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Juvmo (tavapadon)

Parkinson's disease

Also known as CVL-751
Manufacturer
AbbVie
Regulatory submission
NDA submitted September 2025
Last updated
217 sources

Product information and disease descriptionPlace of product in therapyDisease description

Clinical presentation - signs and symptoms

32 evidence topics · 20 sources

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)

AssessmentParticipants assessed, nFreezing 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)

Measure1 year2 years3 years4 years5 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 ratio95% CIp-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 domainAll 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
SettingMajor depressive disorder: number of studiesMajor depressive disorder: prevalence (%)Clinically relevant depressive symptoms: number of studiesClinically 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 disorderNumber of studiesTotal participants with Parkinson's diseaseRange, %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
SubgroupNumber of studiesPooled 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)

SubgroupNumber of studiesEstimated 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 coefficient95% CIP
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)