Skin nerve phosphorylated α synuclein deposits in patients with Parkinson′s disease

Objective To investigate the characteristics of phosphorylated α-synuclein (p-α-syn) deposition in skin nerve fibers and its potential as a peripheral biomarker for Parkinson′s disease (PD). Methods Fifteen PD patients and 31 age-matched healthy controls were evaluated by Small-Fiber Neuropathy and Symptoms Inventory Questionnaire (SFN-SIQ), who were recruited in the Department of Neurology, the First Affiliated Hospital of Zhengzhou University from June 1, 2017 to August 31, 2018. PD patients were divided into two subgroups according to the main clinical manifestations: bradykinesia (n=7) and resting tremor (n=8), and the severity of the disease was evaluated by Honhn-Yahr classification, where 0 to 2.5 indicates early stage (n=11) and 3.0 to 5.0 indicates middle to late stage (n=4). Three-millimeter punch biopsies were taken from cervical seven paravertebral area and distal leg of PD patients, while the skin of the distal leg of healthy control group was only taken, followed by immunohistochemistry and double immunofluorescence staining. The intraepidermal nerve fiber density (IENFD) and the deposition characteristics of p-α-syn were studied. Results P-α-syn immuosignals were observed in 12/15 PD patients while in none of the control subjects, distributed in shape of dots or thread in the subepithelial plexus, dermis nerve tracts, and/or in the nerve fibers innervating sweat gland, muscle arrector pilorum, small blood vessels or hair follicle. The positive rate of p-α-syn deposition in a single site was 6/15 of the distal leg, 7/15 of the cervical, and the total positive rate was 12/15. The IENFD of PD group was 6.85±1.94/mm, which was significantly lower than that of control group (10.45±3.70/mm, t=-3.303, P=0.002), and was negatively correlated with the SFN-SIQ (r=-0.561, P=0.046). There was no statistically significant difference in the positive rate of p-α-syn deposition and IENFD between patients with tremor and bradykinesia, nor between patients at stage of Hoehn-Yahr 0-2.5 and 3.0-5.0. Conclusions Cutaneous p-α-syn deposits in the nerve fibers of PD patients, with a significant decrease in IENFD. P-α-syn deposition in skin nerves may be an intrinsic peripheral pathological change of PD, and skin biopsy immunolabelling p-α-syn merits further study as a potential peripheral biomarker of in vivo PD diagnosis. Key words: Parkinson disease; Alpha-synuclein; Intraepidermal nerve fiber density; Skin biopsy