CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders

Background and Objectives There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as alpha-synuclein (alpha Syn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible alpha Syn copathology in CBS and PSP, as detected in CSF using an alpha Syn SAA (alpha Syn-SAA). Secondary objectives were to evaluate the association of alpha Syn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that alpha Syn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and beta-amyloid (A beta) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. Methods This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for alpha Syn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. Results We tested the CSF of 40 patients with CBS (19 female patients, 65.9 +/- 8.6 years) and 28 with PSP (13 female patients, 72.5 +/- 8.7 years old), mostly White (n = 50) or Asian (n = 14). alpha Syn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, alpha Syn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of alpha Syn-SAA status by age at onset on CSF A beta 42 levels (beta = 0.3 +/- 0.1, p < 0.05). Indeed, age at onset was positively related to A beta 42 levels only in alpha Syn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with alpha Syn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). Discussion We detected a frequency of alpha Syn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low A beta 42) and older age at onset may contribute to alpha Syn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.