens the source at this quote in a new tab)
“All studies used in our analysis dealt with community-dwelling patients with idiopathic PD.” (opens the source at this quote in a new tab)
“Overall, PD patients are three times more likely to have swallowing disorders than healthy controls.” (opens the source at this quote in a new tab)
“We even included two studies that reported both subjective and objective judgments within the same patient population; both studies identified much higher prevalence rates for objective ratings compared to subjective ratings (30% vs. 72% in one study; and 37% vs. 84% in the other study)” (opens the source at this quote in a new tab)
“Overall, there was a significant correlation between subjective dysphagia and disease severity according to five studies” (opens the source at this quote in a new tab)
“For example, when focusing on the three largest studies (>400 patients), the study with the lowest dysphagia prevalence included only 5% of patients with late stage PD (Hoehn & Yahr stage 4 or 5)” (opens the source at this quote in a new tab)
“whereas the study with the highest dysphagia prevalence (55%) included 20% of patients with late stage PD” (opens the source at this quote in a new tab)
“This is further corroborated by one study which included only late stage PD patients (which we excluded from the meta-analysis), where subjective dysphagia was reported to be present in no less than 68% of patients” (opens the source at this quote in a new tab)
“This implies that the prevalence is likely to be higher for the total population, including hospitalized and institutionlized PD patients.” (opens the source at this quote in a new tab)
“Although esophageal dysphagia has been reported to be present in 60–70% of PD patients” (opens the source at this quote in a new tab)
“While most questionnaires included in this review investigated oropharyngeal complaints, others (e.g. SCOPA-AUT and PD NMSQuest) did not differentiate between oropharyngeal and esophageal dysphagia, so the possibility that esophageal complaints have contributed to dysphagia in some PD patients cannot be excluded.” (opens the source at this quote in a new tab)

Sleep symptoms: REM sleep behavior disorder

“A total of 28 studies with 6869 PD cases were deemed eligible and included in our meta-analysis based on the inclusion and exclusion criteria.” (opens the source at this quote in a new tab)
“The RBD prevalence rate ranged from 19 to 70 % with an estimated random-effects pooled prevalence of 42.3 % (95 % CI 37.4–47.1 %) as shown in Fig. 2.” (opens the source at this quote in a new tab)
“Besides, the shape of funnel plot for our meta-analysis seemed symmetrical, and Begg’s test (z = 1.15, P = 0.252) indicated no statistical evidence of publication bias among studies.” (opens the source at this quote in a new tab)
“And in 11 articles, RBD was diagnosed according to ICSD-2, which included both REM sleep without atonia (RWA) on polysomnography (PSG) and violent dream-enactment behavior” (opens the source at this quote in a new tab)
“As we expected, studies that used a stricter diagnosis criteria would report a higher prevalence.” (opens the source at this quote in a new tab)
“In our subgroup analysis, the difference of prevalence is not significant between the studies with the ICSD-RBD and ICSD-2 criteria (44 vs. 48.5 %).” (opens the source at this quote in a new tab)
“In meta-regression analysis, we found that the diagnosis criteria of RBD (P = 0.016) and age of PD patients (P = 0.019) were two important causes for the heterogeneity.” (opens the source at this quote in a new tab)
“Older age and longer duration are risk factors for RBD in PD, while male gender is not a risk factor.” (opens the source at this quote in a new tab)
“Second, our meta-analysis is based on cross-sectional designs, and then, the inferences about causality cannot be made.” (opens the source at this quote in a new tab)

Subgroup	Number of studies	Estimated prevalence (%; 95% CI)	I2 (%)
Diagnosis: REM Sleep Behavior Disorder Screening Questionnaire	“10”	“35.0 (29.0–41.0)”	“92.4”
Diagnosis: ICSD minimal criteria (clinical interview)	“7”	“44.0 (31.6–56.5)”	“96.6”
Diagnosis: ICSD-2 (polysomnography)	“11”	“48.5 (40.6–56.4)”	“81.9”
Age 60 years or less	“11”	“35.7 (25.6–45.8)”	“96.7”
Age more than 60 years	“17”	“46.4 (41.7–51.2)”	“86.5”
Ethnicity: Caucasian	“19”	“42.2 (36.5–48.0)”	“92.5”
Ethnicity: Asian	“9”	“42.2 (32.8–51.6)”	“95.1”
Disease duration 6 years or less	“16”	“41.2 (34.7–47.6)”	“92.8”
Disease duration more than 6 years	“12”	“43.7 (36.1–51.2)”	“94.1”
Male participants 50% or less	“8”	“41.1 (31.2–51.1)”	“95.0”
Male participants more than 50%	“20”	“42.7 (37.0–48.5)”	“93.1”
Publication year 2010 to 2012	“10”	“37.3 (30.3–44.2)”	“86.9”
Publication year 2013 to 2016	“18”	“44.8 (38.8–50.8)”	“94.3”
Estimation of prevalence was the primary objective	“13”	“37.8 (32.2–43.4)”	“89.0”
Other primary objective	“15”	“46.0 (38.2–53.9)”	“95.1”
Sample size 400 or less	“21”	“43.2 (36.1–50.3)”	“91.1”
Sample size more than 400	“7”	“40.5 (32.5–48.5)”	“97.0”

Moderator (meta-regression)	Meta-regression coefficient	95% CI	P
Year of publication	“0.0177002”	“−0.0128755 to 0.048276”	“0.257”
Ethnicity	“−0.0020544”	“−0.1136242 to 0.1095155”	“0.971”
Primary objective of the study	“0.0785029”	“−0.0216877 to 0.1786934”	“0.125”
Sample size	“8.97e−06”	“−0.0001337 to 0.0001516”	“0.902”
Diagnostic criteria for RBD	“0.0677628”	“0.0125304 to 0.1229951”	“0.016”
Age	“0.0122493”	“0.0020541 to 0.0224445”	“0.019”
Male ratio	“−0.0012102”	“−0.005528 to 0.0031076”	“0.583”
Duration of Parkinson's disease	“0.0000548”	“−0.0221684 to 0.022278”	“0.996”

“The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up.” (opens the source at this quote in a new tab)

Advanced disease: characteristic motor and non-motor features

“Advanced Parkinson disease is characterized by severe off periods, dyskinesias, cognitive impairment, apathy, hallucinations, excessive daytime sleepiness, autonomic dysfunction, moderate to severe dysphagia, moderate to severe dysarthria, postural and balance impairments, freezing of gait (sudden brief episodes in which a person is unable to move their feet forward despite trying to walk), recurrent falls, and disability requiring help for activities of daily living (ADLs).” (opens the source at this quote in a new tab)
“Advanced symptoms generally have little to no benefit from Parkinson disease therapies because the changes causing the dysfunction are outside the dopaminergic pathways.” (opens the source at this quote in a new tab)

Dementia, dependency, and nursing home placement at 15 and 20 years

“One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parkinson’s disease have survived.” (opens the source at this quote in a new tab)
“The average follow-up for the 52 surviving patients was 15.2 years (SD = 0.7 years); mean prestudy disease duration 23.5 months.” (opens the source at this quote in a new tab)
“Their average age at presentation was 56 years (SD = 7.9 years) compared to 62 years for the total initial group and their average age at follow-up was 71 years (SD = 7.9; range, 55–86 years).” (opens the source at this quote in a new tab)
“Falls occur in 81% of patients, and 23% sustained fractures.” (opens the source at this quote in a new tab)
“Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia.” (opens the source at this quote in a new tab)
“The mean score of the MMSE was 22.5 (SD = 8.3).” (opens the source at this quote in a new tab)
“Of 46 patients, 22 tested scored ≥ 26 of 30, and 11 of 46 patients scored <20.” (opens the source at this quote in a new tab)
“No patient is still employed, and 40% of patients live in aged care facilities.” (opens the source at this quote in a new tab)
“A total of 30 (58%) were deemed unable to live alone due to physical and/or cognitive disabilities” (opens the source at this quote in a new tab)
“Forty-two patients (81%) had fallen due to their Parkinson’s disease with a mean onset of 11.5 years (SD = 2.8).” (opens the source at this quote in a new tab)
“A total of 7 people had fractured their femur neck, 1 a humerus, 1 her jaw, and 4 various other bones due to falling.” (opens the source at this quote in a new tab)
“A striking finding in this study was that 48% of our patients who survived 15 years were demented; this rate compares to a prevalence of 4.8% to 11% in general population studies of people of similar age” (opens the source at this quote in a new tab)
“The GDS was fully administered to 41 patients: the mean score was 11.7 of 30 (SD = 5.7).” (opens the source at this quote in a new tab)
“There were 19 patients who scored <11 (not depressed), 19 who scored 11 to 20 (mildly depressed), and 3 people scored >20 (definite depression).” (opens the source at this quote in a new tab)
“Formed visual hallucinations were reported at some time by 26 of 52 (50%) by 15 years.” (opens the source at this quote in a new tab)
“The mean time to onset of hallucinations was 10.7 years (SD = 4.0).” (opens the source at this quote in a new tab)
“Orthostatic hypotension (OR, 2.49; 95% CI, 1.08–5.78) remained as the significant factor associated with hallucinations multivariately.” (opens the source at this quote in a new tab)
“Only 7 of 136 (5%) continued to follow a less troublesome course without severe fluctuations, significant imbalance, or dementia.” (opens the source at this quote in a new tab)

“Thirty patients (15 men and 15 women) have survived to be included in the 20-year follow-up that ranged from 19.8 to 22 years.” (opens the source at this quote in a new tab)
“Their average age is now 74 years (SD = 7.9), and was 54 years at presentation compared to 62 years for the initial total group.” (opens the source at this quote in a new tab)
“Dementia is present in 83% of 20-year survivors.” (opens the source at this quote in a new tab)
“Only one person lives independently and 48% are in nursing homes.” (opens the source at this quote in a new tab)
“At 20 years, the mean Hoehn and Yahr stage ‘‘on’’ was 4.2 and ‘‘off’’ was 4.6.” (opens the source at this quote in a new tab)
“Patients lived there for a mean of 34 months (SD = 27) before death.” (opens the source at this quote in a new tab)
“The mean activities of daily living score (UPDRS items 5–17) ‘‘on’’ was 19 (SD = 8) and ‘‘off’’ was 27 (SD = 8).” (opens the source at this quote in a new tab)
“Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%.” (opens the source at this quote in a new tab)
“Another 70 patients were demented before they died prior to 20 years, giving a total of 97 (75%) demented predeath.” (opens the source at this quote in a new tab)
“Urinary incontinence occurred in 22 (71%), fecal incontinence in 5 (17%), and constipation requiring daily laxatives was present in 12 (40%).” (opens the source at this quote in a new tab)
“Of the original cohort, 78 were known to have suffered visual hallucinations prior to death” (opens the source at this quote in a new tab)
“In this group, only 14/30 (47%) still see their neurologist after 20 years.” (opens the source at this quote in a new tab)

Clinical Dementia Rating at 20 years	Participants examined	Mean age at 20 years	Mean MMSE	Constructional apraxia (%)
0 to 0.5	“5”	“64”	“29”	“0”
1	“15”	“75”	“25”	“80”
2	“5”	“76”	“14”	“100”
3	“5”	“79”	“2”	“100”

Motor complications and levodopa-unresponsive disability at 15 and 20 years

“Although approximately 95% have experienced L-dopa–induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling.” (opens the source at this quote in a new tab)
“Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added.” (opens the source at this quote in a new tab)
“The average dose of L-dopa for 49 patients was 734 mg per day (SD = 481) taken on average 4.4 times per day (SD = 2.0).” (opens the source at this quote in a new tab)
“By 15 years, 49 of 52 (94%) had experienced dyskinesia.” (opens the source at this quote in a new tab)
“In this group of survivors, the mean duration of treatment before the onset of dyskinesia was 5.3 years (SD = 3.6): 4.2 years (SD = 2.9) for the L-dopa group and 6.9 years (SD = 4.0) for the bromocriptine group, a significant difference (t test, P = 0.009).” (opens the source at this quote in a new tab)
“Thus, 6 of 52 (12%) had experienced severe dyskinesia by 15 years.” (opens the source at this quote in a new tab)
“Conversely, 28 of 52 (54%) did not consider their dyskinesia disabling.” (opens the source at this quote in a new tab)
“End of dose failure was reported by 50 of 52 (96%) patients.” (opens the source at this quote in a new tab)
“Mean duration of L-dopa treatment was 6.2 years (SD = 3.6) before the onset of end of dose failure: 5.8 years for the L-dopa group and 6.6 years for the bromocriptine group (t test, P = 0.36, not significant)” (opens the source at this quote in a new tab)
“Predictable offs occurred in 44 of 52 (85%), unpredictable offs in 18 of 52 (35%), and sudden offs in 12 of 52 (23%).” (opens the source at this quote in a new tab)
“Offs occupied ≤ 25% of the day in 36 of 52 (69%), and 25 to 50% of the day in 7 of 52 (13%).” (opens the source at this quote in a new tab)
“Nine patients were considered off for ≥ 75% of the day.” (opens the source at this quote in a new tab)
“All were demented: Stage 4 to 5 on low doses of L-dopa (mean 311 mg/day) or on no L-dopa (3).” (opens the source at this quote in a new tab)
“Dystonia, particularly involving the feet in the early morning had occurred in 29 of 52 (56%), mean onset being 4.1 years (SD = 3.4).” (opens the source at this quote in a new tab)
“The mean onset time for the bromocriptine group was 6.0 years (SD = 1.7), but it was significantly earlier at 2.4 years (SD =1.7, t test, P = 0.002) for the L-dopa group.” (opens the source at this quote in a new tab)
“The major causes of disability in patients surviving for 15 or more years are falls, autonomic disturbance, neuropsychiatric symptoms, and dementia, aspects of the disease that are not improved by L-dopa.” (opens the source at this quote in a new tab)
“Motor fluctuations and dyskinesia are common but are a less disabling aspect of the disease in the majority.” (opens the source at this quote in a new tab)

“Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease.” (opens the source at this quote in a new tab)
“The mean levodopa intake is 729 mg/day (SD = 453) with a daily average of 4.7 intakes at 20 years.” (opens the source at this quote in a new tab)
“All of those on at least 300 mg of levodopa per day had experienced end of dose failure and dyskinesia.” (opens the source at this quote in a new tab)
“At 20 years, dyskinesia was graded as mild to moderate (UPDRS 1–2) for both duration and severity in all, but 3 patients where it was graded as 3.” (opens the source at this quote in a new tab)
“Sudden ‘‘offs’’ were reported by 5 of 30 and an equal number lacked a good ‘‘on’’ due to inadequate levodopa dosage because of dementia.” (opens the source at this quote in a new tab)
“All others were on for more than half the day.” (opens the source at this quote in a new tab)

Dementia and functional dependency in population-based incidence cohorts

“Median time to functional dependency was 7.4 years (95% CI 6.4–7.5) and the 10‐year probability was 70.7% (95% CI 65.5–75.7)” (opens the source at this quote in a new tab)
“The 10‐year dementia probability was 49.6% (95% CI 44.6–54.8)” (opens the source at this quote in a new tab)
“We demonstrate that poor outcomes in PD are common and often occur early (eg, about 10% had postural instability and dependency at diagnosis and over 25% developed dementia within 5 years).” (opens the source at this quote in a new tab)

Clinical milestones: hallucinations, recurrent falls, dementia, and nursing home placement

“One or more milestones were reached in 53.0%.” (opens the source at this quote in a new tab)
“The risk of contracting a milestone condition during the study was independently predicted by two baseline factors: Higher age (age 70 years or more resulted in a hazard rate (HR) of 3.5 (95% confidence interval 2.3–5.5), p < 0.001) and presence of PD-MCI (HR 2.1 (1.3–3.4), p = 0.003).” (opens the source at this quote in a new tab)
“In these models, we analyzed the baseline factors age, gender, UPDRS motor score, MADRS score and presence or absence of PD-MCI using Enter method.” (opens the source at this quote in a new tab)
“Of the patients who reached the milestones, visual hallucinations appeared after a median of 3.3 (interquartile range 1.3–4.9) years from diagnosis, recurrent falls after 3.8 (2.8–5.2) years, dementia after 4.0 (2.1–4.8) years and nursing home placement after 5.4 (3.9–6.7) years.” (opens the source at this quote in a new tab)
“We recruited 185 patients with incident PD and monitored prospectively every six months through seven years for emergence and consequences of four clinical milestones.” (opens the source at this quote in a new tab)
“The main reason for loss to follow-up was death; only 9 patients (4.9%) withdrew from study follow-up.” (opens the source at this quote in a new tab)
“Median follow-up time was 7.0 (interquartile range (IQR) 6.8–7.1) years.” (opens the source at this quote in a new tab)
“Visual hallucinations represented the earliest and most frequent milestone, and almost 40% had experienced hallucinations during 7 years of follow-up.” (opens the source at this quote in a new tab)
“The two most frequent milestones, visual hallucinations and recurrent falls, were highly reversible (in 69.1% and 64.9%, respectively).” (opens the source at this quote in a new tab)
“Among patients with reversible visual hallucinations, the RRs of experiencing recurrent falls, dementia and nursing home placement were 2.4 (1.4–4.0), 6.6 (3.3–13.2) and 3.5 (1.7–7.3)” (opens the source at this quote in a new tab)
“In patients with reversible recurrent falling status, the RRs of experiencing visual hallucinations, dementia and nursing home placement were 1.8 (1.2–2.8), 4.2 (2.4–7.3) and 4.4 (2.1–9.3), respectively (all p < 0.01), comparable to the overall RRs presented in Table 2.” (opens the source at this quote in a new tab)
“Presence of any milestone was associated with occurrence of other milestones (relative risks 1.9–6.3; all p ≤ 0.001).” (opens the source at this quote in a new tab)
“Overall, 34 PD patients (18.4%) died during the study.” (opens the source at this quote in a new tab)
“The remaining 23 deaths were preceded by one or more milestone conditions in 69.6% of cases.” (opens the source at this quote in a new tab)
“The median (IQR) time from visual hallucinations to death was 2.7 (1.3–4.6) years, whereas recurrent falls preceded death by 2.4 (1.3–2.6) years.” (opens the source at this quote in a new tab)
“Development of one milestone condition resulted in a trend towards increased mortality (RR of death during the study 2.0 (0.9–4.7, p = 0.1)), and suffering two or more milestones resulted in an RR for death of 2.7 (1.1–6.5, p = 0.03).” (opens the source at this quote in a new tab)
“Experiencing two or more milestones increased the risk of death during the study (relative risk 2.7, p = 0.03).” (opens the source at this quote in a new tab)
“No patients admitted to a nursing home ever returned to independent living, and death ensued after 2.1 years on average.” (opens the source at this quote in a new tab)
“For example, the majority (67.6%) of PD patients with visual hallucinations were classified as still having mild disease according to the Hoehn and Yahr scale, whereas only 10.3% were classified as having severe disease.” (opens the source at this quote in a new tab)
“Despite the long follow-up, most patients did not undergo all milestone conditions, and none of the milestones occurred in half or more of patients.” (opens the source at this quote in a new tab)

Milestone present	Relative risk (95% CI) of visual hallucinations	Relative risk (95% CI) of recurrent falls	Relative risk (95% CI) of dementia	Relative risk (95% CI) of nursing home placement
Visual hallucinations	Not applicable	“2.2 (1.4–3.6)”	“6.3 (3.2–12.4)”	“3.3 (1.6–6.6)”
Recurrent falls	“1.9 (1.3–2.7)”	Not applicable	“4.2 (2.5–7.1)”	“4.7 (2.4–9.2)”
Dementia	“3.2 (2.3–4.5)”	“3.7 (2.4–5.8)”	Not applicable	“5.6 (2.9–10.9)”
Nursing home placement	“2.1 (1.5–3.0)”	“3.2 (2.1–5.0)”	“4.0 (2.5–6.4)”	Not applicable

“Each clinical milestone alone more than doubled the risk of death and had a cumulative effect on mortality, with a HR of 10.83 (95% CI 4.39–26.73) in those experiencing all four milestones.” (opens the source at this quote in a new tab)
“Lastly, for those admitted to a nurse-staffed long-term care facility (n = 43), the median time to admittance from baseline was 6.4 years (IQR 4.5–7.6).” (opens the source at this quote in a new tab)

Falls and recurrent falls

“In these studies, 60.5% (range 35 to 90%) of participants reported at least one fall, with 39% (range 18 to 65%) reporting recurrent falls.” (opens the source at this quote in a new tab)
“Around 70% of people with PD who fall do so recurrently and many fall very frequently.” (opens the source at this quote in a new tab)

Hip and non-vertebral fractures

“Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls.” (opens the source at this quote in a new tab)
“The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04).” (opens the source at this quote in a new tab)
“Seventeen studies (14 cohort and 3 case-control), with a total of 2,329,424 participants, were included in the meta-analysis for hip fractures” (opens the source at this quote in a new tab)
“However, there was substantial heterogeneity between results of the studies (I2=87.4%, p value <0.001).” (opens the source at this quote in a new tab)
“The adjusted estimate using the trim and fill method was 2.26, 95% CI: 1.93 to 2.65.” (opens the source at this quote in a new tab)
“Nine cohort studies, with a total of 1,356,711 participants, were included in the meta-analysis for non-vertebral fractures” (opens the source at this quote in a new tab)
“The heterogeneity observed between the studies was not statistically significant (I2=30.1%, p value= 0.18).” (opens the source at this quote in a new tab)
“Overall, the effect size for non-vertebral fractures in male patients with PD (2.26, 95% CI: 1.37 to 3.73), was higher than the one in women (1.82, 95% CI: 1.33 to 2.48), but the confidence intervals overlapped.” (opens the source at this quote in a new tab)
“This is a clinically important increased risk of hip fracture; for example, the risk is similar to the increased risk of hip fracture in analyses of patients who ever used corticosteroids (2.07 in female and 2.62 in male)” (opens the source at this quote in a new tab)
“In a cross-sectional study, BMD was found to be 7% lower than in controls” (opens the source at this quote in a new tab)
“The mortality rate of patients with this disorder has been reported to be doubled after a hip fracture compared with those without the disease” (opens the source at this quote in a new tab)
“A recent study showed that only 40% of the PD patients diagnosed with fragility fractures were receiving evidence-based treatment for osteoporosis” (opens the source at this quote in a new tab)
“The majority of the published studies have data from white/Caucasian population and were mainly oriented in Europe and the USA; therefore, this might have affected the results.” (opens the source at this quote in a new tab)
“The effect of PD medication would also be an interesting subgroup analysis, but it was not included in our priori analyses, so the data were not extracted.” (opens the source at this quote in a new tab)

Subgroup	Hip fracture: studies	Hip fracture: pooled effect size (95% CI)	Non-vertebral fracture: studies	Non-vertebral fracture: pooled effect size (95% CI)
Men	“7”	“2.93 (2.05, 4.18)”	“2”	“2.26 (1.37, 3.73)”
Women	“6”	“1.81 (1.61, 2.04)”	“2”	“1.82 (1.33, 2.48)”
Cohort studies	“14”	“2.34 (1.98, 2.77)”	Not applicable	Not applicable
Case-control studies	“3”	“3.42 (1.72, 6.79)”	Not applicable	Not applicable
Clinical diagnostic criteria reported	“3”	“3.00 (1.86, 4.83)”	“3”	“1.89 (1.37, 2.61)”
Clinical diagnostic criteria not reported	“14”	“2.37 (2.00, 2.79)”	“6”	“1.82 (1.57, 2.10)”
Diagnosis of Parkinson's disease	“14”	“2.36 (1.98, 2.81)”	“8”	“1.80 (1.59, 2.05)”
Diagnosis of parkinsonism	“3”	“2.46 (1.87, 3.26)”	“1”	“1.87 (1.27, 2.76)”
Asia	“3”	“2.39 (2.02, 2.82)”	“1”	“2.05 (1.71, 2.45)”
Europe	“8”	“2.32 (1.87, 2.89)”	“4”	“1.57 (1.45, 1.71)”
Oceania	“1”	“1.45 (1.14, 1.84)”	Not reported	Not reported
United States	“5”	“3.03 (2.26, 4.05)”	“4”	“1.86 (1.58, 2.19)”

Hip fracture sensitivity analysis with a confidence interval that does not contain its point estimate and four references for three removed studies

“A sensitivity analysis was performed using the studies that scored ≥7 out of 9 stars in the Newcastle Ottawa Scale. Three case-control studies were removed from the analysis (28, 36, 37, 40). The overall effect size was found to be 2.34, 95% CI: 1.98, 2.27, which was similar to the one calculated for all the studies (2.40, 95% CI 2.04 to 2.82).” (opens the source at this quote in a new tab)
“In total, three studies had a case-control design (28, 37, 40) and the rest were cohort studies.” (opens the source at this quote in a new tab)

Aspiration pneumonia and causes of death in late-stage disease

“The most common main cause of death was aspiration pneumonia (34%), followed by sepsis (16%), unspecified pneumonia (13%), ileus (5%) and Covid-19 (5%).” (opens the source at this quote in a new tab)

Dysphagia-related complications: aspiration pneumonia, malnutrition, and difficulty swallowing tablets

“Dysphagia is one of the factors contributing to malnutrition or weight loss in PD, together with increased energy expenditure, loss of appetite and sense of smell and intestinal malabsorption” (opens the source at this quote in a new tab)
“A large follow-up study of 252 patients with PD and confirmed aspiration risk revealed that 10% developed pneumonia” (opens the source at this quote in a new tab)
“Cough reflex sensitivity and cough intensity tend to deteriorate in advanced PD, and this predicts silent aspiration” (opens the source at this quote in a new tab)
“This reduced pulmonary clearance explains why pneumonia (although not necessarily aspiration pneumonia) is a main cause of death in PD” (opens the source at this quote in a new tab)
“Since most PD patients are dependent on taking medication multiple times a day, dysphagia for tablets, especially when severe in the off-phase, may have consequences for the effectiveness of medical treatment” (opens the source at this quote in a new tab)

Health-related quality of life of United States veterans with Parkinson's disease compared with other chronic conditions

“Controlling for sociodemographic factors and co-morbidities, veterans with Parkinson's disease had PCS and MCS below veterans with angina/coronary heart disease, arthritis, chronic low back pain, congestive heart failure, diabetes, and stroke.” (opens the source at this quote in a new tab)
“The unique effect of having Parkinson's disease on HRQoL was to lower PCS and MCS by 4.10 and 3.42 points (0.41 and 0.34 of 1 SD), respectively.” (opens the source at this quote in a new tab)
“Compared with eight other chronic conditions, Parkinson's disease imposes a relatively heavy burden on US veterans in the VHA health care system.” (opens the source at this quote in a new tab)

Determinants of health-related quality of life

“The factor most closely associated with QoL was the presence of depression, but disability, as measured by the Schwab and England scale, postural instability, and cognitive impairment additionally contributed to poor QoL.” (opens the source at this quote in a new tab)
“Depression, disability, postural instability, and cognitive impairment have the greatest influence on QoL in Parkinson's disease.” (opens the source at this quote in a new tab)

Non-motor symptoms and health-related quality of life

“The sample was made up of 411 Parkinson’s disease patients, recruited in 12 movement disorders clinics across 10 countries.” (opens the source at this quote in a new tab)
“Mean age (±standard deviation) was 64.48 (±9.92) years old, and disease duration was 8.07 (±5.75) years.” (opens the source at this quote in a new tab)
“Higher scores mean poorer HRQoL.” (opens the source at this quote in a new tab)
“For each group, PDQ-39 and EQ-5D means and standard deviations were calculated, and group differences were assessed by the Mann-Whitney test.” (opens the source at this quote in a new tab)
“The Benjamini-Hochberg test for multiple comparisons was applied.” (opens the source at this quote in a new tab)
“Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints.” (opens the source at this quote in a new tab)
“The mean number of non-motor symptoms per patient was 11.80 ± 6.03 (range: 0–29), and there was a high correlation between the number of nonmotor symptoms and PDQ-39 and EQ-5D (Table 4).” (opens the source at this quote in a new tab)
“For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms.” (opens the source at this quote in a new tab)
“SCOPA-motor (total, motor examination, and activities of daily living subscales) reached the strongest relationship with the EQ-5D index (rS = from −0.58 to −0.67).” (opens the source at this quote in a new tab)
“The correlation between NMSS and SCOPA-Motor was 0.43.” (opens the source at this quote in a new tab)
“For each NMSS domain, patients with symptoms had significantly worse HRQoL than patients with no symptoms, except for the EQ-5D in the sexual dysfunction domain and the EQ-5D VAS in the urinary domain (Table 5).” (opens the source at this quote in a new tab)
“The corresponding models accounted for 53% (EQ-5D) and 59% (PDQ-39) of the variance.” (opens the source at this quote in a new tab)
“NMSS score had the strongest influence on HRQoL as measured by the PDQ-39, whereas considering EQ5D, both SCOPA-motor examination and NMSS were the strongest predictors and almost equivalent.” (opens the source at this quote in a new tab)
“In the models that included the NMSS domains as independent variables, mood/apathy, sleep/fatigue, and miscellaneous domains were the most significant factors for both the PDQ-39 SI and the EQ-5D index, accounting for 50% and 38% of the variance, respectively.” (opens the source at this quote in a new tab)
“Most of the patient population in the study was on dopaminergic therapy and, therefore, the impact of the motor manifestations may be neutralized by effective antiparkinsonian effect.” (opens the source at this quote in a new tab)
“The results show that non-motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease.” (opens the source at this quote in a new tab)

NMSS domain	With symptoms, n	Without symptoms, n	PDQ-39 SI, with symptoms, mean ± SD	PDQ-39 SI, without symptoms, mean ± SD	PDQ-39 SI, P	EQ-5D index, with symptoms, mean ± SD	EQ-5D index, without symptoms, mean ± SD	EQ-5D index, P	EQ-5D VAS, with symptoms, mean ± SD	EQ-5D VAS, without symptoms, mean ± SD	EQ-5D VAS, P
Cardiovascular	“173”	“238”	“32.45 ± 17.85”	“24.79 ± 15.66”	“<0.0001”	“0.48 ± 0.37”	“0.62 ± 0.32”	“0.0001”	“61.49 ± 21.23”	“65.17 ± 23.01”	“0.05”
Sleep/fatigue	“356”	“54”	“30.11 ± 16.80”	“14.48 ± 11.57”	“<0.0001”	“0.52 ± 0.35”	“0.79 ± 0.20”	“<0.0001”	“61.75 ± 21.77”	“75.74 ± 22.45”	“<0.0001”
Mood/apathy	“310”	“100”	“31.31 ± 16.87”	“17.64 ± 13.01”	“<0.0001”	“0.50 ± 0.35”	“0.74 ± 0.27”	“<0.0001”	“61.66 ± 22.01”	“70.51 ± 21.21”	“0.0002”
Perceptual problems/hallucinations	“123”	“288”	“36.89 ± 17.25”	“24.22 ± 15.47”	“<0.0001”	“0.38 ± 0.39”	“0.63 ± 0.30”	“<0.0001”	“57.15 ± 25.19”	“66.40 ± 20.39”	“0.0004”
Attention/memory	“296”	“115”	“30.65 ± 16.93”	“21.27 ± 15.37”	“<0.0001”	“0.52 ± 0.36”	“0.66 ± 0.30”	“0.0005”	“61.35 ± 22.21”	“69.52 ± 21.58”	“0.0005”
Gastrointestinal	“302”	“109”	“31.02 ± 17.84”	“19.76 ± 10.92”	“<0.0001”	“0.49 ± 0.36”	“0.74 ± 0.23”	“<0.0001”	“61.00 ± 22.48”	“71.04 ± 20.16”	“<0.0001”
Urinary	“338”	“73”	“29.52 ± 17.44”	“21.12 ± 12.97”	“0.0002”	“0.54 ± 0.36”	“0.66 ± 0.28”	“0.001”	“62.82 ± 22.56”	“67.38 ± 20.87”	“0.13”
Sexual dysfunction	“177”	“234”	“29.71 ± 15.97”	“26.75 ± 17.71”	“0.03”	“0.53 ± 0.34”	“0.58 ± 0.35”	“0.09”	“63.17 ± 21.92”	“63.94 ± 22.65”	“0.53”
Miscellaneous	“99”	“312”	“30.38 ± 17.36”	“20.61 ± 13.54”	“<0.0001”	“0.50 ± 0.36”	“0.73 ± 0.25”	“<0.0001”	“61.61 ± 22.32”	“70.02 ± 21.20”	“0.0006”

Multiple linear regression models of PDQ-39 and EQ-5D scores on motor and non-motor symptom measures

Model (dependent variable)	Adjusted R² of the model	Independent variable	Standardized beta	t	Sig.
PDQ-39 SI	“0.59”	Constant (unstandardized value)	“(23.76)”	“5.55”	“0.000”
PDQ-39 SI	“0.59”	NMSS total	“0.52”	“13.64”	“0.000”
PDQ-39 SI	“0.59”	SCOPA-motor complications	“0.20”	“4.81”	“0.000”
PDQ-39 SI	“0.59”	SCOPA-motor examination	“0.17”	“4.15”	“0.000”
EQ-5D index	“0.53”	Constant (unstandardized value)	“(0.83)”	“9.24”	“0.000”
EQ-5D index	“0.53”	SCOPA-motor examination	“−0.38”	“−9.11”	“0.000”
EQ-5D index	“0.53”	NMSS total	“−0.37”	“−8.74”	“0.000”
EQ-5D index	“0.53”	SCOPA-motor complications	“−0.12”	“−2.71”	“0.000”

Non-motor symptom domains and PDQ-39 summary index in a multicenter survey

“Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL.” (opens the source at this quote in a new tab)
“Presence of apathy was associated with the worst QoL score (median PDQ-39 SI score = 36.0; IQR: 23.3–47.0) followed by cardiovascular symptoms, fatigue, attention/memory, and respiratory symptoms (Fig. 3).” (opens the source at this quote in a new tab)
“The greatest difference in PDQ-39 score (present vs. absent NMSd) was recorded in patients presenting apathy followed by fatigue, attention/memory, and psychiatric symptoms (differences ranged from 15.9 points for apathy to 11.8 for psychiatric symptoms; P < 0.0001).” (opens the source at this quote in a new tab)
“Among PDQ-39 dimensions, patients had the best QoL in social support (median = 0; IQR: 12.5) while higher values of PDQ-39 scores (meaning lower QoL) were recorded in emotional wellbeing (median = 31.3) and bodily discomfort (median = 33.3) dimensions scores; for both of them IQR = 16.7–50.0.” (opens the source at this quote in a new tab)
“Twenty-three percent of patients (N = 246) had missing items in the PDQ-39 questionnaire and were thus excluded from the analyses.” (opens the source at this quote in a new tab)

OFF episodes and health-related quality of life in the United States

“Data from 722 patients were analyzed. Overall, 321 patients (44%) had “OFF” episodes (mean of 2.9 h of daily “OFF” time).” (opens the source at this quote in a new tab)
“The presence of “OFF” episodes, regardless of the average hours of daily “OFF” time, was significantly associated with high scores (reflecting poor HRQoL) on most PDQ-39 dimensions and the summary index and low scores (reflecting poor health status) on the EQ-5D health utility index, visual analog scale (VAS), and all dimensions.” (opens the source at this quote in a new tab)
“In our study, the predictive margin from regression analysis showed a difference of 5.2 in the PDQ-39 summary index between patients who experienced “OFF” episodes and those without “OFF” episodes, suggesting that differences between these groups was clinically important.” (opens the source at this quote in a new tab)

Health-related quality of life by hours of daily OFF time

“Linear regression analyses predicted that, for every additional hour of daily “OFF” time, there would be increases of 2.73, 2.60, 2.12, 1.63, 1.04, 2.80, 3.55, and 1.91 on the PDQ-39 mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication, and bodily discomfort dimensions, respectively (Additional file 1), together with an increase of 2.30 on the PDQ-39 summary index (Fig. 2).” (opens the source at this quote in a new tab)
“Linear regression analyses predicted that, for every additional hour of daily “OFF” time, there would be a decrease of 0.02 in the EQ-5D utility index and a decrease of 2.5 in the EQ-5D VAS, indicating deteriorating health status with increasing hours of daily “OFF” time (Fig. 3).” (opens the source at this quote in a new tab)

Patient-reported OFF periods in a United States online cohort

“From a population of 6,757 persons with PD, 88% were non-Hispanic Whites (mean age: 66 ± 8.8 years); 52.7% were males versus 47.3% females; mean PD duration was 5.7 ± 5.2; and 51% experienced OFF periods.” (opens the source at this quote in a new tab)
“The analyses showed that 67% experienced 1–2 episodes/day, 90% experienced >15-minute episodes, and 55% reported slight–mild severity/episode.” (opens the source at this quote in a new tab)
“Longer PD duration was associated with 1.3% more episodes/day (IRR: 1.013; P<0.001) and 10% higher odds of a severe episode (OR: 1.10; P<0.001).” (opens the source at this quote in a new tab)

Motor fluctuations and dyskinesia and health-related quality of life in five European countries

“Data were collected cross-sectionally in clinical practice settings via nationally representative samples of specialized physicians (neurologists, plus geriatricians in the UK) and their PD patients between March and July, 2008.” (opens the source at this quote in a new tab)
“In total, 817 patients were included in our analyses.” (opens the source at this quote in a new tab)
“All multivariable models were adjusted for age, gender, HY stage, disease duration, and country.” (opens the source at this quote in a new tab)
“To facilitate the comparison of the regression coefficients (β) across the QoL instruments the EQ-5D IS was rescaled from 0 (poor QoL) to 100 (good QoL).” (opens the source at this quote in a new tab)
“For the primary hypotheses, the association of motor complication subtypes with QoL, the global significance level was set at 5% and was adjusted per outcome using a Bonferroni correction. A difference was considered statistically significant if p < 0.025.” (opens the source at this quote in a new tab)
“PDQ-39 scores range from 0 to 100. Contrary to the EQ-5D lower values indicate better QoL.” (opens the source at this quote in a new tab)
“These analyses were regarded as explorative, and the p-values of the corresponding regression models are presented for descriptive reasons only.” (opens the source at this quote in a new tab)
“Thirty-three percent of the patients (varying from 23% in Italy to 58% in France) suffered from motor complications, either a single subtype or a combination of different subtypes.” (opens the source at this quote in a new tab)
“Twenty percent of all patients suffered from a single motor complication, 10.0% from two, 2.3% from three, and 0.5% from all four types of motor complications.” (opens the source at this quote in a new tab)
“Twenty-eight percent of all patients had off-times.” (opens the source at this quote in a new tab)
“The mean EQ-5D IS of the total sample was 0.7 (SD 0.2) based on the ratings in the dimensions mobility (33.9% of the patients reported no, 64.8% some,1.2% extreme problems), self-care (55.3% no, 39.9% some, 4.8% extreme problems), usual activities (36.4%, 57.8% some, 5.8% extreme problems), pain/discomfort (45.4% no, 51.1% some, 3.4% extreme problems), and anxiety/depression (54.1% no, 41.6% some, 4.3% extreme problems). The mean PDQ-39 SI was 25.4 (SD 18.5).” (opens the source at this quote in a new tab)
“On-off fluctuations were associated with a 7.1 percentage point decrease in the EQ-5D (p < 0.001) and a 3.6 percentage point deterioration in the PDQ-39 (p = 0.01).” (opens the source at this quote in a new tab)
“None of the dyskinesia subtypes had a significant effect on the EQ-5D IS or the PDQ-39 SI (Table 2).” (opens the source at this quote in a new tab)
“Sensitivity analyses considering motor complication severity indicated that compared to patients without on-off fluctuations the detrimental effect of on-off fluctuations was greater in patients with more severe complications (mild: β=−6.0, p < 0.01; moderate: β=−9.0, p < 0.001; severe: β = −3.2, p = 0.58). A linear trend was, however, not confirmed in the trend analysis (p = 0.48). The same was true for the severity of on-off fluctuations and the PDQ-39 SI (mild: β=2.9, p = 0.09; moderate: β = 5.4, p = 0.01; severe: β = 7.7, p = 0.1; test for linear trend p = 0.07).” (opens the source at this quote in a new tab)
“Dyskinesias were not seen to affect global QoL scores, but had detrimental effects on the PDQ-39 dimensions activities of daily living, cognitions, stigma, and bodily discomfort.” (opens the source at this quote in a new tab)
“In subgroup analyses that excluded patients with present symptoms of depression and/or cognitive impairment the results did not notably alter.” (opens the source at this quote in a new tab)
“On-off fluctuations were associated with poorer EQ-5D IS (β = −6.4, p = 0.003) and PDQ-39 SI (β = 4.5, p = 0.01) whereas dyskinesias did not impact QoL.” (opens the source at this quote in a new tab)
“The motor complications observed in our sample were mainly mild or moderate limiting the generalizability of results for patients with more severe motor complications as well as the power of the linear trend tests.” (opens the source at this quote in a new tab)
“The Adelphi PD Specific Programme is an independent study conducted by the Adelphi group on behalf of Solvay Pharmaceuticals.” (opens the source at this quote in a new tab)

Multivariable associations of motor complication subtypes with EQ-5D and PDQ-39 scores, all subtypes and outcomes

Motor complication subtype	Outcome	Regression coefficient (β)	95% CI	p-Value
On-off fluctuations	EQ-5D index score (rescaled 0 to 100; higher scores represent better QoL)	“−7.1”	“−10.6; −3.6”	“<0.001”
On-off fluctuations	PDQ-39 summary index (0 to 100; higher scores represent worse QoL)	“3.6”	“0.7; 6.5”	“0.01”
On-off fluctuations	PDQ-39 mobility	“8.1”	“4.0; 12.2”	“<0.001”
On-off fluctuations	PDQ-39 activities of daily living	“7.3”	“3.2; 11.5”	“<0.001”
On-off fluctuations	PDQ-39 emotional wellbeing	“3.2”	“−0.5; 6.9”	“0.09”
On-off fluctuations	PDQ-39 stigma	“2.5”	“−1.7; 6.7”	“0.23”
On-off fluctuations	PDQ-39 social support	“2.3”	“−1.1; 5.7”	“0.19”
On-off fluctuations	PDQ-39 cognitions	“2.9”	“−0.4; 6.1”	“0.08”
On-off fluctuations	PDQ-39 communication	“2.4”	“−1.0; 5.8”	“0.17”
On-off fluctuations	PDQ-39 bodily discomfort	“2.5”	“−1.3; 6.3”	“0.20”
Peak-dose dyskinesias	EQ-5D index score (rescaled 0 to 100; higher scores represent better QoL)	“−2.9”	“−6.9; 1.2”	“0.17”
Peak-dose dyskinesias	PDQ-39 summary index (0 to 100; higher scores represent worse QoL)	“2.4”	“−0.9; 5.7”	“0.16”
Peak-dose dyskinesias	PDQ-39 mobility	“3.3”	“−1.3; 8.0”	“0.16”
Peak-dose dyskinesias	PDQ-39 activities of daily living	“5.9”	“1.2; 10.7”	“0.01”
Peak-dose dyskinesias	PDQ-39 emotional wellbeing	“2.7”	“−1.6; 7.0”	“0.22”
Peak-dose dyskinesias	PDQ-39 stigma	“−0.4”	“−5.3; 4.4”	“0.86”
Peak-dose dyskinesias	PDQ-39 social support	“0.1”	“−3.8; 4.0”	“0.96”
Peak-dose dyskinesias	PDQ-39 cognitions	“4.0”	“0.3; 7.7”	“0.03”
Peak-dose dyskinesias	PDQ-39 communication	“3.6”	“−0.3; 7.6”	“0.07”
Peak-dose dyskinesias	PDQ-39 bodily discomfort	“−2.2”	“−6.6; 2.2”	“0.32”
Biphasic dyskinesias	EQ-5D index score (rescaled 0 to 100; higher scores represent better QoL)	“−2.4”	“−10.6; 5.8”	“0.56”
Biphasic dyskinesias	PDQ-39 summary index (0 to 100; higher scores represent worse QoL)	“6.1”	“−0.9; 13.0”	“0.09”
Biphasic dyskinesias	PDQ-39 mobility	“5.4”	“−4.3; 15.1”	“0.28”
Biphasic dyskinesias	PDQ-39 activities of daily living	“4.2”	“−5.4; 13.7”	“0.39”
Biphasic dyskinesias	PDQ-39 emotional wellbeing	“5.9”	“−3.0; 14.7”	“0.19”
Biphasic dyskinesias	PDQ-39 stigma	“12.6”	“2.7; 22.6”	“0.01”
Biphasic dyskinesias	PDQ-39 social support	“2.6”	“−5.4; 10.6”	“0.53”
Biphasic dyskinesias	PDQ-39 cognitions	“0.5”	“−7.2; 8.2”	“0.90”
Biphasic dyskinesias	PDQ-39 communication	“−0.3”	“−8.2; 7.7”	“0.95”
Biphasic dyskinesias	PDQ-39 bodily discomfort	“2.3”	“−6.6; 11.2”	“0.61”
Off-dystonias	EQ-5D index score (rescaled 0 to 100; higher scores represent better QoL)	“−0.02”	“−5.9; 5.8”	“1.00”
Off-dystonias	PDQ-39 summary index (0 to 100; higher scores represent worse QoL)	“1.6”	“−3.1; 6.4”	“0.51”
Off-dystonias	PDQ-39 mobility	“1.9”	“−4.9; 8.6”	“0.59”
Off-dystonias	PDQ-39 activities of daily living	“1.4”	“−5.4; 8.2”	“0.68”
Off-dystonias	PDQ-39 emotional wellbeing	“3.5”	“−2.7; 9.7”	“0.27”
Off-dystonias	PDQ-39 stigma	“4.6”	“−2.4; 11.5”	“0.20”
Off-dystonias	PDQ-39 social support	“0.5”	“−5.1; 6.1”	“0.85”
Off-dystonias	PDQ-39 cognitions	“−2.9”	“−8.3; 2.5”	“0.29”
Off-dystonias	PDQ-39 communication	“−0.4”	“−6.2; 5.3”	“0.88”
Off-dystonias	PDQ-39 bodily discomfort	“7.4”	“1.1; 13.8”	“0.02”

Motor complication subtypes and PDQ-39 dimensions

“The impact of motor complications of Parkinson’s disease (PD), especially levodopa-induced dyskinesias, on quality of life (QL) was studied in 143 patients with PD.” (opens the source at this quote in a new tab)
“Two groups of patients were excluded, those having undergone surgery of the basal ganglia and those having an alteration of cognitive functions (Mini-Mental State Examination score lower than 24).” (opens the source at this quote in a new tab)
“The range of possible values of each QL dimension is 0 (best QL) to 100 (worst QL), and the PDQ-SI is obtained by adding the dimension scores and reducing the range to 0 to 100.” (opens the source at this quote in a new tab)
“Motor complications significantly worsened the PDQ-39 Summary Index (PDQ-SI) of patients with PD.” (opens the source at this quote in a new tab)
“Morning akinesia, end-of-dose fluctuations, and “unpredictable offs” decreased QL on the dimensions of Mobility, Activities of Daily Living, Stigma, and Communication.” (opens the source at this quote in a new tab)
“Nocturnal akinesia led to a deterioration of all dimensions of the PDQ-39.” (opens the source at this quote in a new tab)
“All the motor fluctuations studied significantly worsened the PDQ-SI.” (opens the source at this quote in a new tab)
“Apart from morning dystonias, all the self-reported LIDs studied (peak dose, diphasic, and off) were significantly related to a higher PDQ-SI, as was the dyskinesia score.” (opens the source at this quote in a new tab)
“We were particularly surprised by the impact of nocturnal akinesia, which often faded into the background at the consultation.” (opens the source at this quote in a new tab)

Motor complication	Participants with the complication, n	Percentage (of all participants for any fluctuation or any dyskinesia; of participants in that class for each subtype)	PDQ-SI mean, with the complication	PDQ-SI mean, without the complication	PDQ-SI, P (Student's t test)
Any motor fluctuation	“94”	“66”	Not reported	Not reported	Not reported
Early-morning akinesia	“55”	“58.5”	“40.9”	“33.6”	“0.005”
Nocturnal akinesia	“54”	“57.5”	“44.7”	“31.3”	“<0.0001”
End-of-dose fluctuations	“74”	“78.7”	“41”	“31.6”	“0.0002”
Paradoxical fluctuations	“47”	“50”	“44.2”	“32.6”	“<0.0001”
Unpredictable offs	“34”	“36.2”	“45.5”	“33.5”	“<0.0001”
Any levodopa-induced dyskinesia	“81”	“57”	Not reported	Not reported	Not reported
Peak-dose dyskinesia	“59”	“72.8”	“39.8”	“34.4”	“0.0404”
Diphasic dyskinesia	“14”	“17.3”	“46.1”	“35.5”	“0.0127”
Off dyskinesia	“10”	“12.4”	“49.9”	“35.7”	“0.0097”
Morning dystonia	“27”	“33.3”	“40.7”	“35.6”	“<0.1277”

Clinical correlates and multivariable predictors of the PDQ-39 Summary Index, including levodopa dosing frequency

“A two-tailed 5% threshold of significance was retained, and only P values lying below this threshold are reported.” (opens the source at this quote in a new tab)
“The disease duration led to a significant alteration of the dimensions Mobility (r = +0.46; P < 0.0001), Activities of Daily Living (r = +0.35; P < 0.0001), Stigma (r = +0.27; P = 0.0014), Social Support (r = +0.18; P = 0.03), and Communication (r = +0.35; P < 0.0001).” (opens the source at this quote in a new tab)
“A degradation of the QL was observed with the duration of dopatherapy, in the dimensions Mobility (r = +0.53; P < 0.0001), Activities of Daily Living (r = +0.44; P < 0.0001), Emotional Well-Being (r = +0.26; P < 0.014), Stigma (r = +0.26; P < 0.013), and Communication (r = +0.41; P < 0.0001) and in the PDQ-SI (r = +0.42; P = 0.0002).” (opens the source at this quote in a new tab)
“The severity of disease (H&Y) affected the QL in the dimensions Mobility (r = +0.44; P < 0.0001), Activities of Daily Living (r = +0.49; P < 0.0001), and Communication (r = +0.29; P = 0.0005) and in the PDQ-SI (r = +0.37; P < 0.0001).” (opens the source at this quote in a new tab)
“A higher total Motor score evaluated in an on state according to Part III of the UPDRS led to a degradation of the QL in the dimensions Mobility (r = +0.24; P = 0.0054) and Activities of Daily Living (r = +0.37; P < 0.0001) and in the PDQ-SI (r = +0.24; P = 0.0092).” (opens the source at this quote in a new tab)
“A greater daily dosage of L-dopa significantly worsened the QL in the dimensions Mobility (r = +0.33; P = 0.0003), Activities of Daily Living (r = +0.31; P = 0.0007), Emotional Well-Being (r = +0.26; P = 0.0048), Stigma (r = +0.31; P = 0.0004), Social Support (r = +0.20; P = 0.027), and Communication (r = +0.28; P = 0.0019) and in the PDQ-SI (r = +0.42; P < 0.0001).” (opens the source at this quote in a new tab)
“A larger number of doses of L-dopa was likewise detrimental for the QL in the dimensions Mobility (r = +0.40; P < 0.0001), Activities of Daily Living (r = +0.30; P = 0.0008), Emotional Well-Being (r = +0.26; P = 0.0048), Stigma (r = +0.33; P = 0.0002), Social Support (r = +0.24; P = 0.01), and Communication (r = +0.24; P = 0.007) and in the PDQ-SI (r = +0.42; P < 0.0001).” (opens the source at this quote in a new tab)
“Inclusion of all factors concerning PD patients (sex and age at PD onset), disease (duration of PD at assessment, H&Y stage, and UPDRS III score), L-dopa treatment (daily dose and number of doses/day) and motor complications (occurrence or not of MF/LIDs and AIMS) in a multivariate linear model showed a contribution of 43% (part of total R-square) to the PDQ-SI.” (opens the source at this quote in a new tab)
“Among the explanatory variables, the individual contribution determined by partial R-square was 17% for the number of L-dopa doses per day, 10% for the UPDRS III score, 7% for AIMS, and less than 2% for the other variables.” (opens the source at this quote in a new tab)
“Among clinical characteristics, the number of L-dopa doses was significantly related to age at the onset of PD (r = −0.43; P < 0.0001), disease duration (r = +0.47; P < 0.0001), H&Y stage (r = +0.22; P = 0.012), L-dopa dose (r = +0.83; P < 0.0001), and AIMS (r = +0.47; P = 0.0021) but not to the UPDRS III score.” (opens the source at this quote in a new tab)
“It may only mean that there is an information overlap between MF/LIDs and the “complexity” of treatment (number of L-dopa doses), which might be the best indication of a difficult case of PD management and, thus, a poor QL in the patient.” (opens the source at this quote in a new tab)
“The levels of causality among PD characteristics are somewhat difficult to analyze, because our study did not take into account the chronological sequence of events.” (opens the source at this quote in a new tab)

Health-related quality of life in patients meeting the 5-2-1 criteria for advanced disease

“In total, 396 (36%) of 1085 patients with sufficient information met the 5‐2‐1 criteria. Patients meeting the criteria had a significantly lower HRQoL, as measured by PDQ‐8 and EQ‐5D, compared to those not meeting the criteria. Each additional hour spent in off or with dyskinesia was associated with lower HRQoL, where time in off state had the strongest impact.” (opens the source at this quote in a new tab)
“The mean difference in HRQoL between 5‐2‐1 positive and 5‐2‐1 negative patients was 15.2 in PDQ‐8 SI and −0.17 in EQ‐5D. The 5‐2‐1 positive patients spent an average of 4.1 hours per day in the off state compared to 0.8 h for the 5‐2‐1 negative patients.” (opens the source at this quote in a new tab)

Good ON-time and humanistic burden in advanced Parkinson's disease

“Of 802 patients (mean [standard deviation; SD] age, 76.1 [8.9] years; male, 60.3%) included in the analysis, mean (SD) ‘GOT’ was 13.1 (2.7) hours/day.” (opens the source at this quote in a new tab)
“Hourly increases in ‘GOT’ were significantly associated with reduced humanistic burden (greater ADL independence, OR 1.19; 95% CI [1.04 1.37]) and improved QoL (for Parkinson’s Disease Questionnaire [PDQ]-39: coefficient − 1.49; 95% CI [− 2.46, − 0.52]) and with reduced economic burden, with annual total HRU cost-savings of $8602.24 (95% CI − $12,192.70 to $5011.77).” (opens the source at this quote in a new tab)

Total United States economic burden, 2017

“We estimated a U.S. prevalence of approximately one million individuals with diagnosed Parkinson’s disease in 2017 and a total economic burden of $51.9 billion.” (opens the source at this quote in a new tab)
“The total burden of PD includes direct medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs, including an indirect cost of $14.2 billion (PWP and caregiver burden combined), non-medical costs of $7.5 billion, and $4.8 billion due to disability income received by PWPs.” (opens the source at this quote in a new tab)
“The Medicare program bears the largest share of excess medical costs, as most PD patients are over age 65.” (opens the source at this quote in a new tab)

Excess direct medical cost per person and by type of service, United States

Component	Total excess medical cost due to PD, million $	Percentage of the total	Per PWP, $
Non-acute institutional care	“7,144”	“28.2%”	“6,888”
Hospital inpatient	“7,190”	“28.4%”	“6,932”
Outpatient	“5,506”	“21.7%”	“5,308”
Physician office	“1,226”	“4.8%”	“1,182”
Durable medical equipment	“145”	“0.6%”	“140”
Prescription medication	“4,137”	“16.3%”	“3,988”
Overall	“25,348”	“100%”	“24,439”

Indirect and non-medical costs per person, United States

“Per PWP indirect and non-medical costs (PWP and care partner costs combined) were slightly higher than the per PWP direct medical cost ($25,558 vs. $24,439).” (opens the source at this quote in a new tab)
“For PWPs, the three largest indirect cost categories were future earnings loss due to PD-related premature death, earnings loss from reduced employment, and absenteeism.” (opens the source at this quote in a new tab)

Projected United States economic burden to 2037

“Projected PD prevalence will be more than 1.6 million with projected total economic burden surpassing $79 billion by 2037.” (opens the source at this quote in a new tab)

Earlier United States estimate of economic burden, 2010

“We estimate that approximately 630,000 people in the United States had diagnosed PD in 2010, with diagnosed prevalence likely to double by 2040. The national economic burden of PD exceeds $14.4 billion in 2010 (approximately $22,800 per patient).” (opens the source at this quote in a new tab)
“The population with PD incurred medical expenses of approximately $14 billion in 2010, $8.1 billion higher ($12,800 per capita) than expected for a similar population without PD.” (opens the source at this quote in a new tab)

Longitudinal incremental costs among Medicare beneficiaries

“We identified 27,394 cases and controls who were grouped into 3 survival groups. The mean age of the full study sample was 73 years.” (opens the source at this quote in a new tab)
“Based on the multivariable GLM, the 1-year incremental cost of PD was $9,625 (95% CI, $9,054-$10,197). The 3-year incremental cost of PD was $20,832 (95% CI, $19,390-$22,274). The 5-year incremental cost of PD was $27,466 (95% CI, 25,088-$29,844).” (opens the source at this quote in a new tab)

Medicare costs by disease severity

“The final sample (N = 144,703) had mean observed all-cause, primary PD-related, and any PD-related costs of $23,041 (SD, $34,045), $3429 (SD, $7431), and $9924 (SD, $22,140), respectively. Twenty percent of patients were classified as advanced PD.” (opens the source at this quote in a new tab)
“The incremental costs of advanced PD were $5818 (95% confidence interval [CI]: $5411–$6225) for all-cause costs, $3644 (95% CI: $3484–$3806) for primary PD-related costs, and $6088 (95% CI: $5779–$6398) for any PD-related costs (P < 0.001, all models).” (opens the source at this quote in a new tab)
“All costs were adjusted to 2018 U.S. dollars using the medical care component of the Consumer Price Index.” (opens the source at this quote in a new tab)

Study population and claims-based definition of advanced disease

“Our data source was the 2013 Chronic Conditions Data Warehouse 100% Medicare dataset, which contains comprehensive claims for all patients with fee-for-service Medicare.” (opens the source at this quote in a new tab)
“Next, the algorithm searched chronologically for any consecutive 30-day period where the average LED was > 1000 mg/day. Patients with dosing satisfying this criterion were categorized as having advanced PD, regardless of whether they maintained dosing at that level throughout the year.” (opens the source at this quote in a new tab)
“Our LED > 1000 mg dosing threshold was based on the average medication dose observed in clinical trials of device-aided therapies, such as deep brain stimulation (DBS) and carbidopa-levodopa enteral suspension.” (opens the source at this quote in a new tab)
“Our final study sample included 144,703 Medicare beneficiaries with PD (Supporting Information Fig. S1). Twenty percent (n = 28,974) were categorized as having advanced PD via our medication-based algorithm; the remaining 80% were categorized as having mild/moderate PD (Table 1).” (opens the source at this quote in a new tab)
“Compared with the mild/moderate PD group, the advanced PD group had a greater percentage of individuals who were younger and male, who had a lower mean RxHCC risk score, and who had an outpatient neurologist visit during the year.” (opens the source at this quote in a new tab)

Sample characteristics by claims-assigned disease severity, Medicare

Characteristic	Overall (N = 144,703)	Mild/moderate PD (n = 115,729)	Advanced PD (n = 28,974)
Age 65–69 years, n (%)	“16,702 (11.5)”	“11,964 (10.3)”	“4738 (16.4)”
Age 70–74 years, n (%)	“27,882 (19.3)”	“20,685 (17.9)”	“7197 (24.8)”
Age 75–79 years, n (%)	“33,141 (22.9)”	“26,039 (22.5)”	“7102 (24.5)”
Age ≥80 years, n (%)	“66,978 (46.3)”	“57,041 (49.3)”	“9937 (34.3)”
Male sex, n (%)	“70,127 (48.5)”	“53,321 (46.1)”	“16,806 (58.0)”
Race, White, n (%)	“126,830 (87.6)”	“100,878 (87.2)”	“25,952 (89.6)”
Race, Black, n (%)	“6666 (4.6)”	“5860 (5.1)”	“806 (2.8)”
Race, other, n (%)	“11,207 (7.7)”	“8991 (7.8)”	“2216 (7.6)”
Region, Northeast, n (%)	“28,430 (19.6)”	“23,061 (19.9)”	“5369 (18.5)”
Region, Midwest, n (%)	“38,687 (26.7)”	“30,487 (26.3)”	“8200 (28.3)”
Region, South, n (%)	“52,885 (36.5)”	“43,040 (37.2)”	“9845 (34.0)”
Region, West, n (%)	“24,701 (17.1)”	“19,141 (16.5)”	“5560 (19.2)”
RxHCC risk score, mean (SD)	“1.48 (0.46)”	“1.50 (0.46)”	“1.40 (0.45)”
Outpatient neurologist visit during the study year, n (%)	“101,146 (69.9)”	“76,762 (66.3)”	“24,384 (84.2)”

“Disease severity group comparisons on all patient variables were statistically significant at the P < 0.001 level.” (opens the source at this quote in a new tab)

Unadjusted 12-month Medicare costs by service category and disease severity

Cost category	Overall (N = 144,703), mean (SD), 2018 US$	Mild/moderate PD (n = 115,729), mean (SD), 2018 US$	Advanced PD (n = 28,974), mean (SD), 2018 US$	P value
All-cause, total	“$23,041 ($34,045)”	“$22,553 ($34,147)”	“$24,988 ($33,563)”	“<0.001”
All-cause, medical	“$16,741 ($31,925)”	“$16,737 ($32,309)”	“$16,763 ($30,348)”	“0.896”
All-cause, outpatient	“$8747 ($9983)”	“$8627 ($10,062)”	“$9230 ($9645)”	“<0.001”
All-cause, inpatient	“$3183 ($22,656)”	“$3214 ($22,840)”	“$3059 ($21,903)”	“0.272”
All-cause, durable medical equipment	“$535 ($1636)”	“$519 ($1589)”	“$599 ($1811)”	“<0.001”
All-cause, skilled nursing facility	“$1038 ($6818)”	“$1092 ($7020)”	“$825 ($5932)”	“<0.001”
All-cause, home health services	“$2282 ($5053)”	“$2270 ($5068)”	“$2327 ($4994)”	“0.077”
All-cause, hospice	“$955 ($6177)”	“$1014 ($6399)”	“$722 ($5187)”	“<0.001”
All-cause, pharmaceutical	“$6300 ($9567)”	“$5818 ($8568)”	“$8225 ($12,620)”	“<0.001”
Primary PD-related, total	“$3429 ($7431)”	“$2640 ($5646)”	“$6580 ($11,667)”	“<0.001”
Primary PD-related, medical	“$1882 ($5795)”	“$1634 ($5265)”	“$2877 ($7468)”	“<0.001”
Primary PD-related, outpatient	“$763 ($2344)”	“$619 ($1821)”	“$1334 ($3716)”	“<0.001”
Primary PD-related, inpatient	“$67 ($1643)”	“$44 ($1047)”	“$156 ($3017)”	“<0.001”
Primary PD-related, durable medical equipment	“$94 ($737)”	“$74 ($606)”	“$175 ($1111)”	“<0.001”
Primary PD-related, skilled nursing facility	“$65 ($1561)”	“$60 ($1515)”	“$84 ($1732)”	“0.037”
Primary PD-related, home health services	“$483 ($2004)”	“$428 ($1863)”	“$700 ($2476)”	“<0.001”
Primary PD-related, hospice	“$411 ($3902)”	“$406 ($3926)”	“$428 ($3803)”	“0.387”
Primary PD-related, pharmaceutical	“$1546 ($4431)”	“$1006 ($1947)”	“$3701 ($8783)”	“<0.001”
Any PD-related, total	“$9924 ($22,140)”	“$8922 ($21,524)”	“$13,923 ($24,037)”	“<0.001”
Any PD-related, medical	“$7133 ($21,473)”	“$6674 ($21,282)”	“$8968 ($22,124)”	“<0.001”
Any PD-related, outpatient	“$2199 ($3942)”	“$1925 ($3401)”	“$3289 ($5468)”	“<0.001”
Any PD-related, inpatient	“$2049 ($17,781)”	“$1970 ($17,781)”	“$2367 ($17,780)”	“0.001”
Any PD-related, durable medical equipment	“$145 ($904)”	“$120 ($787)”	“$241 ($1262)”	“<0.001”
Any PD-related, skilled nursing facility	“$550 ($4732)”	“$558 ($4781)”	“$519 ($4529)”	“0.218”
Any PD-related, home health services	“$1693 ($4279)”	“$1597 ($4181)”	“$2074 ($4629)”	“<0.001”
Any PD-related, hospice	“$499 ($4274)”	“$504 ($4337)”	“$477 ($4011)”	“0.327”
Any PD-related, pharmaceutical	“$2789 ($5103)”	“$2247 ($3147)”	“$4956 ($9201)”	“<0.001”

Distribution of costs across patients and drivers of the highest costs

“For instance, when examining any PD-related costs across patient deciles, mean costs were as low as $483 (SD, $166) in the lowest decile and as high as $48,145 (SD, $55,111) in the highest decile.” (opens the source at this quote in a new tab)
“More than half (57%) of the patients in the advanced PD group were in the four deciles with the highest costs (as compared with 35% of patients in the mild/moderate group), whereas more than half (54%) of the patients in the mild/moderate group were in the five deciles with the lowest costs (as compared with 30% of the advanced PD group).” (opens the source at this quote in a new tab)
“Further exploration of specific costs among the tenth (highest) decile compared with the next highest (ninth) decile revealed higher costs in every category we examined, with the biggest differences evident for inpatient and skilled nursing facility care (ie, inpatient costs $27,676 vs $2732 for the tenth vs ninth decile, respectively; skilled nursing care $9926 vs $408; Supporting Information Table S1).” (opens the source at this quote in a new tab)
“Among those in the mild/moderate group who incurred the highest (tenth decile) costs, 42% of those costs were related to inpatient services, 16% were due to home health care, and 13% were due to skilled nursing facility claims (Supporting Information Table S2).” (opens the source at this quote in a new tab)
“The pattern was even more pronounced for primary PD-related costs; the majority of patients in the advanced PD group (57%) were concentrated in the top three deciles (as compared with 23% of patients in the mild/moderate group; Fig. 2).” (opens the source at this quote in a new tab)
“The advanced PD group had mean unadjusted total all-cause costs ($24,988 [SD, $33,563]) that were approximately 10% higher than those of the mild/moderate group ($22,553 [SD, $34,147]), with the majority of the difference coming from higher pharmaceutical costs in the advanced PD group.” (opens the source at this quote in a new tab)
“In keeping with the fact that disease severity was assigned based on medication dose, mean primary PD-related pharmaceutical costs for the advanced PD group were more than triple those of the mild/moderate group ($3701 vs $1006, respectively) and represented a higher proportion of their overall primary PD-related costs (56% vs 38%; data not shown).” (opens the source at this quote in a new tab)
“One in three individuals in our mild/moderate PD group did not have a claim for a neurologist visit during our study year, nor did one in six individuals in our advanced PD group.” (opens the source at this quote in a new tab)

Risk-adjusted costs under alternative definitions of advanced disease

Cost type and definition of advanced disease	Mild/moderate PD, risk-adjusted mean, 2018 US$	Advanced PD, risk-adjusted mean, 2018 US$	Difference	95% CI of difference
All-cause, levodopa > 1000 mg/day	“$22,363”	“$26,688”	“$4325”	“$3862–$4788”
All-cause, LED > 800 mg/day	“$21,681”	“$26,433”	“$4751”	“$4426–$5077”
Primary PD-related, levodopa > 1000 mg/day	“$2923”	“$5657”	“$2734”	“$2578–$2890”
Primary PD-related, LED > 800 mg/day	“$2428”	“$5590”	“$3162”	“$3041–$3283”
Any PD-related, levodopa > 1000 mg/day	“$9103”	“$14,119”	“$5016”	“$4678–$5354”
Any PD-related, LED > 800 mg/day	“$8372”	“$13,708”	“$5336”	“$5090–$5582”

Sensitivity analyses, study limitations, and funding

“Sensitivity analyses using alternate medication thresholds to define advanced PD (ie, levodopa dose > 1000 mg and LED > 800 mg) produced incremental costs of advanced PD that were smaller across all categories, although patterns were similar (Table 3).” (opens the source at this quote in a new tab)
“The medication-based algorithm we used to determine advanced disease status is newly developed and has not undergone full validation testing.” (opens the source at this quote in a new tab)
“In contrast, the nature of Medicare claims may have led us to overestimate the true costs of pharmaceutical treatment, because the Part D event files do not capture manufacturer rebates, remuneration (price concessions), and final adjustment for risk sharing.” (opens the source at this quote in a new tab)
“Although our study offers important insights into the health care cost burden of advanced PD within fee-for-service Medicare, our results did not include and may not generalize to patients covered by Medicare Advantage plans that offer coverage for Medicare Parts A, B, and D together, or to those with fee-for-service Medicare without a Part D prescription drug plan.” (opens the source at this quote in a new tab)
“Further, Medicare does not cover the considerable costs of treatment in long-term care facilities, which have been shown to represent a substantial proportion of overall costs to Medicare beneficiaries.” (opens the source at this quote in a new tab)
“Financial support for the study was provided by AbbVie.” (opens the source at this quote in a new tab)

OFF episodes and healthcare resource utilization in the United States

“Within 5 years of initiating carbidopa/levodopa, ∼50% of patients with Parkinson's disease (PD) experience "OFF" episodes; little is known about the cost burden.” (opens the source at this quote in a new tab)
“Of 1,309 patients, 41% experienced "OFF" episodes, 25% of whom were "OFF" ≥4 h/day.” (opens the source at this quote in a new tab)
“In the past 12 months, the number of hospitalizations, intensive care admissions, and emergency room visits; nights hospitalized; costs of consultations and hospitalizations; and total direct costs were all higher for patients experiencing "OFF" episodes (p < .05).” (opens the source at this quote in a new tab)

Societal costs by Hoehn and Yahr stage and OFF time, Sweden

“Total average cost per patient-year was SEK 168,982 (EUR 15,958) and ranged from SEK 62,404 (EUR 5893) for H&Y stage I to SEK 1,056,324 (EUR 99,755) in H&Y stage V.” (opens the source at this quote in a new tab)
“The dominating part of total costs for early stages were indirect costs accounting for 50–60% while formal care made up for 55% and 81% of total costs in H&Y IV and V, respectively. Total mean costs for formal care, informal care, and productivity loss also increased with increasing off-time.” (opens the source at this quote in a new tab)
“The total mean cost per patient-year was SEK 168,982. Indirect costs accounted for 33% of total cost, formal care accounted for 30%, drugs for 13%, healthcare contacts for 12%, informal care for 11% and transports for less than 1%.” (opens the source at this quote in a new tab)

Registry population, cost methods, and study limitations, Sweden

“Annual costs of healthcare contacts, drugs, formal and informal care, and productivity loss associated with PD were estimated using data from PARKreg linked with regional and national healthcare registers between 2013 and 2019.” (opens the source at this quote in a new tab)
“In total, 960 patients and 1324 observations (patient-years) were included.” (opens the source at this quote in a new tab)
“In this study, we defined H&Y I-II as early stage, III-IV as advanced stage and V as late stage.” (opens the source at this quote in a new tab)
“Most patient-years were found in H&Y I and II (68%), whereas 25% were in H&Y III, 6% in H&Y IV and 1% in H&Y V.” (opens the source at this quote in a new tab)
“The variable was presented in the following categories: 0%, 1-<25%, 25-<50%, and 50–100%.” (opens the source at this quote in a new tab)
“Costs are expressed in Swedish kronor (SEK), 2019 prices.” (opens the source at this quote in a new tab)
“A limitation of the study is that total costs for PD might be underestimated since only healthcare contacts registered with a PD diagnosis as main diagnosis were included.” (opens the source at this quote in a new tab)
“Even though the sample in this study covers all disease severity stages, it should be noted that the sample size in H&Y IV-V is relatively low compared to stages I-III, that is, 6% of all the patient-years are found in H&Y stage IV and only 1% in H&Y stage V.” (opens the source at this quote in a new tab)
“Moreover, off-time is a rough patient-reported estimate which may be affected by a recall bias.” (opens the source at this quote in a new tab)
“The research has received financial support from AbbVie, Medtronic, and Nordic Infucare (Air Liquide Healthcare).” (opens the source at this quote in a new tab)

Cost per patient-year by cost category and Hoehn and Yahr stage, Sweden

Cost category	H&Y I (n = 410), mean (SD), SEK 2019	H&Y II (n = 493), mean (SD), SEK 2019	H&Y III (n = 334), mean (SD), SEK 2019	H&Y IV (n = 73), mean (SD), SEK 2019	H&Y V (n = 14), mean (SD), SEK 2019
Inpatient and outpatient care	“11 245 (22 974)”	“22 865 (55 696)”	“28 492 (50 114)”	“18 765 (19 923)”	“37 035 (94 172)”
Drugs	“10 783 (19 237)”	“18 296 (45 897)”	“31 307 (74 725)”	“69 283 (137 407)”	“60 221 (119 896)”
Formal care	“1 186 (12 783)”	“13 183 (120 159)”	“79 259 (279 433)”	“306 465 (372 060)”	“855 038 (606 877)”
Transport	“447 (844)”	“1 218 (5 254)”	“1147 (3 292)”	“2 061 (5 107)”	“1 075 (2 056)”
Informal care	“1 771 (21 700)”	“7 497 (38 903)”	“30 840 (94 830)”	“122 829 (259 001)”	“55 421 (139 705)”
Productivity loss	“36 974 (138 760)”	“67 383 (186 770)”	“63 351 (189 042)”	“37 266 (156 303)”	“47 535 (177 858)”

Cost per patient-year by cost category and time in OFF, Sweden

Cost category	0% of waking time in OFF (n = 826), mean (SD), SEK 2019	1% to <25% (n = 385), mean (SD), SEK 2019	25% to <50% (n = 94), mean (SD), SEK 2019	50% to 100% (n = 19), mean (SD), SEK 2019
Inpatient and outpatient care	“16 867 (42 326)”	“26 066 (48 136)”	“29 607 (63 105)”	“27 943 (28 305)”
Drugs	“14 050 (39 228)”	“37 372 (85 054)”	“33 738 (75 940)”	“33 355 (82 353)”
Formal care	“39 400 (206 111)”	“63 175 (212 497)”	“95 469 (323 878)”	“103 141 (256 321)”
Transport	“817 (2 391)”	“1360 (6 095)”	“1 311 (2 459)”	“529 (1 047)”
Informal care	“14 684 (86 443)”	“19 692 (84 972)”	“35 577 (90 886)”	“74 223 (117 835)”
Productivity loss	“35 368 (139 615)”	“78 878 (200 345)”	“105 617 (233 495)”	“179 653 (309 621)”

Resource use, drug costs, and formal care by disease stage, Sweden

“The percentage of patient-years with at least one stay increased from less than 1% in H&Y I to 14% in H&Y III, and 21% in H&Y V, whereas only 7% in H&Y IV had inpatient admissions.” (opens the source at this quote in a new tab)
“Overall mean drug cost was SEK 22,506. The mean costs in H&Y IV and V were considerable higher than for stages I and II.” (opens the source at this quote in a new tab)
“The mean (SD) cost for apomorphine infusion, LCIG, and LECIG was SEK 21,635 (85,168) for the 1-<25% off category compared to SEK 4053 (38,622) for the 0% (p < .001), SEK 17,756 (75,592) for the ≥25 to <50% (p < .01) and SEK 19,300 (84,127) for the ≥50% category (p < .01).” (opens the source at this quote in a new tab)
“Overall mean costs for formal care, including costs for nursing home, home help, personal assistance, home health care and electric wheelchair and scooter, were SEK 51,209. Home help and nursing home accounted for most of the costs, 50 and 30%, respectively.” (opens the source at this quote in a new tab)
“The use of informal care was considerably higher in H&Y IV than in the other stages, for 36% of the patient-years informal care of at least 1 h per week was reported and the mean number of hours per year was 634 h.” (opens the source at this quote in a new tab)
“In our study, the cost ranged from about a similar level in H&Y I, SEK 62,000, but to a considerably higher level in stage V, SEK 1 million mainly driven by costs for formal care and especially cost for nursing home (50% of the patient-years in H&Y V included costs for nursing home).” (opens the source at this quote in a new tab)

Long-term care facility residence among Medicare beneficiaries

“We identified 469,055 individuals with PD who received Medicare benefits in 2002. Nearly 25% (more than 100,000 in total) resided in an LTCF.” (opens the source at this quote in a new tab)
“Hip fracture (AOR 2.10, 95% CI 2.04–2.15) and dementia (AOR 4.06, 95% CI 4.00–4.12) were the strongest clinical predictors of LTCF placement.” (opens the source at this quote in a new tab)

Hospitalization costs in Parkinson's disease psychosis with incident dementia

“Approximately, 50.3% with PDP + D reported ≥1 all-cause IP hospitalizations versus 36.0% with PDP (p < 0.05) during 12-month follow-up.” (opens the source at this quote in a new tab)
“Mean PPPY all-cause IP hospitalization costs for PDP + D patients versus PDP patients was $17,891 (±29,882) versus $11,599 (±$25,247) (p < 0.05).” (opens the source at this quote in a new tab)
“No differences in mean PPPY LT-stay costs were seen (Figure 2).” (opens the source at this quote in a new tab)
“In fact, PDP + D patients had 30%–40% higher rates of inpatient hospitalizations.” (opens the source at this quote in a new tab)
“Additionally, examination of hospitalization costs showed that PDP + D reported 54% greater mean PPPY IP hospitalization costs and two times greater mean PPPY SNF‐stay costs compared to patients with PDP.” (opens the source at this quote in a new tab)

Study population, cost methods, and limitations in Parkinson's disease psychosis with incident dementia

“A total of 12,484 patients were eligible after our applying the study inclusion and exclusion criteria. Of these, 85.3% (n = 10,609) patients with PDP had a diagnosis for dementia in the post-PDP diagnosis period, while 14.7% (n = 1875) PDP patients did not have a diagnosis of dementia.” (opens the source at this quote in a new tab)
“Patients in both groups were matched using 1:1 propensity score matching (PSM) methodology using 31 variables (age, sex, race, region and 27 Elixhauser comorbidity characteristics).” (opens the source at this quote in a new tab)
“Patients were propensity score‐matched in a 1:1 ratio from the unmatched pool of PDP + D and PDP groups, yielding 1855 PDP + D and 1855 PDP patients.” (opens the source at this quote in a new tab)
“While other studies have posited that 80% of patients with PD progress to dementia in 2 decades, our analysis shows that approximately 85% of patients with PDP have incident dementia within a year after PDP diagnosis.” (opens the source at this quote in a new tab)
“Mean age (72 years), gender (50% males), race, and comorbidity profile were similar for both groups.” (opens the source at this quote in a new tab)
“Total cost for each claim, were calculated by adding the inpatient Medicare claim payment amount plus the claim pass through amount paid for the days stayed from the inpatient files.” (opens the source at this quote in a new tab)
“All cost amounts were inflated to 2019 dollars using the Medical Consumer Price Index (CPI) as reported by the US Bureau of Labor Statistics.” (opens the source at this quote in a new tab)
“Second, identification of psychosis was based on a diagnosis of psychosis-related hallucinations and delusions – so it is likely that PDP diagnosis is underestimated.” (opens the source at this quote in a new tab)
“Third, residual confounding may still exist, even though the study was adjusted for potential confounding issues through appropriate propensity score matching and covariate adjustment.” (opens the source at this quote in a new tab)
“Finally, it is important to acknowledge that diagnosis of dementia among patients with PDP may be difficult and, as such, result in underestimates of dementia diagnosis among these patients.” (opens the source at this quote in a new tab)
“This study was financially sponsored by Acadia Pharmaceuticals.” (opens the source at this quote in a new tab)

Hospitalization and emergency room visit rates by type of stay, psychosis with and without incident dementia

Outcome during 12-month follow-up	PDP without dementia (n = 1855), n (%)	PDP with incident dementia (n = 1855), n (%)	p-value
All-cause, any hospitalization	“667 (36.0)”	“933 (50.3)”	“<0.05”
All-cause, short-term stay	“662 (33.6)”	“839 (45.2)”	“<0.05”
All-cause, long-term stay	“113 (6.0)”	“158 (8.6)”	“<0.05”
All-cause, skilled nursing facility stay	“291 (15.6)”	“525 (28.4)”	“<0.05”
All-cause, emergency room visit	“1123 (60.6)”	“1346 (72.6)”	“<0.05”
Psychiatric, any hospitalization	“227 (12.2)”	“358 (19.2)”	“<0.05”
Psychiatric, short-term stay	“167 (9.0)”	“228 (12.3)”	“<0.05”
Psychiatric, long-term stay	“23 (1.2)”	“43 (2.4)”	“<0.05”
Psychiatric, skilled nursing facility stay	“64 (3.4)”	“140 (7.5)”	“<0.05”
Psychiatric, emergency room visit	“210 (11.3)”	“246 (13.2)”	“NS”

All-cause short-term, skilled nursing facility, and long-term stay percentages that differ between the abstract and the results

“Specifically, all-cause ST-stay, SNF-stay, and LT-stay among PDP + D versus PDP patients were: 45.2% versus 35.7%, 28.3% versus 15.7%, and 8.5% versus 6.0% (p < 0.05), respectively.” (opens the source at this quote in a new tab)
“Specifically, ST-stays stays were observed in” (opens the source at this quote in a new tab)
“45.2% of PDP + D patients and 33.6% of PDP patients (p < 0.05), while LT-stays were reported in 8.6% of PDP + D patients compared to 6.0% of PDP patients (p < 0.05). SNF-stays were also higher among PDP + D patients (28.4% vs. 15.6%; p < 0.05) compared to those with PDP.” (opens the source at this quote in a new tab)

Table 3, all-cause, during 12-month follow-up	PDP without dementia (n = 1855), n (%)	PDP with incident dementia (n = 1855), n (%)
Short-term stay	“662 (33.6)”	“839 (45.2)”
Skilled nursing facility stay	“291 (15.6)”	“525 (28.4)”
Long-term stay	“113 (6.0)”	“158 (8.6)”

Inpatient costs per patient per year by type of stay, psychosis with and without incident dementia

Type of inpatient stay	PDP without dementia, mean PPPY cost, 2019 US$	PDP without dementia, SD	PDP with incident dementia, mean PPPY cost, 2019 US$	PDP with incident dementia, SD
Any all-cause hospitalization	“$11,599”	“$25,247”	“$17,891”	“$29,882”
Short-term stay	“$6856”	“$16,339”	“$9394”	“$18,360”
Skilled nursing facility stay	“$3385”	“$10,056”	“$6700”	“$14,409”

End-of-life health care use among Medicare decedents

“In all groups, health care service utilization increased over the last year of life, and total costs were predominantly attributable to inpatient care. In the last 6 months of life, neurologist care was infrequent among patients with neurodegenerative disease (AD: 1.5%; PD: 8.6%; ALS: 32.0%).” (opens the source at this quote in a new tab)
“In the last 6 months of life (Table 2), ED utilization rates were greatest among decedents with pancreatic cancer (n = 8,009, 43.1%) and malignant brain tumors (n = 2,835, 42.8%), followed by decedents with PD (n = 20,400, 38.8%), ALS (n = 1,409, 36.2%), and AD (n = 97,022, 35.1%).” (opens the source at this quote in a new tab)

Care partner productivity losses in the United States

“Among the total indirect and non-medical costs of $26.5 billion, nearly $20 billion was attributed to PWPs and more than $6.5 billion was due to PD-related productivity losses among unpaid care partners.” (opens the source at this quote in a new tab)
“For the care partners, on-the-job productivity loss due to absenteeism and presentism surpassed that of PWPs because care partners on average were younger and more likely to be employed (13% employed among PWPs vs. 28% employed among primary and 66% among secondary, care partners).” (opens the source at this quote in a new tab)

Care partner cost components per person with Parkinson's disease

Cost component	Care partner loss, million $	Care partner loss per PWP, $
Reduced employment	“802”	“773”
Absenteeism	“3,655”	“3,524”
Presenteeism	“1,684”	“1,623”
Social productivity loss in volunteer work	“410”	“396”

Direct and indirect costs of working-age caregivers in the 5 years after diagnosis

“A total of 1211 eligible Parkinson's caregivers (mean age, 56 years; 54% female) were matched to 6055 controls.” (opens the source at this quote in a new tab)
“In adjusted analyses, Parkinson's caregivers incurred significantly higher year 1 total all‐cause insurer costs ($8999 vs $7117) and medical costs ($7081 vs $5568) (both P < 0.01) and higher prescription costs (range for years 1‐5, $2506‐2573 vs $1405‐$1687) and total out‐of‐pocket costs ($1259‐1585 vs $902‐$1192) in years 1‐5 (all P < 0.01).” (opens the source at this quote in a new tab)
“Parkinson's caregivers had significantly higher adjusted indirect costs in years 1‐3 (range for years 1‐3, $2054‐$2464 vs $1681‐$1857; all P < 0.05) and higher cumulative income loss over 5 years ($5967 vs $2634 by year 5; P for interaction = 0.03).” (opens the source at this quote in a new tab)

Caregiving hours and work loss reported in prior literature

“These indirect costs are substantial among caregivers, and approximately 30%‐40% of the total indirect costs associated with PD are attributable to lost earnings by caregivers and patients as well as hours required for caregiving.” (opens the source at this quote in a new tab)
“More than 25% of caregivers spend more than 70 hours per week caring for PD patients.” (opens the source at this quote in a new tab)
“Furthermore, a reported 26% of PD caretakers had to reduce or give up work, and 30.4% reported that their finances worsened as a result of caregiving.” (opens the source at this quote in a new tab)

Caregiver burden and workforce participation among United States family caregivers

“This sample reported significant caregiver burden (mean=40.2, SD=13.6), with 92.5% scoring above 17 which indicates high caregiver burden.” (opens the source at this quote in a new tab)
“In this sample of 40, many described being unable able to afford formal caregivers and discussed the decision to cut their own work hours or leave the workforce (e.g., retire) to provide the needed care themselves.” (opens the source at this quote in a new tab)

Risk factors for caregiver burden

“Forty-nine articles that involved 5387 caregivers of patients with PD were included in this study.” (opens the source at this quote in a new tab)
“All scales revealed caregivers of PD patients had mild to moderate caregiver burden. For the PD patients with longer disease duration, severer disease severity, more negative emotion and cognition impairment, their caregivers intended to have higher caregiver burden.” (opens the source at this quote in a new tab)
“Thirty-eight were cross-sectional studies, and eleven were clinic trails.” (opens the source at this quote in a new tab)
“As the included articles had a great deal of clinical heterogeneity in terms of participants, statistical methods and measurement tools. The results of systematic review were described by qualitative analysis.” (opens the source at this quote in a new tab)
“Caregiver spent 6.1 ± 4.5 h per day and 8.1 ± 4.9 years on caregiving.” (opens the source at this quote in a new tab)
“Sixty-four per cent (1465/2264) of patients were in H&Y stage ≤ 2.5, and thirty-two per cent (729/2264) had H&Y stage ≥ 3.” (opens the source at this quote in a new tab)
“All of these studies indicated a higher CB in both patients and caregivers with depression and anxiety.” (opens the source at this quote in a new tab)
“The caregiver burden was not improved after deep brain stimulation (DBS).” (opens the source at this quote in a new tab)

Care partner burden and good ON-time in advanced Parkinson's disease

“Care partner burden, as measured by the ZBI, did not significantly change with incremental increases in 'good ON-time' (regression coefficient − 0.74; 95% CI [− 2.08 to 0.60]; p = 0.276; Table 3).” (opens the source at this quote in a new tab)
“However, completed ZBI data were available for only 183 care partners, representing 22.8% of the total care partner population.” (opens the source at this quote in a new tab)

Reimbursement for dopamine transporter SPECT imaging in the United States

“Average reimbursement per study fell from $2,469 (US dollars) in 2011 to 2012 to $1,657 in 2014. CMS reduced average reimbursement by $1,148 in 2014 because of loss of radiopharmaceutical pass-through status.” (opens the source at this quote in a new tab)
“Average reimbursements from CMS versus private payors markedly differed in 2011 to 2012 at $2,266 versus $2,861, respectively, and in 2014 at $1,118 versus $3,470, respectively.” (opens the source at this quote in a new tab)
“The range of CMS payments narrowed over the two time periods from $0 to $2,254 (average $2,266 ± $452) in 2011 to 2012 to $674 to $1,621 (average $1,118 ± $119) in 2014. The range of private payor payments was larger than CMS payments during both time periods, with $0 to $8,754 (average $2,861 ± $2,054) in 2011 to 2012 and $112 to $9,675 (average $3,470 ± $1,570) in 2014.” (opens the source at this quote in a new tab)
“For example, the first 10 studies from private payors reimbursed, on average, $5,161 more per study than the first 10 CMS studies (average of $7,172 for private payors and $2,011 for CMS).” (opens the source at this quote in a new tab)
“Assuming that I-123 ioflupane cost $2,000, our model based on 2014 data predicts a practice with greater than 60% CMS patients would no longer recover radiopharmaceutical costs.” (opens the source at this quote in a new tab)

Payer mix and reimbursement per dopamine transporter SPECT study by payer and period

Measure	July 2011 to October 2012	January 2014 to December 2014	Difference between periods
CMS, share of studies	“134/247 (54.2%)”	“73/94 (77.7%)”	Not applicable
Private insurance, share of studies	“105/247 (42.5%)”	“21/94 (22.3%)”	Not applicable
Veterans Affairs Health Care System, share of studies	“6/247 (2.4%)”	“0/94 (0%)”	Not applicable
Self-pay, share of studies	“2/247 (0.9%)”	“0/94 (0%)”	Not applicable
CMS, average reimbursement (US$)	“$2,266”	“$1,118”	“-$1,148”
CMS, range of reimbursement (US$)	“$0-$2,254”	“$674-$1,621”	Not applicable
Private insurance, average reimbursement (US$)	“$2,861”	“$3,470”	“$609”
Private insurance, range of reimbursement (US$)	“$0-$8,754”	“$112-$9,675”	Not applicable
Private insurance minus CMS, average reimbursement (US$)	“$595”	“$2,369”	Not applicable

Imaging setting, study volume, and limitations of the reimbursement analysis

“Financial records are from studies performed in a hospital-based outpatient setting.” (opens the source at this quote in a new tab)
“Data included date of study, insurer name, and total reimbursement received (technical fee plus professional fee).” (opens the source at this quote in a new tab)
“Retrospective financial record review yielded 247 studies from July 2011 to October 2012 (average of 16.5 studies per month) and 94 studies from January 2014 to December 2014 (average of 7.8 studies per month), for a total of 341 studies.” (opens the source at this quote in a new tab)
“Thus, a limitation is that our data may not represent reimbursement from practices with free-standing facilities. Because reimbursement values can vary by region and may change rapidly over time, presented data may differ from the most recent values or imaging performed in other regions of the United States.” (opens the source at this quote in a new tab)

Pass-through status, scanner location, and break-even radiopharmaceutical cost

“Pass-through status assures that practices will recover radiopharmaceutical costs by providing a separate, nonbundled radiopharmaceutical payment for at least two years but no more than three years.” (opens the source at this quote in a new tab)
“Consequently, this reduced the total reimbursement for I-123 ioflupane imaging for hospital-based imaging by $1,148, a nearly 50% reduction compared to the year prior.” (opens the source at this quote in a new tab)
“Based on our own payor mix, the radiopharmaceutical cost at which our practice would break even was $2,469 in 2011 to 2012 and $1,657 in 2014.” (opens the source at this quote in a new tab)
“Dopamine transporter imaging performed at freestanding facilities will consequently receive higher CMS reimbursement ($1,148 higher in 2014) compared to hospital-based outpatient imaging.” (opens the source at this quote in a new tab)
“Practices that only have hospital-based scanners may experience financial difficulty providing imaging to CMS patients solely because of the physical location of the scanners.” (opens the source at this quote in a new tab)

Cost-effectiveness of dopamine transporter SPECT in suspected Parkinson's disease, Germany

“Compared strategies were CE only (EXAM+), SPECT only (SPECT+), SPECT following negative CE (SINGLE+), and SPECT following positive CE (DOUBLE+).” (opens the source at this quote in a new tab)
“Costs of SPECT amounted to €789 per investigation.” (opens the source at this quote in a new tab)
“Based on our model, expected costs (and ATME) were €946 (52.85 ATME) for EXAM+, €1352 (53.40 ATME) for DOUBLE+, €1731 (32.82 ATME) for SINGLE+, and €2003 (32.96 ATME) for SPECT+; performance of SPECT was induced in 0%, 54%, 56%, and 100% of the patients, respectively.” (opens the source at this quote in a new tab)
“DOUBLE+ was more effective and less expensive than SINGLE+ or SPECT+; thus these two do not offer reasonable choices. The ICER of DOUBLE+ compared to EXAM+ was €733 per ATME gained. In sensitivity analyses, the ICER of DOUBLE+ versus EXAM+ ranged from €63 to €2411 per ATME gained.” (opens the source at this quote in a new tab)
“If the decision-maker is not willing to spend approximately €733 for the equivalent of a patient-month with adequate treatment, the diagnostic work-up should include only a clinical examination.” (opens the source at this quote in a new tab)
“SPECT should be used as a confirmatory test before treatment initiation and limited to patients with a positive test result in the clinical examination.” (opens the source at this quote in a new tab)

Decision model structure, perspective, and treatment costs, Germany

“We developed a decision tree model for several diagnostic work-up strategies to determine diagnostic, therapeutic, and economic outcomes in patients with symptoms of PD who present to a specialized movement disorder outpatient clinic.” (opens the source at this quote in a new tab)
“We assumed that the correct diagnosis (PD or not) will be available in all patients after 12 months, and therefore chose a time horizon of 12 months.” (opens the source at this quote in a new tab)
“We considered that only patients in Hoehn and Yahr (HY) stage I or II would be examined.” (opens the source at this quote in a new tab)
“In the model, we counted how many months during the 1-year time horizon each individual was treated appropriately, that is, the number of months a patient with PD received antiparkinsonian therapy or the number of months an individual without PD did not receive such treatment.” (opens the source at this quote in a new tab)
“The consequence ratio ranged from 5 to 12, with a mean of 8.5.” (opens the source at this quote in a new tab)
“Economic outcomes included the cost for diagnostic procedures and PD treatment costs. All costs were based on 2002 values. We adopted the perspective of the health care provider.” (opens the source at this quote in a new tab)
“1 full year of PD treatment is associated with medication costs of €1,535 or €128 per patient-month. Including initial and follow-up clinical examinations but assuming no SPECT investigation increases the 1-year health care costs to a total of €1,689, which translates to an average of €141 per patient month.” (opens the source at this quote in a new tab)

Model inputs, SPECT cost components, and ranges tested in sensitivity analyses

Parameter	Base case (costs in euros, 2002 values)	Range in sensitivity analyses
Prevalence of PD among referred patients	“0.53”	“0.20–0.74”
Prevalence of parkinsonism among referred patients	“0.74”	Not applicable
Sensitivity of FP-CIT SPECT for parkinsonism	“0.975”	“0.90–1.0”
Specificity of FP-CIT SPECT for parkinsonism	“1.0”	“0.73–1.0”
Sensitivity of clinical examination for PD	“0.911”	“0.60–0.911”
Specificity of clinical examination for PD	“0.984”	“0.80–0.984”
Radionuclide tracer for FP-CIT SPECT	“746.50”	“373.25–1,493.00”
PD medication per year	“1,534.50”	“767.25–3,069.00”
Initial examination, including tests	“117.98”	“59.00–236.00”
Clinical follow-up examination	“18.50”	“9.25–37.00”
Gamma camera cost per SPECT investigation	“16.22”	Not applicable
Mean personnel cost per SPECT investigation	“25.88”	Not applicable
Total cost per SPECT investigation	“788.60”	Not applicable
Consequence ratio	“8.5”	“1–20”

Base-case expected cost, effectiveness, and ICER by diagnostic strategy

Strategy	Expected 1-year cost per patient (euros)	Adequate treatment month equivalents	ICER (euros per ATME)
Clinical examination only (EXAM+)	“946”	“52.8”	Not applicable
SPECT after positive clinical examination (DOUBLE+)	“1,352”	“53.4”	“733”
SPECT after negative clinical examination (SINGLE+)	“1,731”	“32.8”	“Dom”
SPECT only (SPECT+)	“2,003”	“33.0”	“Dom”

One-way sensitivity analyses, SPECT after positive clinical examination versus clinical examination only

Varied parameter and value	EXAM+ cost (euros)	EXAM+ ATME	DOUBLE+ cost (euros)	DOUBLE+ ATME	DOUBLE+ ICER (euros per ATME)
Base case	“946”	“52.8”	“1,352”	“53.4”	“733”
Prevalence of PD 0.74	“1,245”	“34.3”	“1,810”	“34.6”	“2,411”
Prevalence of PD 0.40	“761”	“64.3”	“1,068”	“65.1”	“409”
Prevalence of PD 0.20	“476”	“81.9”	“632”	“83.0”	“148”
Sensitivity of clinical examination 0.76	“864”	“52.2”	“1,249”	“52.8”	“700”
Sensitivity of clinical examination 0.60	“758”	“51.4”	“1,100”	“51.9”	“619”
Specificity of clinical examination 0.90	“1,033”	“47.0”	“1,451”	“50.7”	“113”
Specificity of clinical examination 0.80	“1,131”	“40.6”	“1,563”	“47.5”	“63”
Sensitivity of FP-CIT SPECT 1.00	“946”	“52.8”	“1,663”	“53.5”	“666”
Sensitivity of FP-CIT SPECT 0.90	“946”	“52.8”	“1,319”	“53.2”	“1,109”
Specificity of FP-CIT SPECT 0.73	“946”	“52.8”	“1,355”	“53.2”	“1,062”
Tracer cost doubled	“946”	“52.8”	“1,756”	“53.4”	“1,462”
Tracer cost halved	“946”	“52.8”	“1,150”	“53.4”	“369”
Initial examination cost doubled	“1,064”	“52.8”	“1,470”	“53.4”	“733”
Initial examination cost halved	“887”	“52.8”	“1,293”	“53.4”	“733”
Medication cost doubled	“1,737”	“52.8”	“2,123”	“53.4”	“696”
Medication cost halved	“551”	“52.8”	“967”	“53.4”	“752”
Consequence ratio 1	“946”	“11.6”	“1,352”	“11.5”	“Dom”
Consequence ratio 5	“946”	“33.6”	“1,352”	“33.9”	“1,397”
Consequence ratio 12	“946”	“72.1”	“1,352”	“72.9”	“497”
Consequence ratio 20	“946”	“116.2”	“1,352”	“117.6”	“286”

Cost of SPECT after positive clinical examination that is inconsistent with its ICER at a SPECT sensitivity of 1.00

Table 5 row	EXAM+ cost (euros)	EXAM+ ATME	DOUBLE+ cost (euros)	DOUBLE+ ATME	DOUBLE+ ICER (euros per ATME)
Base case	“946”	“52.8”	“1,352”	“53.4”	“733”
Sensitivity of FP-CIT SPECT 1.00	“946”	“52.8”	“1,663”	“53.5”	“666”

Interpretation of the incremental gain and limitations of the decision model

“Although DOUBLE+ was more expensive than EXAM+, DOUBLE+ also yielded between 0.23 and 6.91 additional ATMEs with ICERs varying from €63 to €2,411 per ATME, depending on the parameters varied in the sensitivity analyses. Only for consequence ratios smaller than 1.2, which was outside of the expert’s range, EXAM+ was more effective than DOUBLE+. The ICER of DOUBLE+ compared to EXAM+ improved (i.e., decreased) with decreasing prevalence of PD, decreasing accuracy of clinical examination, increasing accuracy of SPECT, and increasing consequence ratio.” (opens the source at this quote in a new tab)
“This strategy remains more expensive than clinical examination only: the expected clinical gain was 0.55 ATMEs and the additional average costs were €406 for each patient of the target population (including those after negative clinical examination).” (opens the source at this quote in a new tab)
“This result represents either assigning 17 additional days of treatment to a patient with PD or withholding about 2 additional days (i.e., 17 divided by 8.5) of treatment and side effects from a patient without PD.” (opens the source at this quote in a new tab)
“However, as in all diagnostic studies, the optimal test strategy depends on the pretest probability of the disease, in this case the prevalence of PD.” (opens the source at this quote in a new tab)
“Increasing PD prevalence to 74%, which may not be entirely unlikely for a highly specialized movement disorder clinic, leads to an ICER of more than €2,400 per ATME.” (opens the source at this quote in a new tab)
“As data were lacking on health-related quality of life indices (utilities) in early treated and nontreated patients with and without PD, we were unable to convert this outcome into QALYs, which was suggested for the reference case of a cost–effectiveness analyses.” (opens the source at this quote in a new tab)
“Hence, our analysis may be biased against SPECT and overestimating the true cost–effectiveness ratios of this technology.” (opens the source at this quote in a new tab)
“Third, we did not consider other types of parkinsonian syndromes such as multisystem atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBGD), or Lewy body disease in our decision analysis.” (opens the source at this quote in a new tab)
“Fifth, it must be kept in mind that the results of this study are limited to a specialized movement disorder clinic.” (opens the source at this quote in a new tab)

Cost-effectiveness of dopamine transporter SPECT for differentiating essential tremor from Parkinson's disease, Italy

“The model suggests that over 5 years, the "current" diagnostic pathway generated an average of 2.3 PBTYs/patient at an estimated cost of 8,864 euros. (123)I-FP-CIT SPECT generated an average of 4.1 PBTYs/patient at an estimated cost of 8,422 euros, which represented an additional 1.8 PBTYs at a cost saving of 442 euros/patient (341 euros when discounted at 5%).” (opens the source at this quote in a new tab)

Effect of dopamine transporter SPECT on management of early probable Parkinson's disease

“There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11).” (opens the source at this quote in a new tab)
“In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm.” (opens the source at this quote in a new tab)

Cost of alpha-synuclein seed amplification assay and skin biopsy testing

No evidence found.

Initial therapy: levodopa compared with dopamine agonists in early disease

“Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia.” (opens the source at this quote in a new tab)
“Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease.” (opens the source at this quote in a new tab)
“There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa.” (opens the source at this quote in a new tab)
“The trend over time demonstrates that levodopa provides greater benefit for motor symptoms than DAs, with the majority of studies demonstrating significantly greater improvement in the participants’ UPDRS part III score for up to 5 years of follow-up.” (opens the source at this quote in a new tab)
“With longer periods of follow-up, an increasing proportion of participants (90% of patients at 6 years and 100% at 10 years) originally randomized to DAs were taking supplemental levodopa, therefore minimizing the difference between groups for this outcome.” (opens the source at this quote in a new tab)
“Initial treatment with levodopa is more likely to induce dyskinesia than initial treatment with DAs for up to 5 years of follow-up, but the prevalence of severe or disabling dyskinesia during this 5-year period is low.” (opens the source at this quote in a new tab)
“The minimal clinically important difference (MCID) in the UPDRS part III score was determined by consensus to be 3 points; changes of 1 point or less were considered unimportant.” (opens the source at this quote in a new tab)
“The MCID in the risk of dyskinesia was determined by consensus to be 15%; RDs ≤5% were considered clinically unimportant.” (opens the source at this quote in a new tab)

Time point	Change in UPDRS part III score, raw mean difference, levodopa minus dopamine agonist (negative values favor levodopa)	Dyskinesia, risk difference, levodopa minus dopamine agonist (positive values indicate higher risk with levodopa)
2 years	“−5.0 [−7.2 to −2.5], moderate confidence”	“18.7% [95% confidence interval (CI) 13.7%–23.8%], moderate confidence”
4 years	“−4.9 [−7.8 to −1.9], low confidence”	“29.2% [19.6%–38.8%], moderate confidence”
5 years	“−3.4 [−5.2 to −1.6], moderate confidence”	“17.5% [4.5%–30.5%], low confidence”

Guideline recommendations for prescribing levodopa in early disease

“Clinicians should initially prescribe IR levodopa rather than CR levodopa or levodopa/carbidopa/entacapone in patients with early PD.” (opens the source at this quote in a new tab)
“In patients with early PD, clinicians should prescribe the lowest effective dose of levodopa (i.e., the lowest dose that provides adequate symptomatic benefit) to minimize the risk of dyskinesia and other adverse effects.” (opens the source at this quote in a new tab)
“Clinical trials in early PD demonstrate symptomatic benefit with levodopa/carbidopa at dosages of 150–300 mg/d and a lower risk of dyskinesia with dosages less than 400 mg/d.” (opens the source at this quote in a new tab)
“IR levodopa is less costly than other levodopa formulations.” (opens the source at this quote in a new tab)

First-line treatment recommendations in the United Kingdom

“Offer levodopa to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life.” (opens the source at this quote in a new tab)
“Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO‑B) inhibitors for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life.” (opens the source at this quote in a new tab)

Levodopa as the reference symptomatic therapy

“Pharmacological dopamine substitution is the mainstay of medical management of PD motor symptoms and levodopa combined with a dopa decarboxylase inhibitor (DDCI) still remains the gold-standard of symptomatic efficacy” (opens the source at this quote in a new tab)
“IPX203 was approved by the FDA in 2024 for the treatment of PD and is marketed in the US as Crexont® at levodopa dose sizes of 140 mg, 210 mg, 280 mg and 350 mg each combined with carbidopa in a ratio of 4:1.” (opens the source at this quote in a new tab)

Extended-release levodopa for motor fluctuations

“One trial evaluated the use of IPX066 for reducing OFF‐time compared with levodopa carbidopa immediate release, showing a difference between groups of 1.2 h (P < 0.0001) in favor of IPX066.” (opens the source at this quote in a new tab)
“There is insufficient evidence to support the efficacy of levodopa carbidopa controlled release to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: placebo-controlled trial

“The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and −1.4 in those receiving 600 mg daily (P<0.001).” (opens the source at this quote in a new tab)
“The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.” (opens the source at this quote in a new tab)
“Of a total of 361 subjects enrolled in the study, 317 (88 percent) took the study medication for 40 weeks, and 311 (86 percent) completed the 2 weeks of washout (Fig. 1).” (opens the source at this quote in a new tab)
“We need to consider that a two-week washout from levodopa may have been insufficient to eliminate fully the effect of the medication on symptoms, and the results observed may be related to a profound effect of levodopa on symptoms that persists for a long time after the drug has been withdrawn.” (opens the source at this quote in a new tab)
“The clinical data suggest that levodopa either slows the progression of Parkinson’s disease or has a prolonged effect on the symptoms of the disease.” (opens the source at this quote in a new tab)
“In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter.” (opens the source at this quote in a new tab)
“The potential long-term effects of levodopa on Parkinson’s disease remain uncertain.” (opens the source at this quote in a new tab)
“At the end of the study, when the SPECT neuroimaging studies were performed, the subjects were still taking levodopa, so it is possible to assume that levodopa has a pharmacologic effect on the dopamine transporter that interferes with and reduces the binding of the β-CIT ligand.” (opens the source at this quote in a new tab)

Characteristic	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value
Participants, no.	“90”	“92”	“88”	“91”	Not applicable
Male sex, %	“72”	“63”	“67”	“68”	“0.62”
White race, %	“90”	“91”	“93”	“88”	“0.67”
Age, years, mean ± SD	“64.9±10.3”	“64.3±10.6”	“63.8±12.1”	“65.2±10.7”	“0.84”
Duration of disease, months, mean ± SD	“5.3±5.6”	“5.7±6.1”	“7.6±7.5”	“6.0±6.1”	“0.10”
Total UPDRS score, mean ± SD	“27.7±12.0”	“27.2±12.6”	“27.5±11.6”	“29.4±13.9”	“0.63”
UPDRS motor component, mean ± SD	“18.8±8.9”	“18.6±9.1”	“18.9±8.8”	“20.5±10.8”	“0.51”
Hoehn–Yahr scale score, mean ± SD	“1.8±0.5”	“1.9±0.6”	“1.8±0.5”	“1.9±0.6”	“0.57”

Change from baseline to week 42, mean ± SD	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value for trend
Primary rater, participants, no.	“70”	“78”	“82”	“81”	Not applicable
Primary rater, total UPDRS score	“7.8±9.0”	“1.9±6.0”	“1.9±6.9”	“−1.4±7.7”	“<0.001”
Primary rater, mental component	“0.3±1.5”	“0.0±1.5”	“0.1±1.2”	“0.1±1.4”	“0.18”
Primary rater, ADL component	“2.3±3.4”	“0.5±2.3”	“0.4±2.9”	“−0.3±3.0”	“<0.001”
Primary rater, motor component	“5.2±6.4”	“1.4±5.5”	“1.4±5.3”	“−1.4±5.9”	“<0.001”
Treating investigator, total UPDRS score	“9.0±10.4”	“4.0±8.2”	“4.0±8.4”	“1.0±9.9”	“<0.001”
Treating investigator, mental component	“0.5±1.3”	“−0.1±1.4”	“0.1±1.4”	“0.1±1.6”	“0.31”
Treating investigator, ADL component	“2.5±4.0”	“0.8±3.1”	“1.0±2.8”	“0.3±3.5”	“<0.001”
Treating investigator, motor component	“6.0±7.6”	“3.2±6.4”	“3.0±6.4”	“0.6±7.7”	“<0.001”

Striatal β-CIT uptake, change from baseline to week 40	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value for dose–response
Substudy cohort, participants, no.	“29”	“33”	“37”	“36”	Not applicable
Substudy cohort, change, %, mean ± SD	“−2.6±11.3”	“−4.7±10.8”	“−3.7±9.1”	“−6.9±8.1”	“0.15”
Substudy cohort, P value compared with placebo	Not applicable	“0.46”	“0.63”	“0.11”	Not applicable
Excluding scans without dopaminergic deficit, participants, no.	“26”	“28”	“34”	“28”	Not applicable
Excluding scans without dopaminergic deficit, change, %, mean ± SD	“−1.4±10.0”	“−6.0±10.3”	“−4.0±9.4”	“−7.2±7.6”	“0.036”
Excluding scans without dopaminergic deficit, P value compared with placebo	Not applicable	“0.16”	“0.40”	“0.015”	Not applicable

Dose-dependent dyskinesia, wearing off, and other adverse events over 40 weeks of levodopa

Adverse event	Placebo (N = 90)	Levodopa 150 mg/day (N = 92)	Levodopa 300 mg/day (N = 88)	Levodopa 600 mg/day (N = 91)	P value for trend
Dyskinesia, no. (%)	“3 (3.3)”	“3 (3.3)”	“2 (2.3)”	“15 (16.5)”	“<0.001”
Dystonia, no. (%)	“19 (21.1)”	“19 (20.7)”	“14 (15.9)”	“12 (13.2)”	“0.30”
Wearing off, no. (%)	“12 (13.3)”	“15 (16.3)”	“16 (18.2)”	“27 (29.7)”	“0.06”
On–off, no. (%)	“3 (3.3)”	“1 (1.1)”	“0”	“3 (3.3)”	“0.26”
Freezing of gait, no. (%)	“13 (14.4)”	“9 (9.8)”	“6 (6.8)”	“5 (5.5)”	“0.15”
Nausea, no. (%)	“12 (13.3)”	“15 (16.3)”	“23 (26.1)”	“29 (31.9)”	“0.001”
Headache, no. (%)	“3 (3.3)”	“7 (7.6)”	“5 (5.7)”	“12 (13.2)”	“0.03”
Hypertonia, no. (%)	“1 (1.1)”	“0”	“1 (1.1)”	“5 (5.5)”	“0.03”
Infection, no. (%)	“1 (1.1)”	“0”	“0”	“6 (6.6)”	“0.01”
Dizziness, no. (%)	“6 (6.7)”	“10 (10.9)”	“5 (5.7)”	“14 (15.4)”	“0.13”
Somnolence, no. (%)	“2 (2.2)”	“0”	“5 (5.7)”	“5 (5.5)”	“0.07”
Fracture, no. (%)	“4 (4.4)”	“0”	“0”	“0”	“0.01”
Leg pain, no. (%)	“7 (7.8)”	“6 (6.5)”	“3 (3.4)”	“0”	“0.006”

“High doses, however, were associated with a greater frequency of adverse events such as dyskinesia.” (opens the source at this quote in a new tab)
“For the present, until more evidence is available, we recommend customizing the dose of levodopa to the needs of the individual patient on the basis of the clinical response and the profile of adverse events.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: delayed-start trial

“A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group.” (opens the source at this quote in a new tab)
“The change in UPDRS score from baseline to week 80 was −1.0±13.1 points and −2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], −1.5 to 3.5; P = 0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect.” (opens the source at this quote in a new tab)
“The change in the UPDRS score from baseline to week 40 was −3.1±10.2 in the early-start group and 2.0±12.3 in the delayed-start group (difference, −5.1 points; 95% CI, −7.2 to −2.9), favoring the early-start group and reflecting the effect of levodopa on symptoms of the disease.” (opens the source at this quote in a new tab)
“Because of a need for symptomatic relief, 87 patients in the delayed-start group proceeded to receive the phase 2 trial medication (levodopa) before week 40, and 24 patients in the early-start group proceeded to open-label treatment with the same dose of levodopa.” (opens the source at this quote in a new tab)
“The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.” (opens the source at this quote in a new tab)
“During the first 40 weeks of the trial, the incidence of nausea was higher in the early-start group than in the delayed start-group (23.0% vs. 14.3%, P = 0.02) (Table 3).” (opens the source at this quote in a new tab)
“At 80 weeks, the percentage of patients with motor complications, including dyskinesias and fluctuations in motor response, did not differ significantly between the two groups (Table S5 in the Supplementary Appendix).” (opens the source at this quote in a new tab)
“In patients with early Parkinson’s disease, the clinical diagnosis may be incorrect in up to 15% of patients.” (opens the source at this quote in a new tab)
“Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: 5-year follow-up of the delayed-start trial

“A total of 321 patients completed the 5-year visit.” (opens the source at this quote in a new tab)
“The adjusted square root transformed total Unified Parkinson’s Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07).” (opens the source at this quote in a new tab)
“We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years.” (opens the source at this quote in a new tab)
“A total of 413 patients (93%) still had the diagnosis PD, and 27 patients (6%) did not have PD.” (opens the source at this quote in a new tab)
“A substantial strength of the study is the high proportion of originally randomly assigned patients (77%) who completed the 5-year follow-up, minimizing the risk of bias caused by dropout.” (opens the source at this quote in a new tab)
“Another limitation is the absence of a distinction between on or off drug state (ie, wearing off) while the UPDRS motor score was administrated.” (opens the source at this quote in a new tab)
“During the study, 11 of 205 patients (5%) in the earlystart group and 22 of 213 patients (10%) in the delayed-start group died (P = 0.06).” (opens the source at this quote in a new tab)
“However, the difference in unadjusted between-group total UPDRS change score from baseline to 5 years is below the clinically important difference” (opens the source at this quote in a new tab)
“The outcomes were square root transformed due to skewness.” (opens the source at this quote in a new tab)
“An estimate higher than zero indicates a higher score in the early-start group.” (opens the source at this quote in a new tab)

Outcome	Early-start group, change from baseline, mean ± SD	Delayed-start group, change from baseline, mean ± SD	Estimated difference, square root transformed (SE)	P value
3 years, UPDRS total (I + II + III)	“2.6±11.4”	“0.9±12.8”	“0.17 (0.13)”	“0.18”
3 years, UPDRS I	“−0.2±1.8”	“−0.3±1.8”	“0.07 (0.09)”	“0.45”
3 years, UPDRS II	“1.3±4.2”	“1.1±3.7”	“0.03 (0.08)”	“0.68”
3 years, UPDRS III	“1.5±8.8”	“0.1±9.7”	“0.16 (0.11)”	“0.18”
3 years, UPDRS IV	“1.0±1.9”	“1.4±2.4”	“−0.13 (0.09)”	“0.18”
3 years, Levy A	“0.6±7.2”	“−0.4±8.1”	“0.14 (0.11)”	“0.20”
3 years, Levy B	“0.7±2.1”	“0.6±2.2”	“0.02 (0.08)”	“0.83”
5 years, UPDRS total (I + II + III)	“11.5±17.0”	“8.2±16.2”	“0.24 (0.13)”	“0.07”
5 years, UPDRS I	“0.4±2.2”	“0.2±1.9”	“0.11 (0.08)”	“0.17”
5 years, UPDRS II	“3.7±4.7”	“3.2±5.3”	“0.09 (0.08)”	“0.25”
5 years, UPDRS III	“7.4±13.7”	“4.7±11.9”	“0.21 (0.12)”	“0.09”
5 years, UPDRS IV	“2.4±2.9”	“2.2±2.4”	“<0.01 (0.09)”	“0.97”
5 years, Levy A	“4.7±10.9”	“2.9±9.4”	“0.15 (0.12)”	“0.20”
5 years, Levy B	“2.1±3.0”	“1.5±2.4”	“0.11 (0.08)”	“0.16”

Timing of levodopa initiation and motor complications: meta-analysis

“Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis.” (opens the source at this quote in a new tab)
“There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11).” (opens the source at this quote in a new tab)
“Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD.” (opens the source at this quote in a new tab)

Initial levodopa compared with levodopa-sparing therapy: evidence-based review conclusions

“Of importance, these studies showed superior benefit of levodopa over DAs in improving motor scores and, where assessed, quality of life, and significantly more nonmotor side effects have been reported with DAs.” (opens the source at this quote in a new tab)
“In addition, in longer term follow-up, the available evidence suggests that there is no clinically relevant difference on motor function, troublesome motor complications, or mortality according to the choice of initial therapy.” (opens the source at this quote in a new tab)
“Factors to be taken into account include the higher risk of motor complications in younger onset patients and personal circumstances.” (opens the source at this quote in a new tab)
“These may include the need for rapid improvement, for example, for reasons of employment (which would favor initial levodopa) or the predominant need or desire to delay dyskinesia for as long as possible (which favors levodopa-sparing initial treatments).” (opens the source at this quote in a new tab)

Levodopa compared with levodopa-sparing initial therapy: pragmatic trial

“Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI).” (opens the source at this quote in a new tab)
“With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5–3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years’ observation.” (opens the source at this quote in a new tab)
“Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy.” (opens the source at this quote in a new tab)
“Patients in the levodopa group were more likely to develop dyskinesias than those in the levodopa-sparing group (hazard ratio [HR] 1·52, 95% CI 1·16–2·00, p=0·003; figure 5), but there was no difference in motor fluctuations (1·11, 0·90–1·37, p=0·3; appendix).” (opens the source at this quote in a new tab)
“Thus, the benefits of levodopa compared with levodopa-sparing are unquestionably small.” (opens the source at this quote in a new tab)
“Thus, there seem to be no grounds for concerns that use of levodopa as first-line therapy results in worse long-term outcome.” (opens the source at this quote in a new tab)

Guideline recommendations for dopamine agonists as initial therapy

“Clinicians may prescribe dopamine agonists as the initial dopaminergic therapy to improve motor symptoms in select early PD in patients <60 years who are at higher risk for the development of dyskinesia.” (opens the source at this quote in a new tab)
“Clinicians should not prescribe dopamine agonists to patients with early-stage PD at higher risk of medication-related adverse effects, including individuals >70 years-of-age, patients with a history of ICDs, and patients with pre-existing cognitive impairment, excessive daytime sleepiness, or hallucinations.” (opens the source at this quote in a new tab)
“Clinicians should prescribe the lowest dose of dopamine agonist required to provide therapeutic benefit.” (opens the source at this quote in a new tab)

Comparative evidence among dopamine agonists and formulations

“This systematic review did not uncover strong evidence supporting the use of ropinirole vs pramipexole for the treatment of early PD.” (opens the source at this quote in a new tab)
“There are preliminary observational data that long-acting and transdermal formulations of dopamine agonists have lower rates of ICDs than short-acting formulations.” (opens the source at this quote in a new tab)
“Clinicians may opt to increase dosages gradually, stopping at the lowest dosage that is recognized to have clinical efficacy (6–9 mg/d of ropinirole, 1.5 mg/d of pramipexole, or 4 mg/24hrs of rotigotine).” (opens the source at this quote in a new tab)

Dopamine agonists compared with levodopa in early disease: impulse control disorders and other adverse effects

“DAs (vs levodopa) are associated with an increased risk of ICDs, EDS, sudden-onset sleep, nausea, and hallucinations in patients with early PD.” (opens the source at this quote in a new tab)
“Conclusion (moderate confidence): In early PD, DAs are probably more likely than levodopa to cause ICDs at 2 years (3 Class III studies, RD 23.2%, 95% confidence interval [CI] 14.3–32.1).” (opens the source at this quote in a new tab)
“Conclusion (low confidence): In early PD, DAs are possibly more likely than levodopa to cause ICDs at 5 years (2 Class III studies, RD 23.7%, 95% CI 1.1–46.3).” (opens the source at this quote in a new tab)
“The MCID in the risk of ICDs was determined by consensus to be 2%; RDs ≤1% were considered clinically unimportant.” (opens the source at this quote in a new tab)
“Although initial treatment with DAs is possibly more likely to cause hallucinations than treatment with levodopa, the difference between treatments for this outcome is small for the first 5 years of treatment.” (opens the source at this quote in a new tab)
“Although the trend suggests that AE-related discontinuation of treatment is higher with DAs than with levodopa at all time points, confidence in the evidence is low or very low due to study quality or poor precision of estimates.” (opens the source at this quote in a new tab)

Non-ergot dopamine agonists: evidence-based review implications for clinical practice by indication

Agent	Implication for clinical practice: symptomatic monotherapy	Implication for clinical practice: adjunct to levodopa in early or stable disease	Implication for clinical practice: motor fluctuations
Pramipexole immediate release	“Clinically useful”	“Clinically useful”	“Clinically useful”
Pramipexole extended release	“Clinically useful”	“Clinically useful”	“Clinically useful”
Ropinirole immediate release	“Clinically useful”	“Clinically useful”	“Clinically useful”
Ropinirole prolonged release	“Possibly useful”	Not reported	“Clinically useful”
Rotigotine	“Clinically useful”	“Clinically useful”	“Clinically useful”

“The relative efficacy of the different DAs appears to be similar.” (opens the source at this quote in a new tab)
“However, there is no evidence of clinical superiority in terms of tolerability or short- and long-term benefits of one DA over the other, including delaying or preventing motor fluctuations (as discussed previously).” (opens the source at this quote in a new tab)
“Deciding which DA to add is thus based on local availability and cost, and the decision whether to switch to a different DA later depends on individual tolerability/efficacy.” (opens the source at this quote in a new tab)
“All widely clinically available nonergot oral and transdermal dopamine agonists are “clinically useful” for reducing motor fluctuations.” (opens the source at this quote in a new tab)

Adjunctive dopamine agonists for motor fluctuations: guideline recommendation

“Offer a choice of dopamine agonists, MAO‑B inhibitors or catechol‑O‑methyl transferase (COMT) inhibitors as an adjunct to levodopa for people with Parkinson's disease who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy, after discussing:” (opens the source at this quote in a new tab)
“Choose a non-ergot-derived dopamine agonist in most cases, because of the monitoring that is needed with ergot-derived dopamine agonists.” (opens the source at this quote in a new tab)

Efficacy conclusions for dopamine agonists in motor fluctuations

“Pramipexole immediate release and extended release are efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“Ropinirole immediate release is efficacious to treat motor fluctuations in PD patients on oral levodopa therapy. Ropinirole prolonged release and ropinirole patch are likely efficacious to treat motor fluctuations in PD patients on oral levodopa therapy.” (opens the source at this quote in a new tab)
“They found a statistically significant and clinically meaningful reduction of OFF‐time by 0.9–1.8 h compared with placebo.” (opens the source at this quote in a new tab)

Adjunctive dopamine agonists: pooled off-time reduction

“DRAs produced a reduction in daily off-medication time with a WMD of −1.1 hours (95% CI −1.4 to −0.8) compared with placebo, whereas both COMT-Is and MAOB-Is were associated with a WMD of −0.8 hours (95% CI −1.0 to −0.6) and −0.9 hours (95% CI −1.2 to −0.6), respectively.” (opens the source at this quote in a new tab)
“Intraclass comparison showed that of the DRAs, pramipexole immediate-release (IR) provided the largest reduction in daily off-medication time with −2.2 hours (95% CI −2.7 to −1.6).” (opens the source at this quote in a new tab)
“The results of the current systematic review suggest that DRAs should be considered as the primary treatment choice for adjunctive oral therapy in PD with motor complications.” (opens the source at this quote in a new tab)

Adjunctive dopamine agonists: network meta-analysis ranking

“According to the SUCRA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in change in daily off-time, followed by pramipexole (0.762), ropinirole ER (0.750), and safinamide (0.691) (Fig. 4, Supplementary Fig. 5A).” (opens the source at this quote in a new tab)
“These results suggest that DAs and MAOBIs are more effective than COMTIs and an A2ARA.” (opens the source at this quote in a new tab)

Efficacy and safety profile of non-ergot dopamine agonists

“Non-ergolinic DA agonists such as pramipexole, ropinirole, and rotigotine are efficacious in treating PD motor symptoms both as monotherapy as well as adjuncts to levodopa in patients with or without motor complications” (opens the source at this quote in a new tab)
“Their major limitations are related to an unfavourable safety profile regarding their potential to induce daytime somnolence and ICDs.” (opens the source at this quote in a new tab)

Receptor selectivity of currently available dopamine agonists

“Currently available oral and transdermal DAs (eg, pramipexole, ropinirole, rotigotine) preferentially target D2/D3 receptors, and are associated with an increased risk of adverse events (AEs) compared with oral levodopa alone, which is hypothesized to be partially attributed to widespread distribution of D2/D3 receptors in the brain and peripheral nervous system.” (opens the source at this quote in a new tab)

Dopamine agonist receptor targets, motor complication risk, and adverse effects

“Dopaminomimetics with direct activity to dopamine receptors (dopamine receptor agonist) mainly target the D2 receptor family and were first introduced into Parkinson disease therapy in the 1970s with the ergot alkaloid bromocriptine and have since become an important medical therapy for motor symptoms” (opens the source at this quote in a new tab)
“Overall, dopamine agonists are believed to induce less pulsatile striatal dopamine receptor stimulation than l-DOPA and this is taken as an explanation for the markedly reduced risk to induce motor complications when dopamine agonists are used as initial monotherapy in Parkinson disease” (opens the source at this quote in a new tab)
“Drawbacks include their reduced overall effect size as compared with l-DOPA and their potential to induce drowsiness and impulse dyscontrol — the latter being possibly associated with their preferential activity at D3 receptors that are located in the ventral striatum, which causes excessive stimulation of the brain reward systems” (opens the source at this quote in a new tab)

Prolonged-release dopamine agonists and early-morning OFF periods: observational study

“When comparing patterns of dopaminergic therapy, those taking PR dopamine agonists (ROP XL, PPX PR and RTG patch) had significantly less EMO periods compared with those taking levodopa therapy only.” (opens the source at this quote in a new tab)
“treated with RTG did not suffer from EMO (50.0%) compared with those receiving levodopa monotherapy (31.7% were free of EMO, p = 0.019; chi-squared test)” (opens the source at this quote in a new tab)
“Cohorts on monotherapy of the respective PR dopamine agonist showed an even higher rate of EMO free patients (RTG: 64.7%, ROP XL: 59.3% and PPX PR: 57.9%) than the ones on combination therapy stated above.” (opens the source at this quote in a new tab)
“Our study was not powered for, or aimed at, addressing the effect of dopaminergic medications on EMO specifically so that we can only make limited observations.” (opens the source at this quote in a new tab)
“Furthermore, we were unable to match the doses of the different DA's and as such direct comparison between the different DA's is not possible.” (opens the source at this quote in a new tab)

Guideline recommendations for MAO-B inhibitors in early disease

“Most patients on monotherapy with a MAO-B inhibitor will require additional therapy within 2 to 3 years compared to those being treated with levodopa or dopamine agonists.” (opens the source at this quote in a new tab)
“Clinicians should counsel patients with early PD on the greater motor benefits of initial therapy with levodopa compared with MAO-B inhibitors to inform treatment decisions (Level B).” (opens the source at this quote in a new tab)
“Clinicians may prescribe MAO-B inhibitors as the initial dopaminergic therapy for mild motor symptoms in patients with early PD (Level C).” (opens the source at this quote in a new tab)

Levodopa compared with MAO-B inhibitors in early disease: systematic review findings

“Studies comparing treatment with levodopa to treatment with MAO-B inhibitors early in the disease course provide Class IV evidence.” (opens the source at this quote in a new tab)
“These studies demonstrate greater improvement in mobility with levodopa than with MAO-B inhibitors, a higher risk of AE-related discontinuation with MAO-B inhibitors, and that >60% of individuals randomized to MAO-B inhibitors will require additional therapy within 2 to 3 years.” (opens the source at this quote in a new tab)
“There were inadequate data on the effect of levodopa vs MAO-B inhibitors on motor symptoms, preventing effect size calculations (Table 1).” (opens the source at this quote in a new tab)
“There are no studies comparing the efficacy of selegiline and rasagiline in the treatment of early PD.” (opens the source at this quote in a new tab)
“Prescribing information for selegiline and rasagiline caution against their use with selective serotonin reuptake inhibitors (SSRIs); however, serotonin syndrome is rarely reported in patients with PD on concomitant therapy with an MAO-B inhibitor and an SSRI.” (opens the source at this quote in a new tab)

Efficacy conclusions for MAO-B inhibitors in motor fluctuations

“Rasagiline is likely efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“These studies found a statistically significant, though not clinically meaningful, reduction in OFF‐time ranging from 0.5 to 0.9 h/day at doses of either 0.5 mg/day” (opens the source at this quote in a new tab)
“Safinamide is efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“These studies found a clinically meaningful reduction in OFF‐time (around 1 h compared with placebo) and an increase in ON‐time without troublesome dyskinesia (also around 1 h compared with placebo).” (opens the source at this quote in a new tab)
“The conclusion on the efficacy of selegiline for treating motor fluctuations on (attempted) optimal oral levodopa therapy is that there is insufficient evidence.” (opens the source at this quote in a new tab)

MAO-B inhibitors compared with dopamine agonists as initial therapy

“PDQ-39 mobility scores were 1·4 points (95% CI 0·0–2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists.” (opens the source at this quote in a new tab)
“MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists.” (opens the source at this quote in a new tab)
“Rates of dyskinesia were similar (HR 0·85, 95% CI 0·60−1·22, p=0·4), but motor fluctuations were higher (HR 1·32, 95% CI 1·01−1·72, p=0·04) in the dopamine agonist group than in the MAOBI group (appendix).” (opens the source at this quote in a new tab)
“5-year decline in MMSE was greater in participants allocated dopamine agonists than in those allocated MAOBI (2·4 [SD 4·4] vs 1·3 [3·7], p=0·04), but there was no significant difference in the number of patients developing dementia (HR 1·11, 95% CI 0·77−1·59, p=0·6; appendix), entering institutional care (1·08, 0·70−1·64, p=0·7, appendix), or dying (0·96, 0·73−1·28, p=0·8, appendix).” (opens the source at this quote in a new tab)
“Notably, the onset of dyskinesia was not significantly higher with MAOBI than with dopamine agonists, and fewer motor fluctuations were reported with initial MAOBI therapy, so avoiding motor complications should not be a reason to prefer dopamine agonists over MAOBI therapy.” (opens the source at this quote in a new tab)

Clinical usefulness for monotherapy of early disease

“For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful.” (opens the source at this quote in a new tab)
“For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful.” (opens the source at this quote in a new tab)
“MAO-B inhibitors (selegiline and rasagiline) improve motor symptoms in early PD, but the effect size has been smaller than with levodopa and DAs.” (opens the source at this quote in a new tab)
“Thus, rasagiline is “efficacious” and “clinically useful” as an adjunct to DA, whereas the new mixed MAO-B/glutamate release inhibitor safinamide was “not useful” in early PD patients.” (opens the source at this quote in a new tab)

Efficacy conclusions for COMT inhibitors in motor fluctuations

“Opicapone is efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“Three trials evaluated the efficacy of opicapone in reducing OFF‐time compared with placebo.” (opens the source at this quote in a new tab)
“the reduction was around 120 min, with a corresponding increase in ON‐time of ~60 min more than placebo.” (opens the source at this quote in a new tab)
“Entacapone is likely efficacious for the treatment of motor fluctuations in patients with PD in comparison with placebo.” (opens the source at this quote in a new tab)

Opicapone added early in motor fluctuations compared with added levodopa

“After 4 weeks, reductions in daily OFF-time were significantly greater after adding 50 mg opicapone vs adding 100 mg levodopa (− 62 vs − 17 min; mean difference − 45.4. min).” (opens the source at this quote in a new tab)
“The pooled analysis of both ADOPTION trials also showed a significant benefit of adding opicapone with a difference vs adding 100 mg of levodopa of 29 min (p = 0.022)” (opens the source at this quote in a new tab)

Levodopa initiated with entacapone in early disease

“We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4× daily at 3.5-hour intervals.” (opens the source at this quote in a new tab)
“Eligible subjects were men or women aged 30 to 70 years with a diagnosis of PD based on UK brain bank criteria and a disease duration of <5 years from time of diagnosis.” (opens the source at this quote in a new tab)
“Prior exposure to L-dopa for >30 days or within 8 weeks prior to entry, and previous use of a COMT inhibitor, were not permitted.” (opens the source at this quote in a new tab)
“L-dopa/carbidopa in both groups was initiated at a dose of 50/12.5mg twice daily, and titrated to 100/25 (target dose) or 150/37.5mg 4× daily administered at 3.5-hour intervals.” (opens the source at this quote in a new tab)
“With a follow-up time of 134 weeks and an estimated dropout rate of 15%, a sample size of 740 patients provided >80% power to detect a 25% reduction in dyskinesia frequency using the 2-sided log-rank test at an alpha level of 5%.” (opens the source at this quote in a new tab)
“In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02).” (opens the source at this quote in a new tab)
“Kaplan-Meier survival curves show that patients randomized to L-dopa/carbidopa/entacapone (LCE) had greater risk of developing dyskinesia than patients receiving L-dopa/carbidopa (LC) (Cox proportional hazard ratio, 1.29; 95% confidence interval [CI], 1.0–1.65; p = 0.038).” (opens the source at this quote in a new tab)
“Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001).” (opens the source at this quote in a new tab)
“There was a trend to improved UPDRS scores in LCE-treated subjects (difference at final visit, 1.2 points; p = 0.1).” (opens the source at this quote in a new tab)
“Survival time estimates for the first quartile of patients were 90.7 weeks (95% CI, 65.3–104.0) for the LCE group and 117.1 weeks (95% CI, 92.1–132.6) for LC-treated patients.” (opens the source at this quote in a new tab)
“A total of 541 subjects (72.6%) completed their study drug treatment as planned; 265 (71.0%) in the LCE group and 276 (74.2%) in the LC group.” (opens the source at this quote in a new tab)
“LCE showed a trend toward improved UPDRS scores and reduced wearing off compared to LC, consistent with the approved indication of entacapone as an adjunct to L-dopa.” (opens the source at this quote in a new tab)
“The mean L-dopa dose at the end of the titration period was 305.2 and 306.8mg/day in the LCE and LC groups, respectively, and they remained comparable throughout the study.” (opens the source at this quote in a new tab)
“This analysis indicates that LCE-treated patients received significantly more L-dopa dose equivalents than LC patients at the completion of titration, at the time of onset of dyskinesia, and at the final study visit (see Table 5).” (opens the source at this quote in a new tab)
“STRIDE-PD does not support the early administration of L-dopa in combination with entacapone to reduce the risk of motor complications using the dosing regimen employed in this trial.” (opens the source at this quote in a new tab)

Baseline characteristic	Levodopa/carbidopa/entacapone (n = 373)	Levodopa/carbidopa (n = 372)
Age, years, mean ± SD	“60.6±8.7”	“59.8±8.2”
Men, no. (%)	“245 (65.7%)”	“222 (59.7%)”
Caucasian, no. (%)	“352 (94.4%)”	“357 (96.0%)”
Weight, kg, mean ± SD	“79.7±15.8”	“79.1±16.9”
Duration of disease, years, mean ± SD	“2.0±1.6”	“2.0±1.7”
UPDRS total (II + III), mean ± SD	“32.7±12.6”	“31.5±11.9”
UPDRS Part III (motor), mean ± SD	“23.1±9.5”	“22.4±9.0”
Hoehn & Yahr stage, mean ± SD	“1.9±0.5”	“1.9±0.5”
PDQ-39, mean ± SD	“25.2±15.0”	“22.9±13.7”
Previous antiparkinson medication, no. (%)	“263 (70.5%)”	“266 (71.5%)”
Dopamine agonist use, no. (%)	“217 (58.2%)”	“217 (58.3%)”

Evidence-based review conclusions for COMT inhibitors

“The COMT-inhibitors entacapone and opicapone are “clinically useful,” without the safety issue of liver function monitoring required with tolcapone.” (opens the source at this quote in a new tab)
“However, the early use of entacapone in nonfluctuating PD patients resulted in increased motor complications, and thus it remains “not useful.”” (opens the source at this quote in a new tab)
“To date, the new COMT-I opicapone has not been evaluated in nonfluctuating PD patients.” (opens the source at this quote in a new tab)

Levodopa/carbidopa/entacapone compared with levodopa/carbidopa: dyskinesia, wearing off, and dose equivalents

Outcome	Levodopa/carbidopa/entacapone (n = 373)	Levodopa/carbidopa (n = 372)	P value
Dyskinesia frequency at 208 weeks, no. (%)	“144 (38.6)”	“123 (33.1)”	“0.110”
Time to dyskinesia, first-quartile estimate, weeks (95% CI)	“90.7 (65.3–104.0)”	“117.1 (92.1–132.6)”	“0.038”
Disabling dyskinesia, no. (%)	“32 (8.6)”	“23 (6.2)”	“0.201”
Dyskinesia by direct observation, no. (%)	“130 (34.9)”	“110 (29.6)”	“0.118”
Dyskinesia by patient history, no. (%)	“141 (37.8)”	“113 (30.4)”	“0.031”
Dyskinesia by direct observation or patient history on 2 consecutive visits, no. (%)	“120 (32.2)”	“99 (26.6)”	“0.092”
Dyskinesia by direct observation on 2 consecutive visits, no. (%)	“84 (22.5)”	“77 (20.7)”	“0.550”
Dyskinesia frequency at 134 weeks, no.	“128”	“103”	“0.016”
UPDRS II + III, change from baseline to week 130	“8.4”	“7.2”	“0.18”
Wearing off frequency at 208 weeks, no. (%)	“165 (44.2%)”	“189 (50.8%)”	“0.07”
Wearing off frequency at 130 weeks, no. (%)	“139 (45.6%)”	“161 (48.3%)”	“0.53”
Time to wearing off, weeks, mean ± SD	“72.9±50.9”	“78.5±51.5”	“0.53”
Time to wearing off, first-quartile estimate, weeks	“78.0”	“76.0”	“0.6”
Time to wearing off, hazard ratio (95% CI)	“0.94 (0.76–1.17)”	Not applicable	Not reported
Hoehn & Yahr stage, change from baseline	“0.4”	“0.3”	“NS”
Schwab & England score, change from baseline	“−1.4”	“−1.4”	“0.95”
PDQ-39, change from baseline	“2.2”	“2.4”	“0.77”
Levodopa dose equivalents at end of titration	“533.4”	“420.1”	“0.001”
Levodopa dose equivalents at onset of dyskinesia	“659.9”	“535.2”	“0.001”
Levodopa dose equivalents at final study visit	“524.1”	“432.6”	“0.001”

“p values are post hoc, are not corrected, and are for descriptive purposes only.” (opens the source at this quote in a new tab)
“Accordingly, we calculated L-dopa dose equivalents by multiplying the L-dopa dose in LCE patients by 1.3.” (opens the source at this quote in a new tab)
“Wearing off occurred more frequently in LC than LCE patients (50.8% vs 44.2%; p = 0.07), but time to onset of wearing off was similar in the 2 groups.” (opens the source at this quote in a new tab)

Adverse events with levodopa/carbidopa/entacapone compared with levodopa/carbidopa in early disease

Adverse event	Levodopa/carbidopa/entacapone (n = 373), no. (%)	Levodopa/carbidopa (n = 371), no. (%)
Any adverse event	“348 (93.3)”	“336 (90.6)”
Nausea	“114 (30.6)”	“71 (19.1)”
Diarrhea	“66 (17.7)”	“28 (7.5)”
Dizziness	“59 (15.8)”	“46 (12.4)”
Somnolence	“37 (9.9)”	“28 (7.5)”
Vomiting	“22 (5.9)”	“10 (2.7)”
Dyskinesia	“21 (5.6)”	“10 (2.7)”
Orthostatic hypotension	“20 (5.4)”	“13 (3.5)”
Myocardial infarction	“7 (1.9)”	“0 (0.0)”
Prostate cancer	“9 (2.4)”	“2 (0.5)”
Skin cancer	“7 (1.9)”	“12 (3.2)”

“Discontinuations due to adverse events and withdrawal of consent were higher in the LCE group, whereas discontinuation due to unsatisfactory therapeutic effect was higher in the LC group.” (opens the source at this quote in a new tab)
“Surprisingly, LCE was associated with increased myocardial infarction and prostate cancer, whereas LC was associated with increased skin cancer.” (opens the source at this quote in a new tab)
“Impulse control disorders were detected in 14 of 103 (13.6% ) evaluable LCE patients and 15 of 102 (14.7%) evaluable LC patients (see Supplementary Table for further details).” (opens the source at this quote in a new tab)
“Of these, 12 LCE patients (85.7% ) and 10 LC patients (66.7%) were receiving a dopamine agonist.” (opens the source at this quote in a new tab)

Efficacy conclusion for amantadine in motor fluctuations

“Amantadine extended release is likely efficacious in increasing ON‐time and decreasing OFF‐time in PD patients with motor fluctuations on (attempted) optimal oral levodopa therapy. There is insufficient evidence for the use of amantadine immediate release.” (opens the source at this quote in a new tab)
“While the reduction in OFF‐time was not clinically meaningful, the difference compared with the placebo group suggested a significant treatment effect.” (opens the source at this quote in a new tab)

Amantadine for levodopa-induced dyskinesia

“Amantadine, however, is still the only efficacious drug to treat levodopa-induced dyskinesias (LIDs)” (opens the source at this quote in a new tab)
“FDA approval as an antidyskinetic agent was only granted in 2017 following two positive placebo-controlled trials of a novel ER formulation of amantadine (marketed as Gocovri® in the US)” (opens the source at this quote in a new tab)
“A pooled analysis of these two randomised-controlled trials demonstrated a placebo-adjusted reduction in OFF-time of 1 h from baseline to week 12” (opens the source at this quote in a new tab)

Amantadine for dyskinesia: evidence-based review conclusion

“Currently, the most effective target appears to be the glutamate-N-Methyl-D-aspartate (NMDA) receptor antagonist, amantadine, which remains clinically useful for treating dyskinesia in PD.” (opens the source at this quote in a new tab)
“There are long-acting preparations in development, but these were not approved within the review dates.” (opens the source at this quote in a new tab)

Guideline position on amantadine for dyskinesia

“If dyskinesia is not adequately managed by modifying existing therapy, consider amantadine.” (opens the source at this quote in a new tab)

Efficacy conclusion for istradefylline in motor fluctuations

“Istradefylline is likely efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“The reduction in OFF‐time with istradefylline was inconsistent and of unclear clinical relevance, ranging from 12 min (in larger studies) to 114 min (in smaller studies).” (opens the source at this quote in a new tab)

Regulatory status and pooled effect of istradefylline

“The classification of istradefylline as "likely efficacious" is interesting, since the EMA issued a negative opinion in 2021,” (opens the source at this quote in a new tab)
“refusing approval for istradefylline as an add‐on treatment for motor fluctuations, considering the available evidence as inconsistent and not satisfactorily showing effectiveness to reduce ‘off’ time.” (opens the source at this quote in a new tab)
“A pooled analysis of eight phase IIb/III trials suggested that istradefylline reduces daily off‐time by only 0.38 or 0.45 hr more than placebo at 20 or 40 mg/day, respectively.” (opens the source at this quote in a new tab)

Approval of istradefylline in Japan and the United States

“Istradefylline is an adenosine A2A receptor antagonist which was shown to reduce OFF-time ranging from 12 to 114 min in several trials and has been in clinical use to treat motor fluctuations in Japan for many years and more recently (2019) also received FDA approval” (opens the source at this quote in a new tab)

Istradefylline for motor fluctuations and as monotherapy: evidence-based review conclusions

“Because of the conflicting evidence but generally positive outcomes, the efficacy conclusion is “likely efficacious,” and the implication for clinical practice is “possibly useful.”” (opens the source at this quote in a new tab)
“However, the lack of efficacy as monotherapy suggests that targeting the adenosine system alone may not be sufficient for treating PD motor symptoms.” (opens the source at this quote in a new tab)

Evidence for intermittent apomorphine as rescue therapy

“There is insufficient evidence to support the use of apomorphine sublingual film and apomorphine subcutaneous pen (intermittent) as a rescue medication for off‐medication episodes in patients with PD.” (opens the source at this quote in a new tab)
“Both treatments improved the off‐medication state to a good on‐medication state within 15–40 min, as measured by the MDS‐UPDRS‐III.” (opens the source at this quote in a new tab)

Intermittent apomorphine injections: evidence-based review conclusion

“Intermittent injections of the DA apomorphine are “clinically useful” for motor fluctuations, particularly for OFF periods that require rapid reversal.” (opens the source at this quote in a new tab)

Inhaled levodopa for off episodes

“There was a significant difference from placebo for the 84 mg dose of − 3.9 points (p < 0.01) in favour of active drug and the proportion of participants achieving a full ON-state after 60 min was 58% in the 84 mg treatment group compared to 36% in the placebo arm (odds ratio of 2.65 and 95% confidence interval of [1.48;4.76], p < 0.01)” (opens the source at this quote in a new tab)
“Discontinuation rates ranged from 15.0% to 30.8% of participants treated with inhaled levodopa in the SPAN-PD trial and its open-label 12-month extension study” (opens the source at this quote in a new tab)

Sublingual apomorphine for off episodes

“The trial found a significant difference of − 7.6 points favouring sublingual apomorphine over placebo at 30 min post-dosing and a statistically significant difference of − 3.4 points was already observed at 15 min” (opens the source at this quote in a new tab)
“Oropharyngeal mucosal irritation occurred in 31% of patients treated with apomorphine and led to treatment discontinuation in 17%.” (opens the source at this quote in a new tab)
“Despite its efficacy sublingual apomorphine has not been commercially successful in the US market where it is currently no longer available.” (opens the source at this quote in a new tab)

Rescue therapies omitted from the evidence-based review

“First, rapid‐release (dispersible/soluble) oral levodopa is still among the most frequently prescribed off‐rescue medication.” (opens the source at this quote in a new tab)
“Inhaled levodopa is not mentioned either in the MDS review,” (opens the source at this quote in a new tab)
“although the criteria set forth by the authors appear to qualify consideration of the pivotal study demonstrating its efficacy to significantly reduce motor fluctuations.” (opens the source at this quote in a new tab)

Efficacy conclusions for infusion therapies

“Levodopa carbidopa intestinal gel is likely efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“One placebo‐controlled study evaluated the use of levodopa carbidopa intestinal gel (~16 h/day) for reducing OFF‐time compared with levodopa carbidopa immediate release, showing a mean difference of −1.9 h (P < 0.01) between groups.” (opens the source at this quote in a new tab)
“One placebo‐controlled trial assessed whether the use of continuous subcutaneous foslevodopa foscarbidopa (24 h/day) reduces OFF‐time compared with levodopa carbidopa immediate release, showing a difference of −1.8 h (P = 0.002) between the two groups.” (opens the source at this quote in a new tab)
“A clinically meaningful difference between the two groups in the reduction of OFF‐time was observed, with a decrease of 1.9 h per day in favor of apomorphine (p = 0.0025).” (opens the source at this quote in a new tab)

Levodopa-carbidopa enteral suspension: off time, on time without troublesome dyskinesia, and device-related adverse events

“Treatment with levodopa-carbidopa enteral suspension reduces off times (−1.19 hours per day [95% CI, −2.25 to −0.12]) and increases time when symptoms are well-controlled without troublesome dyskinesias (0.55 hours per day [95% CI, 0.20-0.90]).” (opens the source at this quote in a new tab)
“Adverse events relating to the percutaneous endoscopic transgastric jejunostomy are common and include complications of device insertion, abdominal pain, tube dislocation, and knotting.” (opens the source at this quote in a new tab)

Subcutaneous foslevodopa/foscarbidopa: approval and tolerability

“Both trials had high discontinuation rates ranging from 35.1% in the 12-week RCT to 44.8% in the 12-month open-label study” (opens the source at this quote in a new tab)
“pLD/pCD has received marketing authorization of the EMA in 2022 and FDA-approval in 2024 for the treatment of motor fluctuations associated with advanced PD.” (opens the source at this quote in a new tab)
“Due to an extensive first-pass effect apomorphine lacks adequate enteral bioavailability and subcutaneous on-demand injections or continuous infusions have been in clinical routine use in Europe for more than 30 years” (opens the source at this quote in a new tab)
“but continuous subcutaneous apomorphine infusions were only recently granted FDA approval in 2025” (opens the source at this quote in a new tab)

Deep brain stimulation: efficacy conclusions

“High‐quality evidence indicates that subthalamic nucleus (STN) deep brain stimulation (DBS) is efficacious to improve motor impairment in patients with PD who experience motor fluctuations on oral levodopa therapy.” (opens the source at this quote in a new tab)
“Seven studies reported improvement in motor impairment, as measured by the UPDRS‐III in the off‐medication state, with an average improvement of 18.6 points in the STN DBS group.” (opens the source at this quote in a new tab)
“Bilateral internal globus pallidus (GPi) DBS is likely efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)

Deep brain stimulation compared with best medical therapy in advanced disease

“Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001).” (opens the source at this quote in a new tab)
“At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage.” (opens the source at this quote in a new tab)

Deep brain stimulation in early motor complications

“In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone.” (opens the source at this quote in a new tab)
“For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P = 0.002).” (opens the source at this quote in a new tab)
“Time with good mobility and no troublesome dyskinesia, as recorded by the patients in daily diaries, increased by 20% in the neurostimulation group, with a between-group difference of 1.9 hours (P = 0.01)” (opens the source at this quote in a new tab)
“Time with bad mobility was significantly shortened in the neurostimulation group, with a between-group difference of 1.8 hours (P = 0.006)” (opens the source at this quote in a new tab)
“The levodopa-equivalent daily dose was reduced by 39% in the neurostimulation group but was increased by 21% in the medical-therapy group” (opens the source at this quote in a new tab)
“Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients.” (opens the source at this quote in a new tab)

Deep brain stimulation in early motor complications: serious adverse events

Serious adverse event	Neurostimulation (N = 124), participants with event (%)	Medical therapy (N = 127), participants with event (%)
Any serious adverse event	“68 (54.8)”	“56 (44.1)”
Death, all by suicide	“2 (1.6)”	“1 (0.8)”
Event related to medication or stimulation	“24 (19.4)”	“38 (29.9)”
Worsening of mobility	“5 (4.0)”	“11 (8.7)”
Motor fluctuations	“0”	“7 (5.5)”
Psychosis or hallucinations	“0”	“6 (4.7)”
Impulse control disorder	“1 (0.8)”	“5 (3.9)”
Depression	“6 (4.8)”	“1 (0.8)”
Suicide attempt	“2 (1.6)”	“2 (1.6)”
Event related to surgery or device	“22 (17.7)”	Not applicable
Impaired wound healing	“4 (3.2)”	Not applicable
Intracerebral abscess or edema	“2 (1.6)”	Not applicable
Dislocation of device	“4 (3.2)”	Not applicable
Reoperation necessary	“2 (1.6)”	Not applicable

“Two patients in the neurostimulation group and 1 in the medical-therapy group committed suicide; these were the only deaths.” (opens the source at this quote in a new tab)
“Suicidal ideation and suicide attempts were of similar frequency in the two groups, but depression was more frequent in the neurostimulation group. Serious adverse events related to motor problems, impulse control disorders, and psychotic manifestations were more common in the medical-therapy group.” (opens the source at this quote in a new tab)
“Of 26 serious adverse events related to surgery or the implanted device, including a brain abscess and a case of unspecific edema, all but 1 resolved completely; the exception was a case of impaired wound healing, which resulted in mild scarring.” (opens the source at this quote in a new tab)

Deep brain stimulation in early motor complications: trial population and funding

“Patients with Parkinson’s disease were eligible for the study if they met the following inclusion criteria: an age of 18 to 60 years; disease duration of 4 years or more; a disease severity rating below stage 3 in the on-medication condition, according to the Hoehn and Yahr scale, with scores ranging from 0 to 5 and higher scores indicating more severe disease” (opens the source at this quote in a new tab)
“The mean duration of Parkinson’s disease was 7.5 years, and patients were included in the study a mean of 1.7 years after the onset of levodopa-induced motor complications of any severity.” (opens the source at this quote in a new tab)
“This patient population with relatively mild parkinsonian motor signs differed from the populations in previous controlled studies of neurostimulation: the mean duration of disease in the patients in our study was only 7.5 years, as compared with 11.1 to 13.8 years” (opens the source at this quote in a new tab)
“Medtronic provided additional funding for the study but had no role in the study design, data accrual, data analysis, or manuscript preparation.” (opens the source at this quote in a new tab)
“Neurostimulation may be a therapeutic option for patients at an earlier stage than current recommendations suggest.” (opens the source at this quote in a new tab)

Focused ultrasound pallidotomy

“In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003).” (opens the source at this quote in a new tab)
“Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness.” (opens the source at this quote in a new tab)
“At 6 months, among 50 patients who initially underwent FUSA of the globus pallidus internus and had available data, 38 (76%) had a response; 53 of 65 patients in the active-treatment group were available for the 12-month follow-up, and 37 of 53 (70%) had a response at 12 months” (opens the source at this quote in a new tab)
“Of the 45 patients in the active-treatment group who had a response at 3 months, 6 were lost to follow-up and 9 no longer had a response at 12 months” (opens the source at this quote in a new tab)
“Gait disturbance and loss of taste were mild, and they resolved; however, moderate dysarthria in one patient persisted for 1 year. Visual disturbance and mild facial weakness were observed in one patient each at 3 months and were resolved by 1 year.” (opens the source at this quote in a new tab)
“Fifteen adverse events in the active-treatment group (10 patients) and 1 adverse event in the control group fulfilled FDA criteria for a serious adverse event during the 12-month follow-up.” (opens the source at this quote in a new tab)
“The nonfatal pulmonary embolism, which occurred within 1 week after treatment, was the only serious adverse event categorized by the data and safety monitoring board as procedure-related.” (opens the source at this quote in a new tab)

Focused ultrasound pallidotomy: procedural and trial limitations

“The procedure has recently been approved by the FDA for unilateral treatment only, whereas most patients with Parkinson’s disease have bilateral motor signs and symptoms.” (opens the source at this quote in a new tab)
“Unlike deep-brain stimulation, there is no opportunity to treat progressive worsening of motor symptoms.” (opens the source at this quote in a new tab)
“Limitations of the trial include missing primary-outcome data for approximately 7% of the patients and unsatisfactory blinding of the trial-group assignments.” (opens the source at this quote in a new tab)
“A total of 62 of 65 patients (95%) in the active-treatment group believed that they had received the active treatment, and 14 of 24 patients (58%) in the control group believed that they had received the active treatment.” (opens the source at this quote in a new tab)

Focused ultrasound subthalamotomy

“Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control).” (opens the source at this quote in a new tab)
“Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia.” (opens the source at this quote in a new tab)
“the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001)” (opens the source at this quote in a new tab)
“The change from baseline to 12 months in the MDS-UPDRS III score for the more affected side among 25 patients with available data in the active-treatment group was 11.6 points (95% CI, 9.9 to 13.3).” (opens the source at this quote in a new tab)
“Among the 27 patients in the active-treatment group, new-onset dyskinesia on the treated side occurred in 12 patients, persisted in 3 at the 4-month primary safety evaluation, and persisted in 2 at 12 months.” (opens the source at this quote in a new tab)
“Speech disturbance developed in 15 patients (56%) in the active-treatment group and persisted in 3 patients at 4 months and in 1 patient at 12 months.” (opens the source at this quote in a new tab)
“Strength in both patients had recovered at 12 months, but hand clumsiness and asymmetric stride persisted in both.” (opens the source at this quote in a new tab)
“In 6 patients in the active-treatment group, some of these deficits were present at 12 months.” (opens the source at this quote in a new tab)
“No complications of the active procedure were detected by MRI, except for perilesional edema, which resolved by 4 months in all the patients in this group” (opens the source at this quote in a new tab)
“There were no intracerebral hemorrhages.” (opens the source at this quote in a new tab)

Device-aided therapies: evidence-based review conclusions and setting of care

“Subcutaneous apomorphine continuous infusion is widely used in clinical practice in patients with motor complications, but to date a double-blind RCT has been published in abstract form only.” (opens the source at this quote in a new tab)
“Percutaneous infusion of levodopa (levodopa-carbidopa intestinal gel) is clinically useful for certain patients with severe motor fluctuations, although it requires appropriate clinical support, restricting use to specialized centers.” (opens the source at this quote in a new tab)
“DBS targeting the STN or GPi remains clinically useful for carefully selected PD patients and is again restricted to specialized centers.” (opens the source at this quote in a new tab)
“There are no RCTs directly comparing device-aided therapies, but expert consensus opinions discussing the pros and cons of each approach have been published.” (opens the source at this quote in a new tab)

Focused ultrasound subthalamotomy: selected population and trial limitations

“Patients chose to participate in this trial of ultrasound subthalamotomy because they declined to undergo deep-brain stimulation (11 patients); had minor motor signs on the less affected side, no meaningful levodopa-related motor complications that would make the patient a candidate for deep-brain stimulation, or both (26 patients); or were poor candidates for intracranial surgery owing to advanced age or coexisting conditions (3 patients).” (opens the source at this quote in a new tab)
“Subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.” (opens the source at this quote in a new tab)
“The small sample size and the enrollment of almost all the patients at one of the two trial sites (36 patients at one site and 4 at the other) limits the generalizability of the results because the trial approximates a single-center trial. Patients and assessors correctly guessed the trial-group assignments, which eliminates the intended effect of blinding.” (opens the source at this quote in a new tab)

Guideline position on device-aided therapy

“Offer people with advanced Parkinson's disease best medical therapy, which may include intermittent apomorphine injection and/or continuous subcutaneous apomorphine infusion.” (opens the source at this quote in a new tab)
“Do not offer deep brain stimulation to people with Parkinson's disease whose symptoms are adequately controlled by best medical therapy.” (opens the source at this quote in a new tab)
“Consider deep brain stimulation for people with advanced Parkinson's disease whose symptoms are not adequately controlled by best medical therapy.” (opens the source at this quote in a new tab)

Summary

No available therapy has been shown to modify the course of Parkinson's disease. The 2018 International Parkinson and Movement Disorder Society evidence-based review found no clinically useful interventions to prevent or delay progression, and in the LEAP delayed-start trial (445 participants) early levodopa had no disease-modifying effect over 80 weeks. Treatment is therefore symptomatic, and each symptomatic class carries a trade-off.

Initial levodopa gives greater motor benefit than initial dopamine agonists, but long-term oral use is complicated by motor and nonmotor fluctuations in up to 80% of patients. In STRIDE-PD (747 participants), dyskinesia was present at week 134 in 42% of participants who started levodopa/carbidopa/entacapone and 32% of those who started levodopa/carbidopa. In the 5-year follow-up of LEAP, 46 of 160 early-start and 62 of 161 delayed-start participants had dyskinesia.

Adjunctive oral therapy for motor fluctuations yields off-time reductions near the 1-hour minimal clinically important difference. In a network meta-analysis of 74 randomized controlled trials (18,693 participants), the weighted mean reduction in daily off-time relative to placebo was 1.1 hours for dopamine agonists, 0.9 hours for MAO-B inhibitors, and 0.8 hours for COMT inhibitors, and all three classes increased the odds of dyskinesia (odds ratios 3.0, 1.6, and 3.3). Head-to-head evidence is limited. In the PD MED trial of initial therapy (1,620 participants), 179 of 632 participants (28%) assigned dopamine agonists and 104 of 460 (23%) assigned MAO-B inhibitors discontinued their allocated treatment because of side effects, compared with 11 of 528 (2%) assigned levodopa.

The currently available dopamine agonists act mainly on D2/D3 receptors and carry neuropsychiatric and sleep-related risks. In a cross-sectional study of 3,090 participants, impulse control disorders were present in 17.1% of those taking a dopamine agonist and 6.9% of those not taking one (odds ratio 2.72). In a longitudinal cohort of 306 participants without impulse control disorders at baseline, the 5-year cumulative incidence was 46.1% overall and 51.5% among dopamine agonist users. The pooled relative risk of somnolence with pramipexole or ropinirole compared with placebo was 4.98. Reducing or stopping a dopamine agonist can cause dopamine agonist withdrawal syndrome, which occurred in 5 of 26 participants (19%) in a retrospective cohort and 12 of 51 (24%) in a prospective cohort.

Device-aided therapies add procedural and tolerability burdens. In EARLYSTIM, serious adverse events related to surgical implantation or the device occurred in 17.7% of participants. Discontinuation with subcutaneous foslevodopa/foscarbidopa was 35.1% in the 12-week randomized trial and 44.8% in the 12-month open-label study.

No intervention prevents or delays disease progression

“There are no clinically useful interventions to prevent/delay disease progression.” (opens the source at this quote in a new tab)

Motor complications with long-term levodopa

“However, together with disease progression, long-term treatment with oral levodopa is complicated by motor and nonmotor fluctuations in up to 80% of patients.” (opens the source at this quote in a new tab)
“Survey data have shown that motor fluctuations are the most bothersome symptom of advanced PD.” (opens the source at this quote in a new tab)

Response oscillations and dyskinesia as drivers of continued development

“Levodopa’s long-term efficacy is, on the other hand, compromised by the development of response oscillations and drug-induced dyskinesias in a majority of patients due to the progressive degeneration of dopaminergic neurons and pulsatile administration of levodopa, and these limitations are the main reasons for continued efforts towards improvements of current dopaminergic strategies.” (opens the source at this quote in a new tab)

Dyskinesia and wearing-off prevalence after early or delayed levodopa initiation

“At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06).” (opens the source at this quote in a new tab)
“The prevalence of wearing off at 5 years did not differ between the early-start (58/160 patients, 36%) and delayed-start group (58/161 patients, 36%) (Supporting Information Table S3).” (opens the source at this quote in a new tab)
“However, the prevalence of any wearing off during the waking day at 5 years was 36% for both treatment groups and mainly consisted of patients with 1% to 25% of the time during the waking day spent in off drug state.” (opens the source at this quote in a new tab)
“In addition, there was no between-group difference at week 80 in the prevalence of dyskinesia, but there was a higher prevalence of early signs of motor response fluctuations in the delayed-start group.” (opens the source at this quote in a new tab)
“The results showed that motor complications are not associated with the duration of levodopa use, but that they are associated with disease duration and a higher levodopa daily dose.” (opens the source at this quote in a new tab)

Levodopa motor complications: pooled risk estimate at 4 to 6 years and its clinical significance

“Hence, it seems likely that the approximate 40% frequency of motor fluctuations and slightly less than 40% frequency of dyskinesias is a very reasonable risk estimate relating to 4–6 years of levodopa treatment.” (opens the source at this quote in a new tab)
“For example, in one series, dyskinesias and motor fluctuations were reported in over 90% of young-onset PD patients within 5 years.” (opens the source at this quote in a new tab)
“However, these findings should not be interpreted as estimates of clinically important levodopa motor complication morbidity.” (opens the source at this quote in a new tab)
“By 4 to 6 years, slightly more than one-third of these modern era patients had experienced dyskinesias (the median of 21 clinical series).” (opens the source at this quote in a new tab)
“As shown in Table 1, only three modern era series were identified that reported the cumulative dyskinesia frequency at very long durations of therapy (≥9 years); the median dyskinesia frequency in this group was nearly 90%.” (opens the source at this quote in a new tab)
“Hence, the clinically important morbidity may be substantially less than the frequency values tabulated herein.” (opens the source at this quote in a new tab)

Duration of levodopa therapy, modern era series	Dyskinesia, median %, unweighted	Dyskinesia, median %, weighted by N	Dyskinesia, range	Dyskinesia, total N	Motor fluctuations, median %, unweighted	Motor fluctuations, median %, weighted by N	Motor fluctuations, range	Motor fluctuations, total N
7–12 months	“7.5”	“7.0”	“0–38.9%”	“432”	“1.5”	“3.0”	“0–16%”	“112”
13–24 months	“25.9”	“28.7”	“10.3–35.4%”	“575”	“45.7”	“47.9”	“0–50.4%”	“700”
2.5–3.5 years	“28.0”	“26.9”	“13.2–40%”	“747”	“23.3”	“31.0”	“5–35.1%”	“849”
4–6 years	“38.5”	“36.2”	“8–64%”	“1,599”	“42.1”	“40.8”	“11.8–60%”	“1,817”
9–15+ years	“87.8”	“87.8”	“60.7–95.5%”	“514”	“69.6”	“69.6”	“40.9–82.9%”	“514”

Levodopa equivalent daily dose 3 and 5 years after early or delayed levodopa initiation

Visit	Early-start group, LEDD change from baseline, median (IQR)	Delayed-start group, LEDD change from baseline, median (IQR)	Estimated difference, square root transformed (SE)	P value
3 years	“400 (300–600)”	“450 (300–600)”	“−0.61 (0.69)”	“0.38”
5 years	“600 (400–800)”	“600 (450–800)”	“−0.16 (0.78)”	“0.84”

Dyskinesia risk with levodopa and dopamine agonist initiation strategies

“Long-acting dopamine agonists are associated with a reduced risk of inducing motor complications” (opens the source at this quote in a new tab)
“but have less efficacy than L-dopa and are associated with other side effects such as psychosis and impulse control disorders.” (opens the source at this quote in a new tab)
“Furthermore, nearly all dopamine agonist-treated patients eventually require L-dopa and develop dyskinesias at a rate similar to what is observed when L-dopa is initiated without dopamine agonists.” (opens the source at this quote in a new tab)
“Thus, the development of a treatment strategy that provides the benefits of L-dopa with reduced motor complications remains among the major unmet medical needs in PD.” (opens the source at this quote in a new tab)
“Further, higher doses of L-dopa in both LC and LCE groups were associated with increased dyskinesias (26.4% of 375 patients receiving ≤400mg/day of L-dopa compared with 45.4% of 370 patients receiving >400mg/day; p = 0.01).” (opens the source at this quote in a new tab)
“The study confirms that higher doses of L-dopa are associated with an increased risk of dyskinesia, and supports careful L-dopa dose titration, using the lowest dose of L-dopa that provides satisfactory clinical control.” (opens the source at this quote in a new tab)

Dyskinesia risk with adjunctive oral therapy

“All drug classes were significantly associated with dyskinesias when compared with placebo: COMT-Is OR 3.3 (95% CI 2.7 to 4.0), NNEH 5; DRAs OR 3.0 (95% CI 2.5 to 3.5), NNEH 7; and MAOB-Is OR 1.6 (95% CI 1.2 to 2.2), NNEH 24 (table 3).” (opens the source at this quote in a new tab)
“DRAs and MAOB-Is were significantly associated with increased occurrence of hallucinations: DRAs OR 3.2 (95% CI 2.4 to 4.1), NNEH 19; MAOB-Is OR 2.3 (95% CI 1.2 to 4.5), NNEH 78.” (opens the source at this quote in a new tab)
“First, the treatment duration was relatively short in most RCTs: in 43 publications, the treatment duration was less than 24 weeks.” (opens the source at this quote in a new tab)

Discontinuation of levodopa-sparing therapy because of side effects

“179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001).” (opens the source at this quote in a new tab)
“For compliance, participants allocated MAOBI or dopamine agonists were significantly more likely to discontinue their allocated drug class than those allocated levodopa: 7-year probabilities were 72% for MAOBI, 50% for dopamine agonists, and 7% for levodopa (p<0·0001, figure 2).” (opens the source at this quote in a new tab)
“The side-effects (mainly psychological, sleep disturbance, and gastrointestinal) were usually mild, only 16 patients (nine given dopamine agonists, four given MAOBI, and three given levodopa) had serious adverse events believed to be possibly related to trial treatment.” (opens the source at this quote in a new tab)
“Participants allocated and still taking MAOBI or dopamine agonists were also significantly more likely than those allocated levodopa to need a drug from another class added to their treatment: 2-year probabilities were 64% for MAOBI, 40% for dopamine agonists, and 20% for levodopa (p<0·0001, appendix).” (opens the source at this quote in a new tab)

Limited comparative evidence to guide adjunct selection

“There are few comparative studies with long‐term follow‐up to support a particular choice.” (opens the source at this quote in a new tab)
“Over a median of 4.5 years of follow‐up, participants in the dopamine agonist group had a mean PDQ‐39 mobility score that was 2.4 points (95% CI −1.3 to 6.0 points) better than that of the combined MAO‐B and COMT groups; however, this difference was not statistically significant.” (opens the source at this quote in a new tab)
“It would be helpful in making a choice between the various options if more studies became available that compare treatments head‐to‐head.” (opens the source at this quote in a new tab)

Side-effect profile of non-ergot dopamine agonists and gaps in comparative safety evidence

“The major issue with DAs (at all disease stages) remains side effects.” (opens the source at this quote in a new tab)
“Overall, nonergot DAs have similar profile of side effects (sleepiness, postural hypotension, peripheral edema, and neuropsychiatric issues).” (opens the source at this quote in a new tab)
“In clinical practice, a significant side effect is the high risk of impulse control disorders (ICDs) with DAs compared to levodopa.” (opens the source at this quote in a new tab)
“Although lower rates of ICDs associated with long-acting or transdermal Das have been reported, to date there has been no interventional study evaluating the relative risk of ICDs between the DAs, and this remains an important area of research.” (opens the source at this quote in a new tab)
“Long-term comparative side effects between nonergot DAs, including risk of ICDs, is as yet unclear.” (opens the source at this quote in a new tab)

Impulse control disorders with dopamine agonists: cross-sectional study

“An ICD was identified in 13.6% of patients (gambling in 5.0%, compulsive sexual behavior in 3.5%, compulsive buying in 5.7%, and binge-eating disorder in 4.3%), and 3.9% had 2 or more ICDs.” (opens the source at this quote in a new tab)
“Impulse control disorders were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs 6.9%; odds ratio [OR], 2.72; 95% confidence interval [CI], 2.08-3.54; P < .001).” (opens the source at this quote in a new tab)
“Impulse control disorder frequency was similar for pramipexole and ropinirole (17.7% vs 15.5%; OR, 1.22; 95% CI, 0.94-1.57; P = .14).” (opens the source at this quote in a new tab)

Impulse control disorders with dopamine agonists: longitudinal cohort

“In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4–55.7, DA ever users 51.5% [95% CI 41.8–62.1], DA never users 12.4% [95% CI 4.8–30.0]).” (opens the source at this quote in a new tab)
“Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships.” (opens the source at this quote in a new tab)
“ICDs progressively resolved after DA discontinuation.” (opens the source at this quote in a new tab)

Somnolence with dopamine agonists

“The pooled relative risk of somnolence in this analysis was 4.98 [95% confidence interval (CI) 1.79 to 13.89].” (opens the source at this quote in a new tab)
“Seven trials were included in the analysis of patients taking levodopa and pramipexole or ropinirole compared with those taking levodopa alone. The pooled relative risk was 2.06 (95% CI 1.47 to 2.88).” (opens the source at this quote in a new tab)

Dopamine agonist withdrawal syndrome: retrospective cohort

“Of 40 subjects treated with a DA, 26 underwent subsequent DA taper. Of these 26 subjects, 5 (19%) developed DAWS and 21 (81%) did not.” (opens the source at this quote in a new tab)
“All subjects with DAWS had baseline DA-related impulse control disorders.” (opens the source at this quote in a new tab)
“Dopamine agonists have a stereotyped withdrawal syndrome that can lead to profound disability in a subset of patients.” (opens the source at this quote in a new tab)

Dopamine agonist withdrawal syndrome: prospective cohort

“Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline).” (opens the source at this quote in a new tab)

Dopamine agonist withdrawal syndrome: review

“Dopamine agonist withdrawal syndrome affects even up to 24% of PD patients treated with DAs in whom the medication was tapered.” (opens the source at this quote in a new tab)
“Dopamine agonist withdrawal syndrome remains a therapeutic challenge as it is refractory to levodopa (LD), other PD therapies, anti-depressants, and anti-psychotics.” (opens the source at this quote in a new tab)
“Based on a thorough literature review, it may develop in around 8–24% of PD patients during DAs withdrawal” (opens the source at this quote in a new tab)
“The majority of the literature agrees that the major risk factors for the development of DAWS are as follows: high cumulative DAs exposure, high baseline dose (the higher the dose and the longer the duration of use, the greater the risk of developing DAWS), high peak DAs dose (≥ 150 mg LEDD), diagnosis of ICD in the past, increased vulnerability to addictive behaviors, and neurobiological causes such as mesocorticolimbic dysfunction” (opens the source at this quote in a new tab)
“Symptoms of DAWS can last for several months or even years or resolve spontaneously without management” (opens the source at this quote in a new tab)
“There is no specific treatment of DAWS with proven efficacy. Treatment in this syndrome should always be individualized, symptomatic, and long-term. This syndrome is refractory to LD. Reintroduction of DAs seems to be the only procedure alleviating the symptoms of DAWS” (opens the source at this quote in a new tab)

Unmet need for sustained, predictable relief with fewer adverse events

“Currently, available therapeutics for the treatment of Parkinson’s disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs).” (opens the source at this quote in a new tab)
“Even with the broad range of symptomatic treatment options that are currently available, patients with PD report significantly less treatment satisfaction than patients with other chronic diseases” (opens the source at this quote in a new tab)

Summary

Tavapadon was studied in 2 settings. As monotherapy in early Parkinson's disease, TEMPO-1 (529 participants) and TEMPO-2 (304 participants) enrolled adults aged 40 to 80 years with disease duration under 3 years who were treatment-naive or had less than 3 months of prior dopaminergic treatment. As an adjunct to levodopa, TEMPO-3 (507 participants) enrolled adults with motor fluctuations on a fixed levodopa dose. The company describes the drug as studied as a once-daily oral treatment.

In early disease, tavapadon enters a setting in which the AAN guideline asks clinicians to counsel on the benefits and risks of levodopa, dopamine agonists, and MAO-B inhibitors, permits a dopamine agonist as initial therapy in select patients younger than 60 years at higher risk of dyskinesia, and advises against dopamine agonists in patients older than 70 years or with impulse control disorders, cognitive impairment, excessive daytime sleepiness, or hallucinations.

As an adjunct, tavapadon joins dopamine agonists, MAO-B inhibitors, COMT inhibitors, extended-release amantadine, and istradefylline. In pooled analyses, oral adjunct classes reduce off-time by 0.8 to 1.1 hours per day relative to placebo; TEMPO-3 reported a 1.1-hour increase in good on-time relative to placebo.

The proposed differentiation is D1/D5 selectivity, hypothesized to lower the risk of impulse control disorders, somnolence, and other adverse events attributed to D2/D3 stimulation. A 2026 meta-analysis rated the estimates for impulse control disorder (relative risk 2.02, 95% CI 0.51 to 8.00; 1 trial) and somnolence (pooled relative risk 1.20, 95% CI 0.37 to 3.92) as very low certainty and found that no trial used an active comparator or lasted longer than 27 weeks. A 2026 review stated that studies of drugs selectively targeting D1 receptors do not support improved safety and tolerability.

NICE advises seeking specialist advice before modifying therapy once dyskinesia or motor fluctuations develop. Analysts quoted at approval expected gradual uptake while Medicare coverage was negotiated.

Populations studied in the TEMPO trials

“This includes two Phase 3 trials (TEMPO-1 and TEMPO-2) in early Parkinson's disease, and one Phase 3 trial (TEMPO-3) with tavapadon as adjunctive to levodopa in patients experiencing motor fluctuations.” (opens the source at this quote in a new tab)
“TEMPO-1 and -2 enrolled patients with early Parkinson's disease (with or without an MAO-B inhibitor) and TEMPO-3 enrolled patients who are on fixed-dose levodopa and had motor fluctuations.” (opens the source at this quote in a new tab)
“For many people living with Parkinson's disease, today's oral standard of care isn't effective enough to manage symptoms” (opens the source at this quote in a new tab)

Place in therapy stated in a 2026 review

“A novel D1 dopamine agonist (tavapadon) has completed late stage clinical development showing efficacy both as monotherapy in early PD and as adjunct to levodopa in patients with motor fluctuations.” (opens the source at this quote in a new tab)
“Tavapadon is a novel selective long-acting dopamine D1/D5 receptor partial agonist suitable for once daily oral administration” (opens the source at this quote in a new tab)
“The prime unmet needs regarding current D2-agonist treatment relate to their AE-profile, in particular regarding daytime somnolence, psychosis and impulse dyscontrol.” (opens the source at this quote in a new tab)
“While the above studies support the antiparkinsonian efficacy of drugs selectively targeting D1-receptors they do not support improved safety and tolerability.” (opens the source at this quote in a new tab)
“Longer term data will be required to assess ICD and dyskinesia risk.” (opens the source at this quote in a new tab)

Unmet need in early disease addressed by the monotherapy trials

“Oral levodopa is the preferred initial treatment for PD, but its long-term use is associated with development of motor complications, including so-called on-off fluctuations and dyskinesias.” (opens the source at this quote in a new tab)
“Therefore, there is a key unmet need for an early PD therapy that improves motor symptoms while reducing the risk of AEs seen with current dopaminergic therapies.” (opens the source at this quote in a new tab)
“By selectively targeting D1/D5 receptors, tavapadon may improve motor symptoms while reducing the risk of AEs linked to D2/D3 receptor overactivation.” (opens the source at this quote in a new tab)

Rationale for adjunctive use in motor fluctuations

“Tavapadon is a novel, oral, once-daily, selective D1/D5 agonist” (opens the source at this quote in a new tab)
“It is hypothesized that tavapadon can improve motor control with once-daily dosing, and may reduce the risk of specific AEs associated with D2/D3 receptor activation observed with currently available D2/D3 DAs.” (opens the source at this quote in a new tab)
“These findings highlight the clinical utility of adjunctive tavapadon for the treatment of PD with off fluctuations.” (opens the source at this quote in a new tab)

Background and interpretation of the flexible-dose monotherapy trial

“Current dopaminergic therapies for Parkinson’s disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects.” (opens the source at this quote in a new tab)
“Although a broad range of investigative therapies are in development for symptomatic treatment of Parkinson’s disease, many recent trials have focused on the treatment of advanced Parkinson’s disease, and few novel therapies have been approved for monotherapy in early-stage Parkinson’s disease.” (opens the source at this quote in a new tab)
“A key unmet need for Parkinson’s disease is the availability of treatment modalities that provide a balance of dopamine signalling to improve motor symptoms while reducing the risk of specific adverse events associated with current D2/D3 receptor-targeting dopamine agonists.” (opens the source at this quote in a new tab)
“Tavapadon showed significant and clinically meaningful improvements in Parkinson’s disease motor symptoms, with low incidence of somnolence and impulse control disorders. However, the short observation period limits conclusions about long-term tolerability.” (opens the source at this quote in a new tab)
“The results of TEMPO-2, alongside the evidence from the TEMPO-1 and TEMPO-3 trials, provide a comprehensive body of evidence supporting the efficacy of tavapadon across the different stages of Parkinson’s disease.” (opens the source at this quote in a new tab)
“More data are required to compare tavapadon with approved D2/D3 dopamine agonists.” (opens the source at this quote in a new tab)

Pharmacological rationale for D1/D5 partial agonism

“Tavapadon, a highly selective partial agonist at D1 and D5 receptors, is being investigated for early through advanced PD” (opens the source at this quote in a new tab)
“First, by acting on D1/D5 dopamine receptors, tavapadon selectively activates direct pathway MSNs, which may provide stronger relief of motor symptoms than D2/D3-selective DAs” (opens the source at this quote in a new tab)
“The partial D1/D5 agonism provided by tavapadon may also reduce the probability of receptor desensitization, increasing the likelihood of sustained treatment benefit” (opens the source at this quote in a new tab)
“If ongoing phase 3 trials confirm the safety and efficacy of tavapadon as a monotherapy and adjunct to levodopa, the future availability of a D1/D5-selective agonist may provide another tool for physicians to manage symptoms and AEs for patients with PD” (opens the source at this quote in a new tab)

Certainty of evidence for the D1/D5 partial agonist class

“In early-stage monotherapy, tavapadon improved the combined MDS-UPDRS Parts II and III score by 10.55 points versus placebo (95% CI − 13.11 to − 7.99; two trials).” (opens the source at this quote in a new tab)
“In levodopa-treated patients with motor fluctuations, good ON-time increased by 1.09 h per day (0.57 to 1.61; two trials).” (opens the source at this quote in a new tab)
“Impulse control disorder (RR 2.02, 0.51 to 8.00; nine events, one trial) and somnolence (1.20, 0.37 to 3.92) were rated at very low certainty.” (opens the source at this quote in a new tab)
“Its proposed neuropsychiatric advantage over D2/D3 agonists remains untested: no trial used an active comparator or exceeded 27 weeks.” (opens the source at this quote in a new tab)

Positioning against existing dopamine agonists and adjuncts in a meta-analysis

“When viewed alongside the existing literature, the efficacy observed with tavapadon appears broadly comparable to that reported for established dopamine agonists.” (opens the source at this quote in a new tab)
“This magnitude of improvement is clinically meaningful and is broadly comparable to benefits reported for established adjunctive therapies such as opicapone, safinamide, and entacapone” (opens the source at this quote in a new tab)
“Discontinuation due to adverse events was, however, significantly more frequent with tavapadon (RR 2.72; 95% CI 1.07 to 6.96), and the substantial heterogeneity of that estimate (I² = 65.2%) indicates that tolerability is strongly influenced by titration strategy, patient population and adverse-event management. Tolerability, rather than serious harm, is therefore the principal safety consideration for clinical use.” (opens the source at this quote in a new tab)
“On present evidence that profile is untested, and the class cannot yet be preferred on neuropsychiatric grounds.” (opens the source at this quote in a new tab)
“Longer-term, adequately powered, head-to-head comparative studies are necessary before its place within treatment algorithms can be defined.” (opens the source at this quote in a new tab)

Positioning against D2 agonists and levodopa in a commentary on TEMPO-2

“Despite this clear positive efficacy signal, TEMPO-2 does not answer some essential questions that are mandatory to anticipate the future positioning of tavapadon among other antiparkinsonian dopaminergic options in clinical practice, especially D2 agonists and L-DOPA.” (opens the source at this quote in a new tab)
“Such an apparent safer profile of tavapadon on drug-induced somnolence is not trivial, especially for drivers carrying the risk of falling asleep at the wheel and people with similar attention-demanding jobs.” (opens the source at this quote in a new tab)
“In summary, adding a D1 agonist into the panel of available dopaminergic antiparkinsonian medications has been long awaited. Tavapadon could fill this gap. It is, however, too early to ascertain whether its benefit–risk ratio will represent a real step forward compared with outdated, off-patent, and cheap D2 agonists, justifying a commercially viable pricing and ultimately a rightful renewed interest in using dopamine agonists to treat patients with Parkinson’s disease.” (opens the source at this quote in a new tab)

Tavapadon among emerging therapies for motor fluctuations

“Preliminary results of a phase III study of dopamine D1/D5 agonist tavapadon and phase II of CVN424, a GRP6 inverse agonist suggest improved ON time.” (opens the source at this quote in a new tab)
“Overall, it is unclear whether the field is significantly further ahead, as the benefit of these emerging drugs in comparison with currently available agents for motor fluctuations needs to be clarified.” (opens the source at this quote in a new tab)

Potential role where dopamine agonist withdrawal is a concern

“Development of new generation DAs, such as tavapadon, which may reduce the side effects of dopaminergic therapy, may set new standards for treatment.” (opens the source at this quote in a new tab)
“The introduction of next-generation DAs (now still in clinical trials) like tavapadon, which focuses on more selective receptor targeting to reduce side effects, and being a D1/D5 partial agonist, shows promise for fewer side effects, including DAWS, as well as ICD and sleepiness, when compared to older D2/D3 agonists” (opens the source at this quote in a new tab)

Care setting: specialist input when fluctuations develop

“If a person with Parkinson's disease has developed dyskinesia and/or motor fluctuations, including medicines 'wearing off', seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying therapy.” (opens the source at this quote in a new tab)

Anticipated uptake after approval

“The drug tavapadon, which AbbVie gained access to through its $8.7 billion acquisition of Cerevel Therapeutics in 2023, comes as a once-a-day pill.” (opens the source at this quote in a new tab)
“Citi analysts had previously said the launch was expected in the third quarter of 2026, but that uptake was likely to be gradual as negotiations progressed on the drug’s Medicare coverage.” (opens the source at this quote in a new tab)

Tavapadon: predefined subgroups in the fixed-dose monotherapy trial

“In addition to the consistent efficacy outcomes in the overall tavapadon group, subgroup analyses of participants treated with both 5-mg and 15-mg doses of tavapadon demonstrated motor improvement across predefined subgroups, although greatest consistency in improvements was seen in the 15-mg group, which suggests a higher dose of tavapadon may be necessary for specific populations.” (opens the source at this quote in a new tab)
“Further study may be needed to confirm these findings.” (opens the source at this quote in a new tab)
“Most participants (514 of 529 [97.2%]) were White, which may impact generalizability.” (opens the source at this quote in a new tab)

Tavapadon: predefined subgroups in the flexible-dose monotherapy trial

“The effect of tavapadon versus placebo on MDS-UPDRS Parts II and III combined scores was consistent at week 26 across subgroups by age (<65 years vs ≥65 years), sex, mH&Y staging at screening, baseline MDS-UPDRS Part II and III individual scores, concomitant use of an MAO-B inhibitor, disease duration (<1 year, 1 year to <2 years), and geographical region (appendix p 5).” (opens the source at this quote in a new tab)
“More than half of the participants were male (169 [56%] of 304) and most were White (268 [88%] of 304)” (opens the source at this quote in a new tab)

Tavapadon: representativeness of the adjunctive trial population

“This study was not designed to compare tavapadon with D2/D3 DAs or other adjunctive therapies for PD.” (opens the source at this quote in a new tab)
“The study population was predominantly White (96.8%), and further study of tavapadon in underrepresented populations may be needed.” (opens the source at this quote in a new tab)

Patient characteristics that modify the risk of dyskinesia and impulse control disorders

“Patient and disease characteristics influence the risk of adverse effects related to the use of levodopa and dopamine agonists and may affect initial treatment choices.” (opens the source at this quote in a new tab)
“Predisposing patient characteristics for ICDs are male sex, younger age, history of ICDs, history of mood disorders (particularly depression), the presence of apathy, and a family history of ICDs and addiction.” (opens the source at this quote in a new tab)
“Older patients are at greater risk for cognitive and behavioral adverse effects of dopamine agonists.” (opens the source at this quote in a new tab)

Predisposing factors for dyskinesia and dopamine agonist adverse effects in early disease

“Younger age at disease onset, lower body weight, female sex, and increased disease severity are all predisposing factors for the development of levodopa-induced dyskinesia.” (opens the source at this quote in a new tab)
“DAs are associated with a greater risk of excessive daytime somnolence and sleep attacks; therefore, patients whose employment requires driving or operating heavy machinery may face greater impairment from these adverse effects.” (opens the source at this quote in a new tab)
“The trend demonstrates that although DAs are more likely than levodopa to cause hallucinations at some time points, the difference between treatments for this outcome is small in early PD for the first 5 years of treatment.” (opens the source at this quote in a new tab)
“This may be related to the inclusion of younger patients without cognitive impairment in early PD trials.” (opens the source at this quote in a new tab)

Clinical and demographic correlates of impulse control disorders

“Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems.” (opens the source at this quote in a new tab)

Impulse control disorders across dopaminergic therapies and disease stages

“Recognise that impulse control disorders can develop in a person with Parkinson's disease who is on any dopaminergic therapy at any stage in the disease course.” (opens the source at this quote in a new tab)
“A history of previous impulsive behaviours.” (opens the source at this quote in a new tab)
“A history of alcohol consumption and/or smoking.” (opens the source at this quote in a new tab)

Concomitant dopamine agonists and dyskinesia with levodopa/carbidopa/entacapone

“These effects were more pronounced in patients receiving dopamine agonists at baseline.” (opens the source at this quote in a new tab)
“In patients receiving dopamine agonists, LCE-treated patients had a greater risk of dyskinesia (hazard ration, 1.55; p = 0.006), and a greater frequency of dyskinesia (41.9% vs 31.3%).” (opens the source at this quote in a new tab)
“However, there was no difference in the time to onset (hazard ratio, 0.99; 95% CI, 0.68–1.45; p = 0.96) or frequency (34% vs 35.5%) of dyskinesia between patients in the LCE and LC groups for those not receiving dopamine agonists.” (opens the source at this quote in a new tab)
“Kaplan-Meier survival curves show that among patients who were receiving dopamine agonists at baseline, those randomized to L-dopa/carbidopa/entacapone (LCE) had greater risk of developing dyskinesia than those receiving L-dopa/carbidopa (LC) (Cox proportional hazard ratio, 1.55; 95% confidence interval [CI], 1.13–2.13; p = 0.006).” (opens the source at this quote in a new tab)
“The estimated first quartile time to onset of dyskinesia was 78.9 weeks for the LCE group and 117.4 weeks for LC.” (opens the source at this quote in a new tab)
“The adjusted mean difference in change from baseline to final visit in UPDRS score between the LCE and LC groups was greater in those receiving concomitant dopamine agonists (difference, 1.8; p = 0.08) than in those who were not (difference, −0.1; p = 0.95).” (opens the source at this quote in a new tab)
“Patients on dopamine agonists were younger (58.7±8.6 vs 62.3±7.8 years; p < 0.001), had longer disease duration (2.5±1.6 vs 1.3±1.5 years; p < 0.001)” (opens the source at this quote in a new tab)
“Patients receiving dopamine agonists had a higher frequency of dyskinesias, and LCE was significantly more prone than LC to induce dyskinesias in this subpopulation.” (opens the source at this quote in a new tab)
“This is likely because patients on dopamine agonists were younger at baseline, were about 5 years younger at disease onset, had longer disease duration, and probably had greater disease severity as they had comparable baseline UPDRS scores despite receiving dopamine agonists.” (opens the source at this quote in a new tab)
“It is interesting that LCE did not increase the frequency or shorten the time to onset of dyskinesia in patients not on dopamine agonists, despite higher L-dopa dose equivalents, similar to what was observed in the FIRST-STEP study.” (opens the source at this quote in a new tab)

Dyskinesia frequency by age, sex, body weight, disease duration, and MAO-B inhibitor use with levodopa/carbidopa with or without entacapone

Subgroup	Levodopa/carbidopa/entacapone, no./total (%)	Levodopa/carbidopa, no./total (%)	P value
Age <65 years	“102/223 (45.7)”	“95/253 (37.5)”	“0.021”
Age ≥65 years	“42/150 (28.0)”	“28/119 (23.5)”	“0.162”
Men	“90/245 (36.7)”	“65/222 (29.3)”	“0.043”
Women	“54/128 (42.2)”	“58/150 (38.7)”	“0.191”
Body weight <75 kg	“61/142 (43.0)”	“67/164 (40.9)”	“0.374”
Body weight ≥75 kg	“83/231 (35.9)”	“56/208 (26.9)”	“0.018”
Disease duration <2 years	“75/157 (47.8)”	“50/168 (29.8)”	“<0.001”
Disease duration ≥2 years	“69/216 (31.9)”	“73/204 (35.8)”	“0.514”
Without MAO-B inhibitor	“123/335 (36.7)”	“115/343 (33.5)”	“0.170”
With MAO-B inhibitor	“21/38 (55.3)”	“8/29 (27.6)”	“0.005”

“Dyskinesias were more common in patients younger than 65 years, and LCE was associated with an increased risk of dyskinesia in younger, but not older, patients.” (opens the source at this quote in a new tab)
“Patients with lower body weight (<75kg) had more dyskinesia, but LCE was more likely to induce dyskinesia in heavier patients.” (opens the source at this quote in a new tab)
“Dyskinesias were more common in those with disease duration <2 years, and LCE was more likely to cause dyskinesia in those with a shorter duration of disease (p < 0.01).” (opens the source at this quote in a new tab)
“Finally, patients receiving monoamine oxidase type B inhibitors were more likely to have dyskinesia than those who were not, and although numbers were small, had a much greater chance of having dyskinesia if they were receiving LCE (p = 0.005).” (opens the source at this quote in a new tab)
“p values are post hoc, are not corrected, and are for descriptive purposes only.” (opens the source at this quote in a new tab)

Dopamine agonist subgroup in early versus delayed levodopa

“Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03).” (opens the source at this quote in a new tab)

Age and the comparison of initial levodopa with levodopa-sparing therapy

“Patients assigned only between dopamine agonists and MAOBI had less severe disease and were younger, with a mean age of 62 years compared with 71 years in the other two randomisation options.” (opens the source at this quote in a new tab)
“Treatment efficacy, as measured by PDQ-39 mobility subscale, did not differ according to baseline stratification variables (age, Hoehn and Yahr stage, and duration of Parkinson’s disease symptoms).” (opens the source at this quote in a new tab)
“Subgroup comparisons in PD MED noted no difference in treatment efficacy in those younger than and older than 70 years and hence do not support age-specific treatment recommendations.” (opens the source at this quote in a new tab)
“few participants (12%) were younger than 60 years at randomisation, particularly in the levodopa versus levodopa-sparing comparison” (opens the source at this quote in a new tab)
“the trial provides little direct evidence for how such patients should be treated.” (opens the source at this quote in a new tab)

Levodopa response in participants without a dopaminergic deficit on baseline imaging

“nor did subjects with such scans in the group receiving the highest dose of levodopa have an improvement in the scores on the UPDRS (i.e., a change between the score at baseline and at week 40 of 3.38±4.25 units, as compared with a change of −4.95±10.4 units in the subjects receiving levodopa at 600 mg daily whose baseline SPECT scans showed abnormalities; P=0.002).” (opens the source at this quote in a new tab)
“Whether the subjects with no evidence of dopaminergic deficit on scanning do or do not have classic Parkinson’s disease remains uncertain.” (opens the source at this quote in a new tab)
“The fact that scans of some patients with early Parkinson’s disease do not have evidence of a dopaminergic deficit needs to be taken into consideration in the planning of future trials to test drugs for neuroprotective effects.” (opens the source at this quote in a new tab)

Young-onset disease, disease duration, and the frequency of levodopa motor complications

“Most notably, we did not include papers where the motor complication rate was assessed specifically among young-onset (< 40 years) PD patients.” (opens the source at this quote in a new tab)
“The literature suggests that this subgroup of PD patients is at a very high risk for developing both dyskinesias and motor fluctuations relatively early in the course of treatment.” (opens the source at this quote in a new tab)
“One might infer from this study that a typical PD patient (excluding young-onset) has about a 40% likelihood of developing motor fluctuations after 5 years of levodopa therapy.” (opens the source at this quote in a new tab)
“The differences in dyskinesia frequencies between pre-levodopa era versus modern era patients may relate to clinical disease durations prior to starting levodopa therapy.” (opens the source at this quote in a new tab)

Patient characteristics associated with deep brain stimulation outcomes

“Characteristics associated with worse deep brain stimulation outcomes include older age (≥75 years), cognitive impairment (particularly dementia), and the presence of levodopa-unresponsive symptoms (eg, gait, balance disturbance).” (opens the source at this quote in a new tab)

Duration of motor fluctuations and response to opicapone

“A pooled post-hoc analysis of these trials showed similar effect sizes in subjects with a short (≤ 1 year) or longer (> 2 years) history of motor fluctuations at trial start” (opens the source at this quote in a new tab)

Patient profile and disease stage in adjunct selection

“Similarly, in clinical practice, consideration must be given to the patient profile and disease stage.” (opens the source at this quote in a new tab)
“In addition to the varying degree of certainty of the efficacy of an intervention, its safety and individual tolerability must be taken into account, together with each patient's preference.” (opens the source at this quote in a new tab)

D1/D5 agonism in late-stage disease: pilot crossover study

“Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients.” (opens the source at this quote in a new tab)

Fixed-dose versus flexible-dose comparison of the monotherapy trials in a meta-analysis

“Because each dosing strategy is represented by exactly one trial, this comparison is equivalent to the between-trial contrast of the primary analysis: fixed-dose TEMPO-1 gave − 11.73 (95% CI − 13.74 to − 9.72) and flexible-dose TEMPO-2 gave − 9.10 (95% CI − 11.70 to − 6.50), a difference of 2.63 points that was not statistically significant (Q(1) = 2.46, p = 0.117). With one trial per stratum this comparison has negligible power and is confounded with every other difference between the two trials; it should not be read as evidence that dosing strategy does not moderate the treatment effect.” (opens the source at this quote in a new tab)

Heterogeneity of pooled adverse event estimates between monotherapy and adjunctive trials

“Overall incidence of AEs was significantly higher in the treatment group (RR 1.36; 95% CI 1.09 to 1.71) with substantial between-study heterogeneity (I² = 72.3%, p = 0.005). The heterogeneity is explained by the adjunctive trials: in B7601003, where 20 of 23 placebo participants (87.0%) reported an adverse event on a background of levodopa, tavapadon added essentially no relative risk (RR 0.97; 95% CI 0.79 to 1.19), whereas in the early-stage monotherapy trials, with placebo event rates of 41% to 55%, risk ratios ranged from 1.39 to 1.72.” (opens the source at this quote in a new tab)
“Discontinuation due to adverse events was also elevated (RR 2.72; 95% CI 1.07 to 6.96), again with substantial heterogeneity (I² = 65.2%, p = 0.015), reflecting variable titration schedules and tolerability management across trials” (opens the source at this quote in a new tab)

Counseling and screening before starting a dopamine agonist

“Clinicians should inform the patient and caregiver (when present) of important side effects of dopamine agonists before prescribing; this discussion should specifically include ICDs, excessive daytime sleepiness, sudden-onset sleep, nausea, postural hypotension, and hallucinations.” (opens the source at this quote in a new tab)
“Clinicians should screen patients for cognitive impairment, excessive daytime sleepiness, sudden-onset sleep, hallucinations, orthostatic hypotension, and the presence of risk factors for ICDs before prescribing a dopamine agonist.” (opens the source at this quote in a new tab)

Ongoing monitoring with caregiver involvement and validated questionnaires

“Clinicians should screen patients for the presence of adverse effects related to dopamine agonists, including ICDs, excessive daytime sleepiness, sudden-onset sleep, orthostatic hypotension, cognitive impairment, and hallucinations repeatedly in follow-up of patients prescribed dopamine agonists.” (opens the source at this quote in a new tab)
“Clinicians should involve caregivers in assessments for ICDs, excessive daytime sleepiness, sudden-onset sleep, orthostatic hypotension, cognitive impairment, and hallucinations in patients with PD.” (opens the source at this quote in a new tab)
“Clinicians may screen patients for the presence of adverse effects associated with dopamine agonists using questionnaires validated for this purpose, including the QUIP for ICDs, and the ESS for the assessment of impaired wakefulness.” (opens the source at this quote in a new tab)
“The QUIP and ESS are patient-completed scales with an administration time of less than 10 minutes and are publicly available for clinical use.” (opens the source at this quote in a new tab)

Monitoring during levodopa therapy

“Clinicians should routinely monitor patients taking levodopa for their motor response to treatment, and for the presence of dyskinesia, motor fluctuations, ICDs, excessive daytime sleepiness, postural hypotension, nausea, and hallucinations, to guide dosage titration over time.” (opens the source at this quote in a new tab)

Tapering dopamine agonists after adverse effects

“Clinicians should recommend tapering or discontinuation of dopamine agonists if patients experience disabling medication-related adverse effects, including ICDs, excessive daytime sleepiness, sudden-onset sleep, cognitive impairment, or hallucinations.” (opens the source at this quote in a new tab)
“When dopamine agonists must be discontinued due to adverse effects, clinicians should monitor patients for symptoms of DAWS and, when possible, gradually decrease the dosage to minimize symptoms.” (opens the source at this quote in a new tab)

Tapering dopamine agonists: approach and management of withdrawal syndrome

“There is scarce information or guidelines on how to discontinue DAs.” (opens the source at this quote in a new tab)
“When reducing the DAs dose, the general rule is to individualize the process, reducing in small doses, and with careful observation. Authors suggest even slower tapering than proposed (according to available sources) in Table 3.” (opens the source at this quote in a new tab)
“The implementation of these new methods implicates the reduction or withdrawal of previously used medications. Dopamine agonists are usually the first ones to be reduced. Thus, advanced therapies can be considered as a factor possibly contributing to the development of DAWS” (opens the source at this quote in a new tab)
“A practical conclusion is to cautiously reduce DAs and LD after implementation of advanced therapies. Our suggestion is even to increase this time and prolong the reduction at small steps during the first 6 months after surgery or pump therapy initiation.” (opens the source at this quote in a new tab)
“Therapeutic decision: consider reintroducing DAs (another type and dose), carefully monitor for ICD or other side effects, consider personalized symptomatic treatment, consider non-pharmacologic treatment (psychotherapy, physiotherapy, occupational therapy, psychosocial support).” (opens the source at this quote in a new tab)
“Nevertheless, the most important management is the slow-as-possible tapering of DAs, and only when necessary.” (opens the source at this quote in a new tab)

Tapering dopamine agonists: proposed reduction rates by agent

Dopamine agonist and dose setting	Quoted rate of reduction
Pramipexole, low doses	“At low doses (e.g., ≤ 1.5 mg/d.): reduce by 25–33% every 7–14 days”
Pramipexole, higher doses	“At higher doses (e.g., > 1.5 mg/d.): reduce by 10–25% every 1–2 weeks”
Pramipexole, long-term treatment or impulse control disorder	“Long-term treatment or ICD, the rate 10% every 1–2 weeks”
Pramipexole extended release	“Reduction by 0.375 mg every second day”
Rotigotine	“Reduction by 2 mg every second day, until discontinuation”
Ropinirole immediate release (one of two listed rates)	“2 mg every second day”
Piribedil	“50 mg every third day”
Apomorphine pump	“0.5 mg/h every second day”

Information, review, and management of impulse control disorders

“Discuss potential impulse control disorders at review appointments, particularly when modifying therapy, and record that the discussion has taken place.” (opens the source at this quote in a new tab)
“When managing impulse control disorders, modify dopaminergic therapy by first gradually reducing any dopamine agonist. Monitor whether the impulse control disorder improves and whether the person has any symptoms of dopamine agonist withdrawal.” (opens the source at this quote in a new tab)
“Offer specialist cognitive behavioural therapy targeted at impulse control disorders if modifying dopaminergic therapy is not effective.” (opens the source at this quote in a new tab)

Continuity of medication during hospital or care home admission

“Antiparkinsonian medicines should not be withdrawn abruptly or allowed to fail suddenly due to poor absorption (for example, gastroenteritis, abdominal surgery) to avoid the potential for acute akinesia or neuroleptic malignant syndrome.” (opens the source at this quote in a new tab)
“In view of the risks of sudden changes in antiparkinsonian medicines, people with Parkinson's disease who are admitted to hospital or care homes should have their medicines:” (opens the source at this quote in a new tab)

Nurse specialist, rehabilitation therapy, and nutrition

“People with Parkinson's disease should have regular access to:” (opens the source at this quote in a new tab)
“Offer Parkinson's disease-specific physiotherapy for people who are experiencing balance or motor function problems.” (opens the source at this quote in a new tab)
“Offer Parkinson's disease-specific occupational therapy for people who are having difficulties with activities of daily living.” (opens the source at this quote in a new tab)
“Offer speech and language therapy for people with Parkinson's disease who are experiencing problems with communication, swallowing or saliva.” (opens the source at this quote in a new tab)
“Discuss a diet in which most of the protein is eaten in the final main meal of the day (a protein redistribution diet) for people with Parkinson's disease on levodopa who experience motor fluctuations.” (opens the source at this quote in a new tab)

Physiotherapy and exercise as adjuncts to medication

“For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly useful.” (opens the source at this quote in a new tab)

Practical adjustments before adding an adjunct

“In clinical practice, the most common approach is to start by adjusting the dosing schedule of levodopa, which may involve taking more frequent doses throughout the day or shortening the interval between doses.” (opens the source at this quote in a new tab)
“Additionally, promoting the predictability of levodopa absorption is important; this can be achieved by taking it on an empty stomach and ensuring normal gastrointestinal transit time through the treatment of constipation.” (opens the source at this quote in a new tab)

Sequence of interventions for motor fluctuations in clinical practice

“In daily clinical practice, adjusting the timing of levodopa preparations to a shorter time interval and improving absorption, for example, by taking levodopa on an empty stomach and by improving gastrointestinal transit by treating constipation are all partly effective methods.” (opens the source at this quote in a new tab)
“In clinical practice there is a hierarchical use of interventions according to safety risks.” (opens the source at this quote in a new tab)
“Thus, earlier in the course of developing motor fluctuations, the first-line treatments are usually oral (or transdermal) agents (dopaminergics, enzyme inhibitors or nondopaminergics), followed by parenteral and surgical techniques for more advanced patients.” (opens the source at this quote in a new tab)

Palliative care referral

“Consider referring people at any stage of Parkinson's disease to the palliative care team to give them and their family members or carers (as appropriate) the opportunity to discuss palliative care and care at the end of life.” (opens the source at this quote in a new tab)

Caregiver-directed cognitive behavior therapy and palliative care: meta-analysis of effect on caregiver burden

“Meta-analysis showed that cognitive behavior therapy and palliative care had no significant effect to reduce caregiver burden in PD patients’ caregiver.” (opens the source at this quote in a new tab)
“Three articles which used CBT as their intervention reported ZBI score on caregivers” (opens the source at this quote in a new tab)
“The results of meta-analysis showed that there was no significant difference in ZBI between intervention group and control group (MD = − 3.56; 95% CI = − 7.78, 0.66; P = 0.10).” (opens the source at this quote in a new tab)
“Three articles which used palliative care as their intervention reported ZBI score on caregivers” (opens the source at this quote in a new tab)
“The results of meta-analysis showed that there was no significant difference in ZBI between intervention group and control group (MD = − 0.41; 95% CI = − 1.06, 0.24; P = 0.22).” (opens the source at this quote in a new tab)

Postmarketing requirements and commitments in the FDA approval letter

No evidence found.

Long-term open-label extension trial

“An open-label extension study (TEMPO-4) is ongoing to assess the long-term safety and efficacy of tavapadon through 58 weeks of treatment. TEMPO-4 enrolled patients who completed participation in TEMPO-1 through 3, as well as patients on stable doses of levodopa who had not been in prior TEMPO trials.” (opens the source at this quote in a new tab)

“Open-label Trial in Parkinson's Disease (PD)” (opens the source at this quote in a new tab)

Adverse reaction reporting

“To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.” (opens the prescribing information at this quote)

Summary

Available treatments, tavapadon included, are symptomatic. Clinically meaningful thresholds used in this indication are about 1 hour per day for change in off-time or on-time without troublesome dyskinesia (MDS review threshold 1 hour; pramipexole extended-release trials 1.0 to 1.3 hours), 4 points for MDS-UPDRS Part III in the MDS review (anchor-based estimates of -3.25 points for improvement and 4.63 points for worsening), and 4.9 points for combined MDS-UPDRS Parts II and III as cited by TEMPO-1. In early disease, tavapadon reduced the combined Parts II and III score from baseline by 9.7 points (5 mg) and 10.2 points (15 mg) at week 26 in TEMPO-1, which the investigators described as approximately twice the minimal clinically important difference, and a meta-analysis of 2 monotherapy trials estimated a placebo-adjusted improvement of 10.55 points. As an adjunct, TEMPO-3 reported a least-squares mean reduction in off-time of 1.88 hours from baseline and a placebo-adjusted increase in good on-time of 1.1 hours; the pooled estimate from 2 adjunctive trials was 1.09 hours. No randomized trial of tavapadon identified by that meta-analysis lasted longer than 27 weeks.

Summary of efficacy and tolerability outcomes across the phase 3 trials

“Both studies met their primary efficacy endpoint of change from baseline of MDS-UPDRS part II + III scores with a statistically significant difference in favour of tavapadon vs placebo: − 11.5 points for 5 mg, − 12.1 points for 15 mg, and − 9.1 points in the flexible-dose study” (opens the source at this quote in a new tab)
“This study also met its primary endpoint with a significantly greater increase in ‘good ON-time’ versus placebo (+ 1.1 h)” (opens the source at this quote in a new tab)
“Discontinuation rates ranged from 24.3% in the 5 mg tavapadon treatment arm of the TEMPO-1 trial to 36.9% in the flexible-dose tavapadon treatment arm of the TEMPO-3 trial compared to 15.4% and 19.2% in the placebo arms” (opens the source at this quote in a new tab)
“Incidence rates for ICDs with tavapadon treatment were 0.8% and 2.4% in the RCTs and 1.4% in a preliminary interim analysis of a 58-week, open-label study (TEMPO-4, NCT04760769)” (opens the source at this quote in a new tab)

Minimal clinically important differences used to judge efficacy

“For changes in duration of ON‐time, OFF‐time, and time without dyskinesia, MCID was 1 h per day.” (opens the source at this quote in a new tab)
“For the UPDRS‐Part III and the MDS‐UPDRS‐Part III, MCID was 4 points.” (opens the source at this quote in a new tab)
“For the UPDRS and MDS‐UPDRS‐Part II, MCID was 3 points,” (opens the source at this quote in a new tab)
“and for the PDQ‐39, MCID was 5 points.” (opens the source at this quote in a new tab)

Minimal clinically important difference for off-time and UPDRS

“MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were -1.8 and -2.0, for UPDRS III -6.2 and -6.1, and for UPDRS II + III -8.0 and -8.1.” (opens the source at this quote in a new tab)
“MCID for "OFF" time (pramipexole ER, pramipexole IR) was -1.0 and -1.3 hours.” (opens the source at this quote in a new tab)

Minimal clinically important difference for MDS-UPDRS Part III

“Therefore, 728 paired follow-up visits of 260 patients were utilized for the analyses.” (opens the source at this quote in a new tab)
“The MCID estimates for MDS-UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening.” (opens the source at this quote in a new tab)
“Based on the ROC analysis, the best cut-off values discriminating no change from minimal clinical improvement and no change from minimal clinical worsening were −3.5 and +4.5, respectively (Table 3).” (opens the source at this quote in a new tab)
“Based on our data, all three measurements gave similar MCID threshold values: Any improvement larger than 3.25 points or any worsening larger than 4.63 points on MDS-UPDRS ME represent minimal, but clinically meaningful change.” (opens the source at this quote in a new tab)
“Based on these data, we can conclude that our MCID estimates for MDS-UPDRS are mostly in the range of previously published estimates for UPDRS and MDS-UPDRS.” (opens the source at this quote in a new tab)

Minimal clinically important differences for MDS-UPDRS Parts I and II

“In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively.” (opens the source at this quote in a new tab)
“Investigations utilizing Parts I and II as outcome measure should apply the threshold of –2.64 and –3.05 points for revealing improvement or the threshold of 2.45 and 2.51 points for observing deterioration.” (opens the source at this quote in a new tab)
“Similarly, any improvement larger than –5.73 points or worsening more than 4.7 points on MDS-UPDRS I+II composite score represents meaningful perceived changes.” (opens the source at this quote in a new tab)
“Though Hauser and colleagues established markedly smaller MCID values for UPDRS-II (0.7 points for improvement and 0.5 points for worsening) examining patients treated with rasagiline” (opens the source at this quote in a new tab)
“they calculated similar estimates for improvement in early (– 1.8 and –2.0) and advanced PD patients receiving pramipexole (–1.8 and –2.3 points).” (opens the source at this quote in a new tab)

Minimal clinically important differences for the MDS-UPDRS composite scores

“Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change.” (opens the source at this quote in a new tab)
“should apply the threshold of –4.9 and +4.2 points for revealing improvement or deterioration.” (opens the source at this quote in a new tab)
“Based on our calculations, the MCID thresholds for the MDS-UPDRS I+II+III are –6.7 and +5.2 points for identifying clinically relevant improvement and worsening.” (opens the source at this quote in a new tab)
“Hauser and colleagues estimated the MCID thresholds for UPDRS 2 + 3 as being – 8.0 and –8.1 points in early PD and –7.1 and -8.8 points for advanced PD.” (opens the source at this quote in a new tab)
“Of note, our thresholds are considerably smaller, which may be partly explained by the different structures of these scales.” (opens the source at this quote in a new tab)

Minimal clinically important change in off time

“MCIC for reduction in ‘‘off’’ hours using this methodology is 1.0 hours (1.9–0.9 hours).” (opens the source at this quote in a new tab)
“Similarly, we found that a reduction in ‘‘off’’ time of 1.2 hours best distinguished active treatment subjects rated minimally improved from those rated unchanged.” (opens the source at this quote in a new tab)
“By definition, MCICs derived from ROC cutoffs are smaller than those derived using mean scores. Whether one approach is superior to the other to MCIC is unknown.” (opens the source at this quote in a new tab)

Expected magnitude of benefit with tavapadon monotherapy

“Once-daily dosing with tavapadon, 5 mg or 15 mg, led to reductions from baseline of MDS-UPDRS parts II and III combined scores at week 26 (−9.7 and −10.2 points with 5-mg and 15-mg doses of tavapadon, respectively) that were approximately twice as large as the minimum clinically important difference (>4.9-point improvement) in MDS-UPDRS parts II and III combined scores seen in other studies.” (opens the source at this quote in a new tab)
“Nominal improvements in MDS-UPDRS parts II and III combined scores and MDS-UPDRS part II individual scores were observed as early as week 5, before the end of the titration period (tavapadon dose, 3 mg), with continued separation from the placebo group through approximately week 11.” (opens the source at this quote in a new tab)
“Further studies are needed to support the long-term safety and efficacy of tavapadon in this population.” (opens the source at this quote in a new tab)

Expected magnitude of benefit with adjunctive tavapadon

“The LSM decrease in off-time from baseline to week 26 observed in the tavapadon group (−1.88 hours) is comparable with improvements in off-time seen with other adjunctive PD therapies, including D2/D3 agonists, and surpasses the previously reported minimum clinically important difference for a reduction in off-time of approximately 1.0 hour.” (opens the source at this quote in a new tab)
“No significant differences between groups were observed in the PDQ-39, EQ-5D-5L index, and VAS scores.” (opens the source at this quote in a new tab)
“The 27-week treatment duration was comparable with other phase 3 trials investigating therapies for PD with motor fluctuations” (opens the source at this quote in a new tab)
“research is needed to support the long-term safety and efficacy of tavapadon.” (opens the source at this quote in a new tab)

Pooled efficacy estimates relative to minimal clinically important differences

“The effect substantially exceeded the minimal clinically important difference for the combined score, variously estimated at approximately 5 to 7 points” (opens the source at this quote in a new tab)
“the pooled estimate exceeds the commonly cited minimal clinically important difference of approximately 0.5 to 1.0 h for this endpoint, ascertained with the validated patient home diary” (opens the source at this quote in a new tab)

Pooled MDS-UPDRS Part II mean differences that differ between the secondary outcome text and figure 4 of a meta-analysis

“Tavapadon significantly improved patient-reported motor experiences of daily living, with a pooled LS mean difference of − 2.00 points (95% CI − 3.11 to − 0.90; p = 0.010) across all four poolable studies (Fig. 4).” (opens the source at this quote in a new tab)
“difference was − 1.65 points (95% CI − 3.01 to − 0.30; p = 0.030). Heterogeneity was moderate (I² = 58.4%, τ² = 0.39, Q(3) = 7.47, p = 0.058)” (opens the source at this quote in a new tab)
“Random effects model (HK) 100.0% -1.65 [-3.01; -0.30]” (opens the source at this quote in a new tab)

MDS-UPDRS Part II trial intervals stated to lie entirely below zero, one of which includes zero

“With the TEMPO-1 dose arms combined, four trials contributed: TEMPO-1 (− 2.55; 95% CI − 3.28 to − 1.81), TEMPO-2 (− 1.50; −2.40 to − 0.60), Fernandez et al. [12] (− 1.20; −2.20 to − 0.20) and B7601003 (− 0.08; −2.68 to 2.52).” (opens the source at this quote in a new tab)
“All individual studies favoured tavapadon with CIs entirely below zero.” (opens the source at this quote in a new tab)

Pooled adverse event profile of the D1/D5 partial agonist class

“Adverse events (RR 1.36, 1.09 to 1.71), nausea (6.38, 3.23 to 12.59), dizziness (3.03, 2.15 to 4.27) and discontinuation due to adverse events (2.72, 1.07 to 6.96) were more frequent with tavapadon.” (opens the source at this quote in a new tab)
“Serious adverse events were not increased (Peto OR 1.13, 0.69 to 1.85).” (opens the source at this quote in a new tab)
“Selective D1/D5 partial agonism improves motor function in early-stage and levodopa-treated Parkinson’s disease, at moderate certainty.” (opens the source at this quote in a new tab)