Clinical Utility of Skin Biopsy in Differentiating between Parkinson's Disease and Multiple System Atrophy

Abstract

Background. It is often difficult to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), especially in their early stages. Objectives. To examine the clinical utility of histopathological analysis of biopsied skin from the chest wall and/or leg in differentiating between the two diseases. Methods. Skin biopsies from the lower leg and/or anterior chest wall were obtained from 38 patients with idiopathic PD (26 treated with levodopa and 12 levodopa-naïve) and 13 age-matched patients with MSA. We sought aggregates of phosphorylated α-synuclein on cutaneous nerve fibers using double fluorescence immunohistochemistry and confocal microscopy and measured intraepidermal nerve fiber density (IENFD). Results. Phosphorylated α-synuclein aggregates were identified on cutaneous nerves in two patients with PD (5.3%) but in none of the patients with MSA, and IENFD was significantly lower in patients with PD when compared to those with MSA. There was no difference in IENFD between levodopa-treated and levodopa-naïve patients with PD. Conclusions. Our findings suggest that an assessment of IENFD in biopsied skin could be a useful means of differentiating between PD and MSA but that detection of α-synuclein aggregates on cutaneous nerves in the distal sites of the body is insufficiently sensitive.

Figure 1

Phosphorylated α-synuclein accumulation in the skin nerve fiber. Confocal microscopic colocalization study of phosphorylated α-synuclein deposits (red) in skin biopsied from the lower limb of a patient with Parkinson's disease. The pan-axonal marker PGP-9.5 in green reveals nerve fibers (arrow) and fibroblasts (arrowheads). Colocalization (yellow) is observed in a subcutaneous nerve fiber. Bar = 10 μm.

Figure 2

Intraepidermal nerve fiber density in patients with multiple system atrophy (MSA) and patients with Parkinson's disease (PD). ((a) and (b)) Confocal digital images showing a decrease in intraepidermal nerve fiber density in Parkinson's disease (a) compared with multiple system atrophy (b). Nerve fibers and fibroblasts are labeled by PGP-9.5 (in green) and the basement membrane of the skin is labeled by collagen IV (in red; arrowheads). The number of nerve fibers penetrating the basement membrane (arrows) was quantified. (c) Intraepidermal nerve fiber density in patients with multiple system atrophy (MSA) and patients with Parkinson's disease (PD). Fiber density is expressed as the number of counted nerves per linear millimeter at the basement membrane. Fiber density was significantly decreased in patients with PD compared with those with MSA. Error bars show standard error of the mean. (d) Intraepidermal nerve fiber density in patients with PD exposed to levodopa (levodopa+) and those naïve to levodopa (levodopa−). No significant difference was observed between two groups. IENFD: intraepidermal nerve fiber density; MSA: multiple system atrophy; PD: Parkinson's disease.