Parkinson's disease (PD)
Diagnosis
Diagnosis of Parkinson’s disease (PD) requires obtaining history regarding prodromal symptoms, family history, and current concerns.1 The clinical diagnosis of PD is primarily based on motor features, such as a slowly progressive asymmetric resting tremor, cogwheel rigidity and bradykinesia, although non-motor features, including anosmia, constipation, depression, and REM sleep behavior disorder can develop years before motor deficits.2 Other examination features such as the presence of orthostatic hypotension can also be helpful.1 Once history and physical examination features of parkinsonism are confirmed, the clinician excludes features potentially indicative of atypical parkinsonism (“red flags”) and assesses the patient response to levodopa to confirm PD.1 During later stages of PD, additional non-motor features appear, such as autonomic dysfunction, pain, and cognitive decline, can appear.2
| Four-step approach to the diagnosis of PD: 4,* |
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Step 1: Establish the presence of parkinsonism
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Step 2: Identify features supporting the diagnosis of PD
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Step 3: There should be no absolute exclusion criteria
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Step 4: Search for red flags that cast doubt on the diagnosis of PD
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Movement Disorder Society (MDS) for PD Criteria
The prerequisite to apply the MDS Clinical Diagnostic Criteria for PD is the diagnosis of parkinsonism, which is based on three cardinal motor manifestations. Parkinsonism is defined as bradykinesia, in combination with either rest tremor, rigidity, or both. These features must be clearly demonstrable and not attributable to confounding factors.3
- Bradykinesia3
Bradykinesia is defined as slowness of movement and decrement in amplitude or speed (or progressive hesitations) as movements are continued. Bradykinesia can be evaluated by using finger tapping, hand movements, pronation-supination movements, toe tapping, and foot tapping. Although bradykinesia also occurs in voice, face, and axial/gait domains, limb bradykinesia must be documented to establish a diagnosis of PD.3 - Rigidity3
As outlined in the MDS-Unified PD Rating Scale (MDS-UPDRS), rigidity is slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.3 - Rest Tremor3
Rest tremor refers to a 4 to 6 Hz tremor in the fully resting limb, which is suppressed during movement initiation. Rest tremor can be assessed during the entire interview and examination. Kinetic and postural tremors alone (MDSUPDRS 3.15 and 3.16) do not qualify for parkinsonism criteria.3
Ancillary tests in the differential diagnosis of PD5
Although some core clinical characteristics differ between the various forms of degenerative parkinsonism, there is broad clinical overlap. Error rates in clinicopathological studies draw attention to the need for additional diagnostic tests to solidify differential diagnostic accuracy.5
- Genetic testing5
An increasing number of loci linked to familial parkinsonism have been found (PARK1–PARK11). Of these, four genes causing autosomal dominant parkinsonism (α-synuclein, UCHL1, NURR1, LRRK2) and three causing autosomal recessive disease (DJ-1, PINK1, parkin). Currently, molecular genetic testing for the two most common mutations (parkin [PARK2], LRRK2 [PARK8]) are still restricted to research centers and the costs are high.5 - Clinical neurophysiology5
Clinical neurophysiological examinations such as electroencephalography, somatosensory evoked potentials, anal sphincter-electromyography, or acoustic startle responses are usually normal in PD patients. Neurophysiological tests, such as measurements of long latency-reflex times, and intracortical inhibition studied with transcranial magnetic stimulation have yielded abnormal findings indicative of subcorticomotor or corticomotor loop dysfunction.5 - Olfactory testing5
Various studies suggested that olfactory dysfunction as an early clinical sign in PD, which affects 90% of patients. Olfactory dysfunction is a less frequent finding in the parkinsonian variant of multisystem atrophy, it is also mild in patients with progressive supranuclear palsy, and has been shown to be largely intact in vascular parkinsonism.5 - Imaging5
Structural brain imaging with cranial CT is normal in uncomplicated PD. There may be age associated mild-to-moderate degrees of cortical and subcortical atrophy or signs of cerebrovascular disease with lacunar white matter lesions. Cranial CT is useful also in detection of normal pressure hydrocephalus in patients with lower body parkinsonism with small stepped gait, freezing, and instability.5 MRI has better differential diagnostic potential in degenerative parkinsonian disorders. The value of MRI is in differentiation of PD and atypical parkinsonism. Several structural MRI changes have been described for multisystem atrophy, progressive supranuclear palsy, or corticobasal degeneration and some of these changes have high specificity and positive predictive values. However, sensitivity is generally only around 60–80% or less.5 - Autonomic function testing5
Autonomic failure is a key diagnostic feature of multisystem atrophy and an essential part of current diagnostic criteria. Cardiovascular reflex testing and urodynamic function studies have been used to differentiate the parkinsonian variant of multisystem atrophy from PD.5
Table. Existing and proposed biomarkers for diagnosis and progression in PD.6,†
| Biomarker class | Existing and proposed biomarkers |
|---|---|
| Clinical | |
| Prodromal non-motor symptoms | RBD, late onset hyposmia/anosmia, episodic major depression, constipation, excessive daytime somnolence, fatigue, abnormal colour vision/visual perception, erectile dysfunction, pain (often unilateral), cognitive impairment, hyperechogenicity, apomorphine |
| Motor symptoms | Tremor, postural instability, dyskinesias, micrographia |
| Scales | UPDRS, Scopa Autonomic, PD Non-motor Symptoms Scale |
| Genetic markers | |
| Blood-based | GBA, LRRK2, α-synuclein, Parkin, PINK1, DJ-1 |
| Biochemical markers | |
| Blood-based | α-synuclein, neuromelanin antibodies, oxidative and mitochondrial markers, uric acid and serum urate, EGF, Apo A1 |
| Cerebrospinal fluid-based | α-synuclein, DJ-1, GBA activity, Aβ-42, neurofilaments, α-synuclein, RT-QuIC |
| Submandibular gland, biopsy | α-synuclein |
| Urine | 8-Hydroxydeoxyguanosine |
| Faeces | Decreases in protective gut microbiota composition in PD (needs further validation) |
| Imaging techniques | 18F-DOPA PET, 123I-beta-CIT SPECT, MIBG scintigraphy, functional imaging |
Footnotes:
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* Adapted from Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for PD. Mov Disord 2015;30(12):1595; with permission.
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† None of the tests provide robust diagnostic proof in isolation. Multimodal validity is being tested. Adapted from Titova et al. 2017,57 and Gerlach et al. 2008.
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123I-beta-CIT SPECT, Iodine (123) beta carboxymethoxy-3 beta-(4-iodophenyl) tropane single-photon emission computed tomography imaging; 18F-DOPA PET, 18F-
dihydroxyphenylalanine positron emission tomography; Aβ-42 = A beta containing amyloid; Apo A1, apolipoprotein A1; α-synuclein RT-QuIC, α-synuclein real time quaking-
induced conversion assay; DJ-1, an oncogene associated with autosomal recessive early-onset Parkinson’s disease; EGF, epidermal growth factor; GBA, glucocerebrosidase;
LRRK2, leucine-rich repeat kinase 2; MDS, Movement Disorder Society; MDS-UPDRS, MDS-Unified Parkinson’s Disease Rating Scale; MIBG, 123I-meta-iodobenzylguanidine;
PARK, Parkinson’s disease loci; PD, Parkinson’s disease; PINK1, PTEN-induced putative kinase 1; RBD, REM sleep behaviour disorder; REM, rapid eye movement;
UPDRS, Unified Parkinson’s Disease Rating Scales.
References:
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Armstrong MJ, Okun MS. JAMA. 2020;11;323(6): 548-560.
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Simon DK, et al. Clin Geriatr Med. 2020;36(1): 1-12.
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Postuma RB, et al. Mov Disord. 2015;30(12):1591-601.
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Reich SG, Savitt JM. Med Clin North Am. 2019;103(2):337-350.
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Tolosa E, et al. Lancet Neurol. 2006;5(1):75-86.
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Chaudhuri SG, Titova N. European Neurological Review. 2019;14(1):28–35.