Validation of Cerebrospinal Fluid Alpha‐synuclein Assay against Autopsy in Non‐Parkinson’s Disease Neurodegenerative Syndromes

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AbstractBackgroundAlpha‐synuclein (αSyn) is the underlying neuropathology in both Parkinson’s Disease (PD) and non‐PD neurodegenerative syndromes, e.g. dementia with Lewy bodies (DLB). Importantly, αSyn is also a common co‐pathology, especially in Alzheimer’s disease (AD), where autopsy studies reveal comorbid αSyn in >50% of cases. A seeded aggregation amplification (SAA) assay (SynTap) has been shown to be highly sensitive and specific for pathogenic αSyn seeds in patients with PD and DLB, with lower performance in amygdalar‐predominant Lewy Body disease (LBD). Here we evaluated the antemortem CSF performance of SynTap in patients with non‐PD syndromes, with specific attention to performance in brainstem‐predominant αSyn and patients with atypical PD, e.g. progressive supranuclear palsy Richardson’s syndrome (PSP‐RS, N = 6) and corticobasal syndrome (CBS, N = 11).MethodPatients were evaluated through observational studies at the UCSF Alzheimer’s Disease Research Center and neuropathologic evaluation was performed by the Neurodegenerative Disease Brain Bank. Antemortem CSF samples were tested with SynTap. Operators were blinded to diagnosis, and all samples were run as a single batch. Sensitivity and specificity were compared, and clinical correlations were examined across pathological groups and clinical diagnoses, using antemortem clinical records.ResultOverall, in 56 patients, SynTap was 59% sensitive and 96% specific for autopsy‐confirmed αSyn pathology of any type. SynTap had perfect performance for diffuse (4/4) and transitional (5/5) LBD, and correctly identified 3/3 cases where LBD was primary. Consistent with prior reports, sensitivity was low in amygdalar‐predominant LBD (6/14, 43%), and lower in brainstem‐predominant LBD (1/6, 17%). A false positive result was present in 1/27 cases (4%). In the PSP‐RS cohort, SynTap positively identified 1 case caused by diffuse LBD and AD, and was true negative in 5/5. Within CBS, SynTap positively identified 1/1 case with diffuse LBD co‐pathology, 1/2 cases with brainstem‐predominant LBD, but missed 1 case with amygdalar‐predominant LBD.ConclusionSynTap best identifies αSyn pathology in patients with diffuse and transitional LBD, though specificity is high in the entire cohort. The etiology of low sensitivity in amygdalar‐ and brainstem‐predominant LBD co‐pathology requires further elucidation. The test may aid diagnostically in atypical PD syndromes, but results should be carefully considered, given the possibility of co‐pathology.