Parkinson’s Disease

Improving Diagnostic Confidence for Complex Clinical Presentations

Parkinson’s disease (PD) remains a clinically diagnosed disorder, but early and accurate identification is often limited by overlapping phenotypes, nonspecific early symptoms, and the absence of reliable pathology-specific biomarkers. Clinical misclassification is common, particularly in prodromal and early stages, where the distinction between PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) is critical to prognosis, treatment selection, and care planning.

The SAAmplify-ɑSYN cerebrospinal fluid (CSF)-based seed amplification assay (SAA) addresses this unmet need by detecting misfolded ɑ-synuclein aggregates with high specificity and sensitivity, even before motor symptoms manifest. Incorporating SAAmplify-ɑSYN into the diagnostic workflow enables biologic evidence of a synucleinopathy, helping clinicians:

• Rule in or out ɑ-synuclein pathology in clinically ambiguous cases
• Rule in or out PD from atypical parkinsonian syndromes (e.g., PSP)
• Inform prognosis, medication selection, and clinical trial eligibility
• Avoid misdiagnosis and inappropriate therapies (e.g., dopaminergic trials in PSP)

Parkinson’s Disease Stages and Clinical Characteristics

PD progresses through clinical stages, often beginning years before a formal diagnosis is made:

1. Prodromal Stage: Characterized by non-motor symptoms such as idiopathic REM sleep behavior disorder (iRBD), hyposmia, constipation, and subtle autonomic dysfunction. These signs may appear 5-10 years before any motor symptoms develop.
2. Early Motor Stage: Bradykinesia, rigidity, resting tremor, and postural instability symptoms begin to emerge. These motor symptoms usually begin asymmetrically.
3. Moderate to Advanced Stages: Disease progression leads to bilateral motor symptoms, gait disturbances, falls, and increasing disability. Cognitive decline and neuropsychiatric symptoms such as visual hallucinations may emerge.
4. Advanced Disease Stage: Severe motor and cognitive dysfunction are observed, and patients often require extensive caregiving. This can lead to Parkinson’s disease dementia (PDD), which shows symptoms that overlap with features of dementia with Lewy bodies (DLB).

PD Diagnostic Criteria and Tools

The Movement Disorder Society (MDS) Clinical Diagnostic Criteria for PD requires bradykinesia plus either rigidity or rest tremor and the absence of absolute exclusion criteria (e.g., vertical gaze palsy, cerebellar signs). Supportive criteria (i.e., robust levodopa response, olfactory loss, or presence of iRBD) improve diagnostic confidence. While clinical assessment remains the cornerstone of diagnosis, there are supporting tools that can increase diagnostic accuracy:

• DaTscan (Ioflupane SPECT) provides visualization of presynaptic dopaminergic deficits but cannot differentiate Parkinson’s disease from MSA or PSP.

• MRI is useful in excluding structural lesions or identifying patterns more consistent with atypical parkinsonism (e.g., pontine or cerebellar atrophy in MSA).

• CSF Alzheimer’s disease biomarkers (Ab42, tTau, pTau 181) may aid in identifying comorbid pathology, particularly in patients with cognitive symptoms.

However, clinical diagnosis alone can have inaccuracies. Up to 25% of clinically diagnosed PD cases may have alternative pathologies present that contribute to symptoms that mimic Parkison’s disease. Until recently, no in vivo biomarker was available to detect ɑ-synuclein pathology directly, limiting biologically grounded diagnosis.

Clinical Use Cases

1. Prodromal Syndromes (iRBD, hyposmia)
   • “Detected” SAAmplify-ɑSYN result enables early detection of a synucleinopathy
   • Supports earlier diagnosis and more accurate prognostic counseling
   • SAA is positive in >90% of patients with iRBD who later convert to PD or DLB (REFs)
2. Atypical Parkinsonism
   • “Not Detected” SAAmplify-ɑSYN result in clinically diagnosed parkinsonism raises suspicion for non-ɑ-synuclein pathology (e.g., PSP, CBS), prompting reconsideration of diagnosis and management
   • Can include or exclude underlying synucleinopathy in patients with parkinsonism and equivocal imaging or partial levodopa response
3. Cognitive-Motor Overlap Syndromes
   • Detecting coexisting ɑ-synuclein pathology in patients with AD biomarkers informs reclassification to mixed pathology (e.g., AD with contributing synucleinopathy)
4. Trial Stratification and Enrollment
   • As ɑ-synuclein-targeting disease-modifying therapies enter clinical trials, SAAmplify-ɑSYN can enrich for patients with positive ɑ-synuclein status, improving trial validity and individual benefit-risk assessment

ɑ-Synuclein Pathology and Its Role in Parkinson’s Disease

PD is pathologically defined by the progressive accumulation and propagation of misfolded ɑ-synuclein proteins, which forms intracellular aggregates and spreads transneuronally through synaptic connected regions. This protein accumulation results in the formation of Lewy bodies and Lewy neurites, which leads to selective neuronal vulnerability, particularly in the substantia nigra and interconnected basal ganglia circuitry, resulting in striatal dopamine depletion and motor dysfunction.

Diagnostic Innovation

The SAAmplify-ɑSYN assay is a unique technology that addresses the urgent need for biological evidence of ɑ-synuclein pathology in PD. SAAmplify-ɑSYN is a qualitative assay that detects the presence of misfolded ɑ-synuclein seeds in CSF. The principle of the assay is similar to prion amplification technologies: if misfolded ɑ-synuclein “seeds” are present in the patient’s CSF, they induce aggregation of the recombinant protein in vitro. These aggregates incorporate a fluorescent dye and emit a signal that can be read over time. The readout is binary (“Detected” or “Not Detected”). In research studies, the assay has shown the ability to differentiate PD/DLB from MSA synucleinopathies, and clinical validations are underway to better understand sensitivity and specificity.

In Practice: Incorporating Alpha-Synuclein as a Biomarker for Parkinson's Disease  

PD is a clinically heterogeneous condition that benefits from the biological support of ɑ-synuclein pathology. While PD diagnosis remains fundamentally clinical, the emergence of SAAmplify-ɑSYN (ɑSYN SAA) marks a new era in biomarker-supported precision neurology. The SAAmplify-ɑSYN assay bridges this gap by providing a reliable, autopsy-validated method for detecting misfolded ɑ-synuclein in CSF. Integrating the assay into clinical workflows has the potential to transform diagnostic accuracy, enable earlier intervention, and enhance the design and execution of clinical trials. Its integration enables timely and accurate stratification of parkinsonian syndromes, improves clinical confidence, and supports personalized care in a field poised for therapeutic breakthroughs. In the evolving landscape of neurodegenerative disease diagnostics, SAAmplify-ɑSYN offers clinicians and patients the power to know and act sooner.

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