The levels of evidence (Class I–IV) supporting the recommendations and ratings of recommendations (A–C) are defined at the end of the "Major Recommendations" field.
Section 1: Clinical Diagnostic Criteria for Parkinson's Disease (PD)
Only the Queen Square Brain Bank (QSBB) clinical diagnostic criteria have been validated by Hughes et al. (2002) and are therefore recommended as probably effective (Level B) for clinical practice.
Section 2: Genetic Testing
Available evidence provides a Level B recommendation for the use of genetic testing in the diagnosis of PD. Genetic testing for specific mutations is recommended on an individual basis, and specific features, particularly family history and age of onset, must be taken into account:
- Testing for alpha-synuclein (SNCA) point mutations and gene multiplications is recommended only in families with multiple affected members in more than one generation suggestive of dominant inheritance, with early- or late-onset PD.
- Leucine-rich repeat kinase 2 (LRRK2) genetic testing for counselling purposes, specifically directed at known pathogenic variants is recommended in patients with a clinical picture of typical PD and a positive family history suggestive of dominant inheritance.
- In sporadic patients, genetic testing should be limited to the search for known LRRK2 founder mutations in the appropriate populations (i.e., with known high mutation frequencies).
- Genetic testing for glucocerebrosidase (GBA) gene mutations is recommended in patients with typical PD with or without a positive family history, limited to the known founder mutations of established pathogenic role in the appropriate populations.
- Genetic testing of the parkin, PINK1 and DJ-1 genes for counselling purposes is recommended in patients with typical PD and positive family history compatible with recessive inheritance, particularly when the disease onset is before the age of 50 years. For sporadic cases, parkin, PINK1 and DJ-1 genetic testing is recommended when onset is very early, particularly before the age of 40.
- Testing of the ATP13A2, PLA2G6 and FBXO7 genes might be considered in cases with very-early-onset PD, if no mutation in parkin, PINK1 and DJ-1 gene has been found.
Section 3: Autonomic Function Tests
Neurophysiological Assessment of Autonomic Function
Autonomic function tests (AFTs) are principally helpful to detect autonomic impairments in patients with PD. Some dysautonomic features, like orthostatic hypotension (OH) or post-void residual volume, have important therapeutic implications. However, at the moment, there is insufficient evidence to provide a level of recommendation for AFTs in PD.
Section 4: Olfactory Tests
Olfactory testing differentiates PD from:
- Atypical and secondary parkinsonian disorders (Level A)
- Recessive forms of PD (Level A)
Current evidence suggests that olfactory testing may be considered as a diagnostic screening procedure (Level A), but not as an indicator of disease progression (Level B) in PD. Olfactory testing is a sensitive screening test for pre-motor PD (Level A), but not specific. Thus, olfactory testing can be envisioned in a screening battery for PD. If hyposmia is detected, then other specific tests for PD should follow.
Section 5: Drug Challenge Tests
Drug challenge tests are not recommended for the diagnosis of de novo parkinsonian patients. There is insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes.
Section 6: Neurophysiological Tests
No recommendation can be given on neurophysiological tests because of the low evidence level of the available studies.
Section 7: Neuropsychological Tests
An assessment of neuropsychological functioning in a person presenting with parkinsonism suspected of being PD is recommended (Level A) and should include:
- A collateral history from a reliable carer
- A brief assessment of cognition
- Screening for rapid eye movement (REM) sleep behaviour disorder (RBD), psychotic manifestations and severe depression
Section 8: Neuroimaging
Transcranial Sonography (TCS)
TCS is recommended (Level A) for:
- Differential diagnosis of PD from atypical parkinsonian syndromes (APS) and secondary parkinsonian syndromes
- Early diagnosis of PD
- Detection of subjects at risk for PD
The technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests.
Magnetic Resonance Imaging
The Task Force concludes that conventional magnetic resonance imaging (cMRI) at 1.5 T is principally helpful to exclude symptomatic parkinsonism due to other pathologies (Level B).
1.5-T cMRI is also useful in the differentiation of PD from APS as follows:
- Multiple system atrophy (MSA) signs – putaminal atrophy and rim sign, pontocerebellar atrophy, middle cerebellar peduncle (MCP) hyperintensity and hot cross bun sign (all Level A)
- Progressive supranuclear palsy (PSP) signs – midbrain atrophy and hummingbird sign (both Level B), superior cerebellar peduncle (SCP) atrophy (Level C)
Specificity of these abnormalities to differentiate APS from PD is considered quite high, whereas sensitivity, particularly in early disease stages, seems to be insufficient. A normal routine 1.5-T cMRI does not exclude MSA or PSP, if the clinical presentation is suggestive and supported by the current diagnostic criteria.
Abnormalities on diffusion-weighted imaging (DWI) at 1.5 T including diffusivity changes in:
- Putamen in patients with APS versus PD in early disease stages (especially MSA-parkinsonian subtype [MSA-P], Level A)
- SCP in patients with PSP (Level B) have been described as markers, which can point the diagnosis towards MSA or PSP instead of PD
Newer quantitative imaging techniques implemented on 3-T systems have shown promising results. However, they require further confirmatory studies.
Single Photon Emission Tomography
Dopamine transporter-single photon emission tomography (DaTscan-SPECT) is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonism and essential tremor (Level A). More specifically, DaTscan-SPECT is indicated in the presence of significant diagnostic uncertainty and particularly in patients presenting atypical tremor manifestations. Cardiac [123I] meta-iodobenzylguanidine (MIBG)/SPECT imaging may assist in the differential diagnosis of PD versus APS (Level A).
All other SPECT imaging studies do not fulfill registration standards and cannot be recommended for routine clinical use.
Positron Emission Tomography (PET)
None of the reviewed PET studies has been performed according to regulatory standards with the exception of the study by Whone et al. (2003). Therefore, the Task Force cannot make any formal recommendation for the routine use of PET studies in the diagnostic work-up of PD.
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.