Objective: To determine intravitam prevalence of α-synuclein (αSyn) pathology in primary tauopathies, such as PSP and CBS, by αSyn seed amplification assay (synSAA)

Background: Neuropathological evidence suggests that ~11% of PSP cases also present αSyn pathology in the form of Lewy body disease (LBD), characterized by Lewy bodies and Lewy neurites(1). CBD, PSP, AD, FTLD, LBD, and prion pathologies can present clinically as CBS(2). Identification of underlying pathologies is important as different pathologies translate into different clinical trajectories(3). synSAA has emerged as a highly specific test for LBD that detects misfolded αSyn aggregates (αSyn-seeds) in CSF(4, 5). This high specificity has been demonstrated with neuropathologically confirmed samples in the context of AD and related pathologies(6)

Method: The synSAA conditions used in this study have been described elsewhere(7). Analyzed samples include 26 pathologically confirmed 4R tauopathies, 13 CBS cases with neuropathology, 68 clinical PSP, 15 CBS, 11 clinical frontotemporal dementia (FTD), 80 clinical PD, and 60 CTRL. Detected αSyn-seeds were classified into Type1 and Type2 depending on the maximum fluorescence of each sample.

Results: Among the cases with neuropathology, only 2 samples were synSAA+ in the 4R group (both Type1) and they had either AD or LBD co-pathology. Most (10/13) of the CBS samples were synSAA+, of which 6 had LBD (5 Type1 and 1 Type2) and 1 had MSA (Type2). The other 3 synSAA+ had FTLD/AD, AD/LATE, and Pick’s disease. synSAA- samples had CBD/cardiovascular disease, argyrophilic grain disease/AD, and globular glial tauopathy/AD. Among the clinical cases, 26.5% of the PSP, 40.0% of the CBS, and 36.4% of the FTD cases were synSAA+. PD and CTRL showed 95% sensitivity and specificity. Except for 1 PSP sample, all the synSAA+ clinical samples presented Type1 αSyn-seeds

Conclusion: In agreement with earlier studies using pathologically confirmed samples, synSAA is highly specific for misfolded αSyn in the context of co-pathologies. synSAA can identify synuclein pathology in patients with complex clinical presentations and in combination with other biomarkers could aid in the differential diagnosis of these cases to determine the underlying pathologies at play

References: 1. J. A. Steiner, E. Quansah, P. Brundin, Cell Tissue Res. 373, 161–173 (2018).
2. S. Koga, K. A. Josephs, I. Aiba, M. Yoshida, D. W. Dickson, J. Neurol. Neurosurg. Psychiatry. 93, 919–29 (2022).
3. D. Shir et al., Neurology. 101, e289–e299 (2023).
4. A. Siderowf et al., Lancet. Neurol. 22, 407–417 (2023).
5. L. Concha-Marambio et al., Mov. Disord. 38, 567–578 (2023).
6. M. R. Arnold et al., Ann. Neurol. 92, 650–662 (2022).
7. G. Bellomo et al., Alzheimer’s Dement. (2024), doi:10.1002/alz.13658.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-underlying-lewy-body-pathology-in-primary-tauopathies-by-%ce%b1-synuclein-seed-amplification-assay/