Objective: The goals of this longitudinal, prospective study are 1) to determine rates of P-SYN deposition in RBD and quantify changes in PSYN deposition over time and 2) to determine if the pattern of P-SYN deposition is a predictor of phenoconversion to a central synucleinopathy.

Background: REM sleep behavior disorder (RBD) is a prodromal neurodegenerative disease characterized by the deposition of phosphorylated alpha-synuclein (P-SYN) within the central and peripheral nervous system.  RBD has a high risk of phenoconversion to a clinically apparent synucleinopathy (including Parkinson’s disease (PD), multiple system atrophy (MSA) or dementia with Lewy bodies (DLB)) with >90% of patients converting over 15 years.

Method: After informed consent, detailed neurologic examinations, cognitive evaluation, orthostatic vital signs and questionnaires were completed.  Medical history, ancillary testing and polysomnograms were reviewed. Skin biopsies at the distal leg, distal thigh and posterior cervical sites were performed.  Dual immunohistochemical immunostaining of the skin biopsies for nerve fibers (protein gene product 9.5) and P-SYN was completed using standard methodology.  Quantitative measures of P-SYN and nerve fiber density were measured blinded to any clinical data.

Results: To date, 80 subjects (30% female) have been enrolled from 10 study sites across the United States.  The mean age of the enrolled subjects is 67.8±8.6 years.  Of the 80 enrolled subjects, 59/80 are P-SYN positive (74%).  P-SYN positive subjects tended to be older (68.8±7.4 (P-SYN+) vs. 64.9±10.9 (P-SYN-).  There were no differences in P-SYN positivity in patients who demonstrated REM sleep without atonia on polysomnogram (PSG) and those whose diagnosis was confirmed using the REM sleep behavior disorder questionnaire (RBDSQ) (30/41 with PSG [73%] vs 29/39 using the RBDSQ [74%]).

Conclusion: Skin biopsies are a simple, low-risk outpatient procedure to test for P-SYN as a diagnostic biomarker for prodromal synucleinopathies.  At initial study visit, 74% of RBD cases contain P-SYN with equal rates of P-SYN positivity in those with and without polysomnography confirmed RBD.  Longitudinal reassessment of these subjects is in progress to determine if quantification of P-SYN can serve as a biomarker of disease progression and phenoconversion.

Funding: NIH NINDS R44NS127696

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-syn-sleep-study-detection-of-cutaneous-phosphorylated-alpha-synuclein-in-rem-sleep-behavior-disorder/