Objective: To identify soluble αSyn-seed types present in brain homogenate (BH) and CSF using αSyn seed amplification assay (synSAA)

Background: Lewy bodies and neurites are comprised of misfolded αSyn aggregates and characterize Lewy body disease (LBD) pathology in PD and DLB. Glial cytoplasmic inclusions (GCI), comprised of misfolded αSyn in oligodendrocytes, characterize MSA. synSAA reliably detects αSyn-seeds in CSF from patients with underlying αSyn pathology even before motor symptoms present

Method: All samples were analyzed blindly by synSAA, as described[1]. Positive samples with high (≥45,000RFU) and low (≥3,000RFU & <45,000RFU) maximum fluorescence indicate Type1 and Type2 amplification pattern, respectively. 23BH [5PD, 12MSA, 1AD, 5CTRL], 21 pathologically confirmed CSF [4LBD, 4MSA, 13OND (other neurodegenerative disease)], and two real-life cohorts; A [n=215: 84PD, 23MSA, 21iRBD, 27OND, 60CTRL] and B [n= 395: 101PD, 74DLB, 34MSA, 48vPD (vascular PD), 21AD, 117OND] were analyzed

Results: All PD and MSA BH produced Type1 and Type2 patterns, respectively; AD and CTRL were negative. All LBD and MSA pathologically confirmed CSF presented Type1 and Type2 patterns, respectively; all OND were negative. In cohort A, 80(95.2%) PD, 20(95.2%) iRBD, and 20(87.0%) MSA cases were positive. Of the positives, 79(98.8%) PD and 20(100%) iRBD were Type1; conversely, 16(80.0%) MSA were Type2. 20(74.1%) OND and 55(94.8%) CTRL were negative. In cohort B, 99(98.0%) PD, 71(95.9%) DLB, and 32(94.1%) MSA were positive. Of the positives, 98(99.0%) PD and 71(100%) DLB were Type1, while 28(87.5%) MSA were Type2. 13(61.9%) AD, 37(77.1%) vPD, and 95(81.2%) OND were negative

Conclusion: Amplification patterns from BH matched those from pathologically confirmed CSF. Type1 was observed in LBD cases while Type2 was present in GCI cases, in agreement with cryoEM data demonstrating structural differences in these types of αSyn-seeds[2,3]. Clinical samples from both real-life also present a correlation between αSyn-seed type and clinical presentation, as the majority of participants with clinical presentation associated to LBD and MSA presented Type1 and Type2, respectively. synSAA can differentiate these two αSyn-seed types and improve the differential diagnosis of patients with a movement disorder or dementia

References: 1. Bellomo et al. Investigating alpha-synuclein co-pathology in Alzheimer’s disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay. Alzheimer’s & Dementia. Jan 2024.
2. Schweighauser et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. Sep 2020.
3. Yang et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature. Oct 2022

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MDS Abstracts - https://www.mdsabstracts.org/abstract/seed-amplification-assay-for-the-differentiation-of-%ce%b1syn-seed-subtypes/