Objective: To assess differences in kinetics parameters of the αSyn seeding amplification assays in CSF (CSF-αSyn-SAA) in Parkinson’s Disease (PD) subtypes based on the presence of REM sleep behaviour disorder (RBD) and Dysautonomia (Dys) Symptoms.

Background: PD is not a homogenous disorder. Among various attempts to distinguish the heterogeneity, the ones based on non-motor and potentially peripheral symptoms are most consistent^1,2. We have identified subtypes of PD simply based on RBD and Dys symptoms with remarkable clinical differences³. The identification of biomarkers associated with these clinical subtypes would further strength their biological relevance. CSF-αSyn-SAA has shown to be sensitive and specific biomarkers for PD. Phenotype heterogeneity among synucleinopathies has been linked to variable alpha-synuclein strains that could be reflected by different kinetics of the CSF-αSyn-SAA⁴, but kinetic parameters among the PD subjects do not show strong correlation with clinical features ⁵.

Method: We used clinical-biochemical data from the PPMI dataset (Datacut 09/2023). We compared subject with vs. without RBD (RBDSQ-q6≥1) and/or Dysautonomia (SCOPA-AUT score ≥8) in sporadic subjects (n=308). CSF-αSyn-SAA kinetic data from PPMI using the assay by Concha were analyzed^6,7. Available kinetics parameters follow: Fmax (maximum fluorescence), T50 (time to reach 50% of the Fmax), TTT (time to threshold), Slope and AUC (area under the curve).

Results: Both RBD+ and Dys+ PD patients showed shorter T50 compared to the counterpart (n=137 RBD+ vs n=171 RBD-, p=0.050; n=167 Dys+ vs n=136 Dys-, p=0.023). Dys+ group also showed shorter TTT (p=0.038) and greater AUC (p=0.043). Consistently, in subject with PD and both RBD+ and Dys+, T50 was significantly shorter compared to subjects negative for both traits (p = 0.038). SCOPA-AUT and RBDSQ total scores correlated with T50 (r=-0.145, r=-0.148), TTT (r=-0.137, r=-0.130), and AUC (r=0.129, r=0.149).

Conclusion: Kinetics parameters derived from CSF-αSyn-SAA differed between PD subtypes based on RBD and Dys symptoms. In particular, T50 was shorter in the RBD+ and Dys+ group. This supports the clinical PD subtypes that were previously identified¹. These parameters can be considered for PD patient stratification and could also suggest different aSyn seeding species underlying these subtypes of PD.

References: 1. Borghammer, P. et al. A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease. npj Parkinson’s Disease 8, 166 (2022).
2. Fereshtehnejad, S.M., Zeighami, Y., Dagher, A. & Postuma, R.B. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain 140, 1959-1976 (2017).
3. Riboldi, G.M., Russo, M.J., Pan, L., Watkins, K. & Kang, U.J. Dysautonomia and REM sleep behavior disorder contributions to progression of Parkinson’s disease phenotypes. NPJ Parkinsons Dis 8, 110 (2022).
4. Shahnawaz, M. et al. Discriminating alpha-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 578, 273-277 (2020).
5. Russo, M.J. et al. High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease. Acta Neuropathol Commun 9, 179 (2021).
6. Siderowf, A. et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. The Lancet Neurology 22, 407-417 (2023).
7. Concha-Marambio, L., Pritzkow, S., Shahnawaz, M., Farris, C.M. & Soto, C. Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc 18, 1179-1196 (2023).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-between-kinetic-parameters-of-alpha-synuclein-seed-amplification-assay-in-csf-and-parkinsons-disease-subtypes/