Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease

Abstract

Background: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.Methods: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.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.Discussion:Alpha-synuclein is present in peripheral autonomic nerves of MSA patients, and when combined with synuclein distribution, accurately distinguishes MSA from PD.Classification of Evidence:This study provides Class II evidence that measurement of phosphorylated alpha-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

Pain in Multiple System Atrophy a Systematic Review and Meta‐Analysis

“…The mechanisms underlying neuropathic forms of pain in MSA are not fully understood to date. Reduced subjective and objective pain thresholds have been reported in MSA individuals 21,[41][42][43] and both peripheral, that is, large and small fiber neuropathy, 31,[44][45][46][47] as well as central mechanisms likely contribute to such phenomenon. Within the central nervous system, nociception may be facilitated by neurodegenerative changes affecting the spinal cord, 41,42,48,49 or supraspinal pain-processing relays, including serotoninergic and noradrenergic brainstem nuclei, thalamus, and basal ganglia.…”

What's in a Name? The Time Has Come to Unify Parkinson's Disease and Dementia with Lewy Bodies

“…The recent introduction of α‐synuclein SAA as a highly sensitive and specific biomarker of the core PD pathophysiological process has been transformative for the field and has led to a proposal for a new biological staging system for PD that would allow either motor, cognitive, or other nonmotor features to be the defining clinical characeristics 49 . The SAA assay has been used primarily with cerebrospinal fluid 13,14 and skin tissue, 50,51 but more recently serum as well, 52 with similar results for all three tissues. Preliminary evidence is that it can accurately diagnose persons with prodromal or at‐risk PD (ie, either hyposmia or iRBD persons enriched to be DAT scan positive 13 or those just with polysomnogram‐confirmed iRBD 53 ).…”

Validation Study of the MDS Criteria for the Diagnosis of Multiple System Atrophy in the Mayo Clinic Brain Bank

“…Reliable biomarkers for MSA are still under development, and pathologic evaluation of autopsy brains postmortem remains the gold standard. [18][19][20][21] Neuropathologically established MSA requires the neuropathologic confirmation of widespread and abundant α-synuclein-positive glial cytoplasmic inclusions with neurodegeneration in striatonigral and/or olivopontocerebellar systems. 22 For the clinical diagnosis, essential features, including onset after 30 years of age, a negative family history, and a progressive disease course, are required.…”