Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of alpha-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA, and, specifically, a critical need to distinguish MSA from the other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathological signature of phosphorylated alpha-synuclein that could distinguish patients with MSA from patients with PD and healthy controls.

We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing and skin biopsies at three locations. The density of intra-epidermal, sudomotor and pilomotor nerve fibers was measured. The deposition of phosphorylated alpha-synuclein was quantified. Results were compared to clinical rating assessments and autonomic function test results.

Patients with PD had reduced nerve fiber densities compared to patients with MSA (P<0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated alpha-synuclein in at least one skin biopsy. No phosphorylated alpha-synuclein was detected in controls. Patients with MSA had greater phosphorylated alpha-synuclein deposition (P<0.0001) and more widespread peripheral distribution (P<0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the two disorders.

Alpha-synuclein is present in peripheral autonomic nerves of MSA patients, and when combined with synuclein distribution, accurately distinguishes MSA from PD.

This study provides Class II evidence that measurement of phosphorylated alpha-synuclein in skin biopsies can differentiate patients with MSA from those with PD.