Category: Parkinsonism (Other)
Objective: To report the quantitative change in cutaneous phosphorylated alpha-synuclein (P-SYN) deposition over time in patients with dementia with Lewy bodies (DLB) in a longitudinal clinical trial.
Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease characterized by progressive accumulation of a misfolded protein, phosphorylated alpha-synuclein (PSYN) that can be quantified from standard punch biopsies. At present there is no surrogate endpoint biomarker and no in-vivo human measure of target engagement.
Method: After informed consent, 130 participants enrolled in a blinded, randomized trial across 31 sites in the USA. Subjects completed neurologic examinations (MDS-UPDRS III), medical history review and cognitive evaluation (MoCA). DLB was defined using consensus criteria for probable DLB. Skin biopsies (3mm) were taken from the distal leg, distal thigh and posterior cervical regions at baseline and 6 months with quantitation of P-SYN and intraepidermal nerve fiber density (INFD).
Results: A total of 109 DLB participants (age 72.7±6.1 years: 16 Female, 93 Male) had skin biopsies obtained at baseline and 6 months. The group had a mean MoCA score of 18.4±4.9 and MDS-UPDRS III score of 27.6±13.4. P-SYN was detected in 91/109 participants at baseline (83%) and 96/109 (88%) at 6-month follow up. The total amount of P-SYN at baseline was 7.2±5.8 PSYNU’s; at 6 months the P-SYN amount increased to 8.0±5.7 PSYNU’s (P<0.001). No adverse events related to biopsies were noted.
Conclusion: Skin biopsies offer a simple, low-risk outpatient test to detect and quantify phosphorylated alpha-synuclein in patients with DLB. In this study, phosphorylated alpha-synuclein detected from skin biopsies of patients with DLB increased by 11% over 6 months. These results support the use of skin biopsy assessment of P-SYN as a surrogate outcome and measure of target engagement in clinical trials with drugs that target synuclein.
To cite this abstract in AMA style:
C. Gibbons, T. Levine, B. Bellaire, R. Freeman. A Longitudinal Quantitative Assessment of Phosphorylated Alpha-Synuclein Deposition in Dementia with Lewy Bodies [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/a-longitudinal-quantitative-assessment-of-phosphorylated-alpha-synuclein-deposition-in-dementia-with-lewy-bodies/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-longitudinal-quantitative-assessment-of-phosphorylated-alpha-synuclein-deposition-in-dementia-with-lewy-bodies/