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

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 96; no. 5; p. 500
• Main Authors: Koay, Shiwen, Provitera, Vincenzo, Caporaso, Giuseppe, Vichayanrat, Ekawat, Valerio, Fernanda, Stancanelli, Annamaria, Borreca, Ilaria, Lunn, Michael P, Nolano, Maria, Iodice, Valeria
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2025
• Subjects: Aged; alpha-Synuclein - metabolism; Atrophy; Biomarkers; Biomarkers - metabolism; Biopsy; Blood pressure; Diagnosis, Differential; Disease; Early Diagnosis; Exocrine glands; Female; Heart rate; Humans; Male; Medical diagnosis; Middle Aged; Multiple System Atrophy - diagnosis; Multiple System Atrophy - metabolism; Multiple System Atrophy - pathology; Neurodegeneration; Orthostatic hypotension; Phosphorylation; Pure Autonomic Failure - diagnosis; Pure Autonomic Failure - metabolism; Pure Autonomic Failure - pathology; Skin - metabolism; Skin - pathology; AUTONOMIC; Patient Outcome Assessment; PERIPHERAL NEUROPATHOLOGY; MULTISYSTEM ATROPHY
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp-2024-334615

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. 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). 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). 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.