Kinetic parameters of alpha-synuclein seed amplification assay correlate with cognitive impairment in patients with Lewy body disorders

Abstract

The alpha-synuclein (aSyn) seed amplification assay (SAA) can identify aSyn aggregates as indicator for Lewy body pathology in biomaterials of living patients and help in diagnosing Parkinson´s disease and dementia syndromes. Our objective was to confirm that qualitative results of aSyn SAA are reproducible across laboratories and to determine whether quantitative findings correlate with patient clinical characteristics. Therefore cerebrospinal fluid samples were re-analysed by aSyn SAA in a second laboratory with four technical replicates for each sample. Kinetic parameters derived from each aggregation curve were summarized and correlated with patient characteristics. We found that qualitative findings were identical between the two laboratories for 54 of 55 patient samples. The number of positive replicates for each sample also showed good agreement between laboratories. Moreover, specific kinetic parameters of the SAA showed a strong correlation with clinical parameters, notably with cognitive performance evaluated by the Montreal Cognitive Assessment. We concluded that SAA findings are highly reproducible across laboratories following the same protocol. SAA reports not only the presence of Lewy pathology but is also associated with clinical characteristics. Thus, aSyn SAA can potentially be used for patient stratification and determining the target engagement of aSyn targeting treatments.

Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer’s Disease Neuroimaging Initiative Study

“…Future longitudinal studies with larger sample sizes are warranted to further understand whether the associations between SAA kinetic parameters with these demographic and AD characteristics are reflections of a widespread α-syn-driven LB pathology and a greater leakage of misfolded α-syn species from degenerating neurons. Accordingly, recent studies suggest that SAA kinetic parameters, particularly TTT and TSmax, were associated with clinical and cognitive characteristics of PD and DLB patients, measured by Unified Parkinson's disease rating scale part (UPDRS) III and Montreal Cognitive Assessment [41,42]. Although not survived correction for multiple comparison, TSmax was associated with cognitive impairment (ADAS-Cog11, CDR-SB, and language function) and decline (language domain).…”