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. 2025 Apr 10;96(5):500-507.
doi: 10.1136/jnnp-2024-334615.

Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure

Shiwen Koay  1   2   3   4 , Vincenzo Provitera  5 , Giuseppe Caporaso  5 , Ekawat Vichayanrat  1   2 , Fernanda Valerio  2 , Annamaria Stancanelli  5 , Ilaria Borreca  5 , Michael P Lunn  3   4 , Maria Nolano  5   6 , Valeria Iodice  7   2
Affiliations

Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure

Shiwen Koay et al. J Neurol Neurosurg Psychiatry. .

Abstract

Background: Pure autonomic failure (PAF) presents with progressive autonomic failure without other neurological features. Atypical presentations may lead to diagnostic uncertainty. We studied whether cutaneous phosphorylated-alpha-synuclein (p-syn) could distinguish between PAF, multiple system atrophy (MSA) and non-synucleinopathy-related autonomic failure, and examined its relationship with quantitative markers of cardiovascular autonomic failure.

Methods: All individuals underwent Composite Autonomic Symptom Score-31 autonomic questionnaires, cardiovascular autonomic testing and bilateral distal leg skin biopsies. We noted whether p-syn was present in nerves supplying autonomic adnexa, including sweat glands, blood vessels, arrector pili muscles, and subepidermal fibres, dermal fibres and nerve fascicles (maximum autonomic subscore 3, total p-syn score 6 for each sample, average calculated for both sides).

Results: 36 individuals were studied: 11 PAF, 13 MSA and 12 non-synucleinopathy-related autonomic failure. P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies. Mean total p-syn score was significantly higher in PAF compared with MSA (median 4.5 vs 1, p<0.001). Total p-syn score >3 distinguished PAF from MSA with 100% specificity and 82% sensitivity. Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (ρ=0.63, p=0.0004), blood pressure recovery time following Valsalva manoeuvre (r=0.44, p=0.03) and patient-reported orthostatic intolerance (ρ=0.57, p=0.006).

Conclusion: Cutaneous p-syn was abundant in PAF, a predominantly peripheral alpha-synucleinopathy. It is a promising biomarker to help distinguish between PAF, MSA and non-synucleinopathy-related autonomic failure to aid early diagnosis and recruitment to future clinical trials. P-syn deposition on autonomic nerves may impair control of total peripheral resistance giving rise to symptomatic orthostatic hypotension.

Keywords: AUTONOMIC; MULTISYSTEM ATROPHY; PERIPHERAL NEUROPATHOLOGY; Patient Outcome Assessment.

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Conflict of interest statement

Competing interests: VI has received honoraria from Theravance Biopharma. MPL has given advice on ad hoc advisory boards particularly on trial design to Roche, AstraZeneca, Sanofi, UCB, Takeda, Polyneuron and BeiGene (conference expenses and advisory board); unrestricted speaker fees for BeiGene and Grifols for the production of educational materials. Unrestricted conference expenses have been received from BeiGene and CSL Behring. He has received research grants from charitable foundations: Patrick Berthoud Charitable Trust, ABN, Guarantors of Brain, National Brain Appeal, UCLH Charities, Leonard Wolfson Foundation, Medical Research Council, GBS/CIDP Foundation International, New Zealand Medical Foundation and GAIN UK.

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