Objective: (1) To validate serum-based enrichment of neuronal (L1CAM+) and microglial (TMEM119+) EVs in PSP; (2) to characterize α-synuclein, tau, and inflammatory/autophagic mediators in EVs and CSF; and (3) to evaluate their longitudinal changes and clinical correlates in PD and PSP.
Background: Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) share overlapping clinical features but differ in underlying proteinopathy and disease course. Brain-derived extracellular vesicles (EVs) and CSF/serum biomarkers may provide non-invasive tools to differentiate PD from PSP and to monitor disease progression.
Method: We isolated total, L1CAM+, and TMEM119+ EVs from serum of PD, PSP, and control participants, characterized by NTA, TEM, and EV markers. Phosphorylated α-syn (pY39, pS129), tau species (total tau, pTau-S396, pTau-181), and candidate proteins (ATP6AP2, CHGB, CA11, CHI3L1/2, CBLN3, FAT2, NLRP3, cytokines) were quantified by immunoassays. α-Syn aggregation was assessed by RT-QuIC in L1CAM+ EVs and CSF. A prospective cohort (DIVA study) with baseline, year 1, and year 2 follow-up enabled longitudinal analyses and correlations with UPDRS and PSPRS.
Results: pY39 and pS129 α-syn in L1CAM+ EVs were significantly higher in PD versus controls and PSP, with high–molecular weight α-syn oligomers detectable in PD and PSP. RT-QuIC positivity in L1CAM+ EVs was increased in PD and closely mirrored CSF RT-QuIC profiles. ATP6AP2 levels were significantly elevated in PSP compared with PD and controls. In the DIVA cohort, PSP showed longitudinal increases in CHI3L1, CHI3L2, CA11, CBLN3 and CHGB, many correlating with disease severity (r ≈ −0.6 to −0.7, p ≤ 0.04). PD exhibited distinct trajectories, including increased CHI3L1/CBLN3 and decreased FAT2. Tau assays highlighted differential pTau-S396 versus pTau-181 patterns in PSP, supported by tau seeding in FRET biosensor cells.
Conclusion: Combined EV, CSF, and serum profiling reveals distinct α-syn, tau, and inflammatory signatures in PD and PSP. These molecular patterns, along with their longitudinal changes and clinical correlations, support development of composite biomarker panels for diagnosis and progression tracking in atypical parkinsonism.
To cite this abstract in AMA style:
A. Roy, S. Brahmachari, A. Pantelyat, L. Rosenthal, V. Dawson, T. Dawson. Molecular Profiling of Brain-Derived Extracellular Vesicles and Fluid Biomarkers in Parkinsonism: Distinct Signatures and Clinical Correlates in Progressive Supranuclear Palsy [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/molecular-profiling-of-brain-derived-extracellular-vesicles-and-fluid-biomarkers-in-parkinsonism-distinct-signatures-and-clinical-correlates-in-progressive-supranuclear-palsy/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/molecular-profiling-of-brain-derived-extracellular-vesicles-and-fluid-biomarkers-in-parkinsonism-distinct-signatures-and-clinical-correlates-in-progressive-supranuclear-palsy/