α-Synuclein in cutaneous autonomic nerves

Abstract

Objective: To develop a cutaneous biomarker for Parkinson disease (PD).Methods: Twenty patients with PD and 14 age-and sex-matched control subjects underwent examinations, autonomic testing, and skin biopsies at the distal leg, distal thigh, and proximal thigh. a-Synuclein deposition and the density of intraepidermal, sudomotor, and pilomotor nerve fibers were measured. a-Synuclein deposition was normalized to nerve fiber density (the a-synuclein ratio). Results were compared with examination scores and autonomic function testing.Results: Patients with PD had a distal sensory and autonomic neuropathy characterized by loss of intraepidermal and pilomotor fibers (p , 0.05 vs controls, all sites) and morphologic changes to sudomotor nerve fibers. Patients with PD had greater a-synuclein deposition and higher a-synuclein ratios compared with controls within pilomotor nerves and sudomotor nerves (p , 0.01, all sites) but not sensory nerves. Higher a-synuclein ratios correlated with Hoehn and Yahr scores (r 5 0.58-0.71, p , 0.01), with sympathetic adrenergic function (r 5 20.40 to 20.66, p , 0.01), and with parasympathetic function (r 5 20.66 to 20.77, p . 0.01). Conclusions:We conclude that a-synuclein deposition is increased in cutaneous sympathetic adrenergic and sympathetic cholinergic fibers but not sensory fibers of patients with PD. Higher a-synuclein deposition is associated with greater autonomic dysfunction and more advanced PD. These data suggest that measures of a-synuclein deposition in cutaneous autonomic nerves may be a useful biomarker in patients with PD. Accumulating evidence suggests that a-synuclein deposition occurs early in the course of PD and may antedate the appearance of the clinical features of the disease.2 This has provided the rationale for the use of a-synuclein as a biomarker in PD. 3Skin punch biopsy could provide a simple means to measure a-synuclein deposition in the peripheral nervous system; however, preliminary studies used techniques optimized for CNS tissue, relied on small tissue volumes, and did not systematically study autonomic substructures, and therefore detected a-synuclein in only a minority of subjects with PD. [4][5][6][7][8] We recently reported novel methods to study the cutaneous autonomic innervation in skin biopsies of patients with peripheral nerve disease.9,10 We hypothesized, based on the prominent autonomic manifestations of PD, that a-synuclein deposition would be elevated in cutaneous structures with autonomic innervation.The aims of the study were to determine 1) whether a-synuclein was present in cutaneous sensory and autonomic nerves, 2) the relationship between cutaneous a-synuclein deposition and *These authors contributed equally to this work.

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“…These are promising approaches to detect a-synuclein neuropathology in the autonomic nervous system of PD cases. [130][131][132][133][134][135] In addition, the presence of a-synuclein in ENS and submandibular gland is likely to occur at a very early stage in the course of the disease. 126,136 As of now, the abnormal a-synuclein accumulation has been identified in the biopsies within the salivary glands, 8,45,56 stomach, duodenum, 55,57 colon and rectum of PD patients.…”

Autonomic dysfunction predicts poor outcome in stroke: Updates on recent autonomic research

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