Skin nerve α-synuclein deposits

TLDR

The study aimed to determine whether phosphorylated α‑synuclein deposits in skin nerve fibers could serve as a biomarker for idiopathic Parkinson disease and to elucidate the pathogenesis of its associated peripheral neuropathy. Twenty‑one IPD patients, 20 parkinsonism controls lacking α‑syn deposits, and 30 healthy controls underwent nerve conduction studies and cervical and distal skin biopsies to assess small‑fiber integrity and phosphorylated α‑syn deposition. IPD patients exhibited leg small‑fiber neuropathy with preserved large fibers, and phosphorylated α‑syn was present only in cervical skin of IPD patients, correlating with epidermal denervation; thus proximal skin α‑syn deposition is a sensitive biomarker distinguishing IPD from other parkinsonisms and is linked to peripheral nerve damage.

Abstract

<h3>Objective:</h3> To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD. <h3>Methods:</h3> Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein. <h3>Results:</h3> Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation. <h3>Conclusions:</h3> The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage. <h3>Classification of evidence:</h3> This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.