Objective:

 1) Determine rates of phosphorylated alpha-synuclein (P-SYN) deposition in idiopathic REM sleep behavior disorder (iRBD) and quantify changes in P-SYN deposition over time. 2) Determine if patterns of P-SYN deposition predict phenoconversion.  

Background:

iRBD is a prodromal neurodegenerative disease characterized by dream reenactment and REM sleep atonia. IRBD is characterized pathologically by the deposition of P-SYN within the central and peripheral nervous systems. iRBD has a high risk of phenoconversion to a clinically apparent synucleinopathy (Parkinson’s disease (PD), multiple system atrophy (MSA), or dementia with Lewy bodies (DLB)), with >73% of patients converting over 12 years.

Design/Methods:

Patients with a confirmed diagnosis of iRBD (by polysomnography or validated questionnaire and history) were included in this multicenter study. Detailed examinations, orthostatic vital signs, and questionnaires were completed. Medical history, ancillary testing, and polysomnograms (PSG) were reviewed, if applicable. Skin biopsies at the distal leg, distal thigh, and posterior cervical sites were collected. Dual immunohistochemical immunostaining for nerve fibers (protein gene product 9.5) and P-SYN were completed.  

Results:

80 subjects (31% female) were enrolled. The mean age of the subjects was 67.8±8.7 years.  P-SYN was detected in 75% (60/80) of subjects. In a preliminary analysis of the first 33 patients to complete follow-up, there was a significant increase in P-SYN between baseline and 12 months (p=0.04). The average P-SYN composite score at baseline was 4.09±4.99, and at the 12-month follow-up was 5.63±5.87. No complications were noted in the biopsy procedure.   

Conclusions:

Final longitudinal reassessment of these subjects is in progress to determine if P-SYN can serve as a biomarker of disease progression and predict phenoconversion in iRBD patients. Preliminary analysis shows a significant increase in measured cutaneous P-SYN levels between baseline and 12 months.  Full follow-up data, including any evidence of phenoconversion, will be presented at the 2026 AAN Meeting.