Alpha-Synuclein and Autonomic Neuropathy Progression in a Longitudinal Study of Parkinson’s Disease

Background: We recently reported that α-synuclein can be detected within cutaneous autonomic nerve fibers of patients with Parkinson’s disease (PD) (Wang N. et. al. Neurology 2013). The long-term implication of this finding on autonomic nerve fiber structure and function is unknown. Objective: To determine the relationship between α-synuclein deposition, autonomic nerve fiber density and autonomic function in a longitudinal study of patients with PD. Methods: Twenty-eight individuals with PD and 23 age and gender-matched healthy control subjects had clinical examinations, autonomic function testing and skin biopsies from 4 sites taken at an initial visit and repeated 1 year later. Skin biopsies were stained for PGP9.5, and total α-synuclein (both phosphorylated and non-phosphorylated). The ratio of α-synuclein to nerve innervation (α-synuclein ratio) was calculated for each sample. The density of intra-epidermal (IENFD), sudomotor (SGNFD) and pilomotor (PMNFD) nerve fibers was determined. The initial α-synuclein ratio was compared against the change in nerve fiber density (IENFD, SGNFD and PMNFD) over 1 year. Results: Patients with PD had higher α-synuclein ratios compared to controls within pilomotor nerves and sudomotor nerves at all sites (P < 0.01, all biopsy sites). Higher α-synuclein ratios measured at the baseline visit were correlated with a greater decline in SNGFD (r = −0.46, P < 0.01) and PMNFD (r = −0.61, P < 0.001) 1 year later. There was a correlation between higher α-synuclein ratios and greater decline in heart rate variability (r = 0.39, P < 0.05), Valsalva Ratio (r = 0.42, P < 0.05) and orthostatic hypotension (r = 0.46, P < 0.01). Discussion: These data support the pathophysiologic association between α-synuclein deposition, autonomic nerve fiber degeneration and autonomic dysfunction in individuals with PD. The results of this longitudinal study further support the role of the α-synuclein as a biomarker in patients with Parkinson disease. Acknowledgement: Study supported by the RJG Foundation (CHG), and the Michael J. Fox Foundation (RF).