Objective: To use a novel quantitative assessment of cutaneous P-SYN in a pilot study of patients with Parkinson’s disease (PD) and healthy volunteers (HVs) to determine inter and intra-day variability and obtain preliminary data to power a larger interventional trial.

Background: Skin immunofluorescent immunostaining of phosphorylated alpha-synuclein (P-SYN) offers an objective, continuous, quantitative measure of P-SYN deposition.

Method: We recruited 10 patients with PD and 10 HVs.  They participated in a 3-visit study at baseline, 4 weeks and 8 weeks.  All participants had skin biopsies at the distal leg, distal thigh and posterior cervical region with immunostaining for P-SYN and protein gene product 9.5 at each time point.  All tissue sections from each biopsy underwent complete confocal slide scanning. We used our quantitative pathology detection algorithm (NerValence, CND Life Sciences) with AI driven quantitation of intra-axonal misfolded P-SYN within cutaneous nerves.  Analysis of individual and group change are reported across a range of theoretical drug effect sizes.

Results: A total of 10 patients with PD participated (age 66.7±7.5 years, 6 female) and 10 HVs (63.4±8.6 years, 8 female).  The MDS-UPDRS score was 38±16 (PD), and 1.9±2.7 (controls) P<0.001.  The mean deposition of P-SYN (μm² P-SYN/mm²) across all 3 time points was 11.5±12.6 μm² P-SYN/mm² (PD), and 0±0 (controls), P<0.0001.  The absolute variance in P-SYN values in subjects with PD at each individual time point (compared to the mean values across the 3 time points) was -0.7±2.4 (baseline), 0.8±3.0 (week 4) and -0.1±1.6 (week 8).   Using these values to calculate a sample size number for a theoretical 15%, 25% and 50% reduction in P-SYN due to drug effect (80% power, 2-sided alpha of 0.05) results in a sample size calculation of 62 patients per arm (15% drug effect), 24 patient per arm (25% drug effect) and 7 patients per arm (50% drug effect) based on a 1:1 randomization of treatment/placebo.

Conclusion: Digital pathologic detection and quantitation of cutaneous P-SYN proteins offer a dramatic potential reduction in the number of subjects required for clinical trials of novel synuclein targeted therapies. These preliminary results support the use of this assay to assess on-target engagement of a-synuclein targeted therapies and a surrogate endpoint of disease modification in PD and LBD clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/quantitative-measures-of-cutaneous-phosphorylated-alpha-synuclein-powering-a-disease-modification-clinical-trial-in-parkinsons-disease/