The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease

Abstract

Objective: To determine the diagnostic discrimination of cutaneous α-synuclein deposition in individuals with Parkinson disease (PD) with and without autonomic dysfunction on autonomic testing, in early and late stages of the disease, and of short and long duration.

Methods: Twenty-eight participants with PD and 23 control participants were studied by skin biopsies at multiple sites, autonomic function testing, and disease-specific scales.

Results: Skin biopsies provide >90% sensitivity and >90% specificity to distinguish PD from control participants across all biopsies sites with quantification of either pilomotor or sudomotor α-synuclein deposition. All individuals with PD have significantly higher cutaneous α-synuclein deposition than control participants, even those individuals with PD and no evidence of autonomic dysfunction. Deposition of α-synuclein is most prominent in sympathetic adrenergic nerve fibers innervating the arrector pili muscles, but is also present in sudomotor (sympathetic cholinergic) nerve fibers. α-Synuclein is present even in the early stages of disease and disease of short duration. α-Synuclein ratios were higher in individuals with autonomic failure, with more advanced stages of disease and disease of longer duration.

Conclusions: The α-synuclein ratio provides a sensitive and specific diagnostic biomarker of PD even in patients without autonomic failure.

Classification of evidence: This study provides Class III evidence that cutaneous α-synuclein deposition accurately identifies patients with PD.

Figure 1. Standards for reporting diagnostic accuracy studies diagram

A total of 52 participants were screened and 51 participants were eligible, all of whom completed the study. One individual had a diagnosis of multiple system atrophy (MSA), not PD, so was not included in this study. The average α-synuclein (ASN) ratio across all 4 biopsy sites is reported. The results of the ASN ratio for sudomotor and pilomotor nerve fibers are reported separately.

Figure 2. α-Synuclein images

Confocal images from control participants are seen in (A–F), and from individuals with Parkinson disease (PD) in (G–L). The images in the left column are stained with the panaxonal marker protein gene product 9.5 (PGP 9.5). The center column of images is stained with α-synuclein. The right column of images is merged PGP 9.5 and α-synuclein. In (A–C), a sweat gland from a control subject is shown. In (D–F), pilomotor innervation from a control participant is seen. In (G–I), the sweat gland from an individual with PD is shown. In (J–L), the pilomotor muscle from an individual with PD is seen. The amount of α-synuclein in the PD participants (H, K) is greater than that of control participants (B, E).

Figure 3. α-Synuclein ratio across biopsy sites and dermal organelles

In (A), the pilomotor α-synuclein ratio (ASN) is shown across all 4 biopsy sites. Individual data points are plotted as individual circles. The 3 groups of participants include controls, Parkinson disease with no autonomic failure (PD-NAF), and Parkinson disease with autonomic failure (PD-AF). In (B), the same data are shown for the sudomotor α-synuclein ratio.