{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T08:14:55Z","timestamp":1778228095902,"version":"3.51.4"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient\u2010reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a cross\u2010sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician\u2010reported measures and 3\u2010mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score\u20106 (<jats:italic>R<\/jats:italic>\u2009=\u20090.46, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01); pain measured with the Brief Pain Symptom Inventory (<jats:italic>R<\/jats:italic>\u2009=\u20090.44, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire (<jats:italic>R<\/jats:italic>\u2009=\u20090.38, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire (<jats:italic>R<\/jats:italic>\u2009=\u20090.44, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv\u2010associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease\u2010modifying therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51636","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T05:39:30Z","timestamp":1660109970000},"page":"1370-1383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Cutaneous amyloid is a biomarker in early <scp>ATTRv<\/scp> neuropathy and progresses across disease stages"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-6022","authenticated-orcid":false,"given":"Roy","family":"Freeman","sequence":"first","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"Gonzalez\u2010Duarte","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Ciencias Medicas y Nutrici\u00f3n Salvador Zubir\u00e1n  Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Barroso","sequence":"additional","affiliation":[{"name":"Ra\u00fal Carrea Institute for Neurological Research, FLENI  Ciudad Aut\u00f3noma de Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Campagnolo","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School  Boston 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