Objective:

To report the quantitative change in cutaneous phosphorylated alpha-synuclein (P-SYN) in patients with dementia with Lewy bodies (DLB) over 6 months of longitudinal follow up in a blinded clinical trial.  

Background:

Dementia with Lewy bodies (DLB) is a neurodegenerative disease characterized by progressive accumulation of a misfolded protein, phosphorylated alpha-synuclein that can be quantified from standard punch biopsies.

Design/Methods:

After signed consent, study participants 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 75 DLB participants had skin biopsies obtained at 2 time points (age 72.2±5.6 years: 10 Female, 65 Male).  P-SYN was detected in 67/75 participants (89.3%).  The total amount of P-SYN at baseline was 8.8±5.7 SU’s, and at 6 months the P-SYN amount increased to 11.1±5.6 SU’s (P<0.01).  P-SYN burden increased in 42/67 patients, decreased in 14/67 patients and was stable in 11/67 patients.  No adverse events related to biopsies were noted. 

Conclusions:

Skin biopsies offer a simple, low-risk outpatient test to detect and quantify phosphorylated alpha-synuclein in patients with DLB.  Quantitative measures of cutaneous deposition suggest an annual increase in P-SYN deposition of 52% in patients with DLB and suggest that skin biopsy can serve as a novel therapeutic target for pharmaceutical trials that seek to alter the natural history phosphorylated alpha-synuclein deposition or aggregation. The rapid increase in P-SYN in patients with DLB also suggests a leveraged population of patients appropriate for disease modifying therapies that could include clinical trials of shorter duration.