{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T18:15:18Z","timestamp":1780596918180,"version":"3.54.1"},"reference-count":42,"publisher":"BMJ","issue":"5","funder":[{"DOI":"10.13039\/501100000627","name":"Guarantors of Brain","doi-asserted-by":"publisher","award":["2018 Entry Fellowship (Dr Shiwen Koay)"],"award-info":[{"award-number":["2018 Entry Fellowship (Dr Shiwen Koay)"]}],"id":[{"id":"10.13039\/501100000627","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["Ricerca Finalizzata 2013 - project code PE-2013-02"],"award-info":[{"award-number":["Ricerca Finalizzata 2013 - project code PE-2013-02"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute for Health Research University College London Hospitals Biomedical Research Centre","award":["Support Prof M Lunn and Dr V Iodice"],"award-info":[{"award-number":["Support Prof M Lunn and Dr V Iodice"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2024,10,24]]},"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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&lt;0.001). Total p-syn score &gt;3 distinguished PAF from MSA with 100% specificity and 82% sensitivity. Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (\u03c1=0.63, p=0.0004), blood pressure recovery time following Valsalva manoeuvre (r=0.44, p=0.03) and patient-reported orthostatic intolerance (\u03c1=0.57, p=0.006).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2024-334615","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T04:15:14Z","timestamp":1732767314000},"page":"500-507","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Cutaneous phosphorylated-synuclein: an early diagnostic biomarker for pure autonomic failure"],"prefix":"10.1136","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0860-9211","authenticated-orcid":false,"given":"Shiwen","family":"Koay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-942X","authenticated-orcid":false,"given":"Vincenzo","family":"Provitera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Caporaso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekawat","family":"Vichayanrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Valerio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Stancanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Borreca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-6027","authenticated-orcid":false,"given":"Michael P","family":"Lunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Nolano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Iodice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"2025041009251783000_96.5.500.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(25)90007-5"},{"key":"2025041009251783000_96.5.500.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2019.03.009"},{"key":"2025041009251783000_96.5.500.3","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1960.03840110025004"},{"key":"2025041009251783000_96.5.500.4","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29005"},{"key":"2025041009251783000_96.5.500.5","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050693"},{"key":"2025041009251783000_96.5.500.6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.56.7.980"},{"key":"2025041009251783000_96.5.500.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01623-2"},{"key":"2025041009251783000_96.5.500.8","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2017.00225","article-title":"Iodine-123-meta-iodobenzylguanidine Myocardial Scintigraphy in Isolated Autonomic Failure: Potential Red Flag for Future Multiple System Atrophy","volume":"8","author":"Baschieri","year":"2017","journal-title":"Front Neurol"},{"key":"2025041009251783000_96.5.500.9","article-title":"Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. 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