Objective: To assess alpha-synuclein (a-syn) and 4-repeat tau (4RT) seed amplification assay (SAA) positivity rates in biosamples from people with Parkinson’s disease (PD) and Progressive supranuclear palsy (PSP).

Background: In the absence of an objective diagnostic biomarker, achieving an early and accurate diagnosis in patients presenting with parkinsonism is challenging due to clinical overlap between a-syn (PD, multiple system atrophy) and 4RT (PSP, corticobasal degeneration) disorders. There is emerging evidence that a-syn SAA, a marker of Lewy body pathology, can reliably differentiate PD from healthy controls with high sensitivity and specificity [1].

Method: We applied a research-based a-syn SAA [2] to ante-mortem CSF samples from people with clinically diagnosed: PD (n=66) from the Exenatide-PD3 clinical trial; PSP (n=52) and healthy controls (n=9) from the PROSPECT-UK study. We also applied the a-syn SAA and a 4RT SAA [3] to frontal cortex brain tissue samples from 6 neuropathologically diagnosed PSP cases (4 of whom had matched ante-mortem CSF for analysis as above). Robust criteria were used to define SAA positivity in both CSF and brain experiments.

Results: 4/52 (7.7%) of PSP CSF samples were a-syn SAA positive, in line with previously reported rates of Lewy body co-pathology in PSP [4][5]. 63/66 (95%) of PD CSF samples were a-syn SAA positive, although this contained a subgroup, n=9/63 (14%), which had low maximum ThT values similar to those seen in the PSP a-syn SAA positive cases. 9/9 (100%) of healthy control CSF samples were a-syn SAA negative. In our PSP brain samples, 6/6 (100%) were 4RT SAA positive. There was 100% concordance for negative a-syn SAA results in the 4 PSP brain samples that had matched ante-mortem CSF available. The other 2 PSP brain samples were a-syn SAA positive but did not have detectable Lewy body co-pathology at post-mortem.

Conclusion: Our results have highlighted the potential value of combined application of a-syn and 4RT SAAs to patient biosamples for the differential diagnosis of parkinsonian disorders and the stratification of patients for inclusion in clinical trials. There is ongoing work to optimise the CSF 4RT assay to enable this approach. We also highlight that a-syn SAA positivity in PSP may be reflective of Lewy body co-pathology.

References: [1] Siderowf A, Concha-Marambio L, Lafontant DE, et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurology 2023; 22: 407-417.
[2] Saijo E, Metrick II MA, Koga S, et al. 4-repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration. Acta Neuropathol. 2020; 139: 63-77.
[3] Groveman BR, Orru’ CD, Hughson AG, et al. Rapid and ultra-sensitive quantitation of disease-associated a-synuclein seeds in brain and cerebrospinal fluid by aSyn RT-QuIC. Acta Neuropathol Comms. 2018; 6: 7.
[4] Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 2018; 133: 2045-2057.
[5] Lukic MJ, Kurz C, Respondek G, et al. Copathology in progressive supranuclear palsy: does it matter? Mov Disord. 2020; 35: 984-993.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/combined-application-of-alpha-synuclein-and-4-repeat-tau-seed-amplification-assays-for-the-differential-diagnosis-of-parkinsonian-disorders/