Objective: To assess the sensitivity of CSF α-synuclein RT-QuIC in pathologically-confirmed MSA.

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterised pathologically by the presence of oligodendrocytic glial cytoplasmic inclusions containing misfolded α-synuclein. The clinical phenotype of MSA is heterogeneous and the diagnosis can be challenging. Real-time Quaking Induced Conversion (RT-QuIC) exploits the ability of misfiled proteins in the cerebrospinal fluid (CSF) to induce misfolding and subsequent aggregation of normally folded recombinant proteins. In recent years, RT-QuIC has been adapted to detect the pathological forms of α-synuclein associated with Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Several groups have also performed RT-QuIC in MSA, but the reported sensitivity in these clinically diagnosed cohorts has varied substantially.

Method: Post-mortem CSF samples from neuropathologically-confirmed MSA patients were obtained from Parkinson’s UK Brain Bank, Imperial College (n=32) and Queen Square Brain Bank, University College London (n=18). CSF samples were purified using a technique to remove blood contamination, after which they were analysed in duplicate using RT-QuIC and blinded to the neuropathology reports.

Results: Mean age of MSA symptom onset was 64 years and median disease duration was 7 years. Sensitivity of CSF α-synuclein RT-QuIC was 72% after single purification, increasing to 89% after second purification. There was no correlation between RT-QuIC positivity and clinical or pathological MSA subtype.

Conclusion: Using post-mortem CSF samples from individuals with pathologically-proven MSA, we have shown that CSF α-synuclein RT-QuIC is capable of detecting MSA with high sensitivity. The assay is influenced by blood contamination, but using a CSF purification method we have shown the potential of RT-QuIC as a diagnostic MSA biomarker. Future studies are required in larger MSA cohorts across the entire disease course.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebrospinal-%ce%b1-synuclein-rt-quic-in-pathologically-confirmed-multiple-system-atrophy/