Cutaneous α-Synuclein Pathology as a Differential Marker: A Histological and Statistical Comparison across Neurodegenerative Disease Groups

There is an urgent need for early and accurate biomarkers of neurodegenerative disorders. Due to the high innervation and accessibility of the skin, a skin biopsy is a minimally invasive method of detecting phosphorylated α-synuclein (p-α-syn) and assessing intraepidermal nerve fiber density (IENFD). We analyzed biopsies taken from the back and the leg of patients with parkinsonian syndromes (Park.sy.), α-synucleinopathies, multiple system atrophies (MSA), tauopathies, and other neurological disorders, as well as from healthy controls. Double immunofluorescence was performed for p-α-syn (Ser129) and protein gene product 9.5 (PGP 9.5), alongside quantitative IENFD assessment. p-α-syn was significantly more prevalent in the patient groups than in the control group. The highest prevalence was observed in patients with parkinsonian syndromes, α-synucleinopathies and MSA. Tauopathies showed preferential paravertebral positivity. Reduction or absence of IENFD was most pronounced in tauopathies (75%), while IENFD was most commonly preserved in MSA (83.3%), indicating that disease-specific patterns of peripheral nerve involvement are exhibited. p-α-syn positivity was found to correlate with shorter disease duration, suggesting its potential as an early biomarker. Combined with olfactory testing, cutaneous markers improved diagnostic discrimination. Our findings support the use of skin biopsies as a promising clinical tool in diagnosing biomarker-based neurodegenerative diseases.