{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:46:04Z","timestamp":1790282764570,"version":"4.1.0"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012621","name":"University College London Hospitals Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012621","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000627","name":"Guarantors of Brain","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000627","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The current research challenge in pure autonomic failure (PAF) lies in identifying specific biomarkers that can differentiate it from the other Lewy body disorders (Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies) and multiple system atrophy in the early stages and predict phenoconversion trajectories to more widespread impairment.<\/jats:p>\n                  <jats:p>In this study, we described the natural history of our cohort of patients with PAF over five decades and validated a cluster of clinical, autonomic, and neuroimaging biomarkers that help identify clinical profiles susceptible to further neurodegeneration, working towards a biological definition of PAF.<\/jats:p>\n                  <jats:p>Consecutive patients with an initial diagnosis of PAF were recruited and monitored through key milestones (disease onset, first and repeat autonomic assessment, phenoconversion, and death\/final contact). A subset underwent brain MRI and DaTSCAN (dopamine transporter single-photon emission CT scan). Uni- and multivariate regression analyses explored the associations among different factors, survival times, and phenoconversion, and were used to predict the probability of phenoconversion.<\/jats:p>\n                  <jats:p>Altogether, 281 patients with PAF were followed for a median of 10 years. Of these, 33% (91) converted to a more widespread synucleinopathy, and 41% (115) died during follow-up, of whom 53% (61) retained a PAF phenotype. Baseline cardiovascular autonomic biomarkers were key in differentiating disease trajectories and repeat testing indicated worsening of autonomic failure during the disease course. Median survival of patients with PAF was 15 years from orthostatic symptoms onset and was mostly influenced by age and the severity of orthostatic hypotension. Overall, 39% of patients had abnormal DaTSCAN results up to 7 years before phenoconversion, with 84% of these patients progressing to more widespread synucleinopathy. Male sex, older age, dream enactment behaviour and supine noradrenaline levels &amp;gt;200\u2005pg\/ml correlated with the risk of phenoconversion to Lewy body disorders, whereas younger age, bladder dysfunction, catheter use and dream enactment behaviour were associated with phenoconversion to multiple system atrophy.<\/jats:p>\n                  <jats:p>Our natural history study involves the largest single-centre longitudinal cohort of patients with an initial diagnosis of PAF and identifies robust clinical, autonomic, and neuroimaging biomarkers that, when used together, could serve as a novel and sensitive screening tool for early identification and stratification of patients at risk of phenoconversion to more widespread synucleinopathy.<\/jats:p>","DOI":"10.1093\/brain\/awaf191","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T09:10:58Z","timestamp":1747818658000},"page":"606-619","source":"Crossref","is-referenced-by-count":11,"title":["Pure autonomic failure: a natural history study of the Queen Square cohort"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-2559","authenticated-orcid":false,"given":"Giacomo","family":"Chiaro","sequence":"first","affiliation":[{"name":"Autonomic Unit, National Hospital Neurology and Neurosurgery, University College London Hospital NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6183-0997","authenticated-orcid":false,"given":"Ekawat","family":"Vichayanrat","sequence":"additional","affiliation":[{"name":"Autonomic Unit, National Hospital Neurology and Neurosurgery, University College London Hospital NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwen","family":"Koay","sequence":"additional","affiliation":[{"name":"Queen Square Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Rogeau","sequence":"additional","affiliation":[{"name":"Institute of Nuclear Medicine, University College London Hospital NHS Foundation Trust , London NW1 2BU ,","place":["UK"]},{"name":"Department of Nuclear Medicine, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, APHP Sorbonne Universit\u00e9 , Paris 75651 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon T","family":"Ingle","sequence":"additional","affiliation":[{"name":"Autonomic Unit, National Hospital Neurology and Neurosurgery, University College London Hospital NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"McNamara","sequence":"additional","affiliation":[{"name":"Autonomic Unit, National Hospital Neurology and Neurosurgery, University College London Hospital NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Watson","sequence":"additional","affiliation":[{"name":"Autonomic Unit, National Hospital Neurology and Neurosurgery, University College London Hospital NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamshed","family":"Bomanji","sequence":"additional","affiliation":[{"name":"Institute of Nuclear Medicine, University College London Hospital NHS Foundation Trust , London NW1 2BU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9716-9782","authenticated-orcid":false,"given":"Christopher J","family":"Mathias","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience and Stroke, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG 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