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Diagnosis

27 evidence topics · 12 sources

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)