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

Neurology. 2024 Sep 24;103(6):e209818. doi: 10.1212/WNL.0000000000209818. Epub 2024 Aug 29.

Abstract

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 α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and β-amyloid (Aβ) 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 αSyn-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). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-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 αSyn-SAA status by age at onset on CSF Aβ42 levels (β = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aβ42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01).

Discussion: We detected a frequency of αSyn-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 Aβ42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / diagnosis
  • Amyloid beta-Peptides* / cerebrospinal fluid
  • Biomarkers* / cerebrospinal fluid
  • Cross-Sectional Studies
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neurofilament Proteins / cerebrospinal fluid
  • Parkinsonian Disorders / cerebrospinal fluid
  • Parkinsonian Disorders / diagnosis
  • Peptide Fragments / cerebrospinal fluid
  • Supranuclear Palsy, Progressive / cerebrospinal fluid
  • Supranuclear Palsy, Progressive / diagnosis
  • alpha-Synuclein* / cerebrospinal fluid

Substances

  • alpha-Synuclein
  • Biomarkers
  • Amyloid beta-Peptides
  • amyloid beta-protein (1-42)
  • Peptide Fragments
  • Neurofilament Proteins
  • neurofilament protein L
  • SNCA protein, human