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Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are potential biomarkers for astrocyte activation and neuroaxonal damage, respectively. This study investigates serum GFAP (sGFAP) and NfL (sNfL) levels in ATTRv patients, pre-symptomatic subjects, and healthy controls (HCs) to evaluate their utility as biomarkers of disease progression and CNS involvement.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Our multicenter cross-sectional study included 111 ATTRv patients (56 symptomatic, 55 pre-symptomatic subjects) and 183 HCs. Serum levels of sGFAP and sNfL were measured using ultrasensitive immunoassays. The statistical comparisons were performed using ANCOVA models (age and sex adjusted), with correlations examined between serum biomarkers and disease severity (Neuropathy Impairment Score, NIS).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>sGFAP levels were elevated in symptomatic (median: 238.35 pg\/ml) and pre-symptomatic subjects (median: 105.50 pg\/ml) <jats:italic>vs.<\/jats:italic> HCs (median: 75.5 pg\/ml, <jats:italic>p<\/jats:italic>\u2009&lt; 0.001). sNfL was elevated only in symptomatic patients (median: 43.68 pg\/ml) compared to pre-symptomatic subjects (median: 9.36 pg\/ml) and HCs (median: 7.54 pg\/ml, <jats:italic>p<\/jats:italic>\u2009&lt; 0.001). Both biomarkers correlated significantly with NIS, reflecting disease severity. Female HCs had higher sGFAP levels than males (median 88.6 pg\/ml <jats:italic>vs.<\/jats:italic> 59.8 pg\/ml; <jats:italic>p<\/jats:italic> 0.011).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>sGFAP and sNfL mark distinct ATTRv stages, with sGFAP indicating early preclinical changes and sNfL correlating with neurological progression. Sex differences in sGFAP levels among HCs suggest that sex should be considered as a covariate in biomarker analyses.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00415-025-13072-6","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T12:38:37Z","timestamp":1744720717000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Elevated serum concentrations of GFAP in hereditary transthyretin amyloidosis since pre-symptomatic stages"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6666-7244","authenticated-orcid":false,"given":"Domenico","family":"Plantone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Luigetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Manco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Leonardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Guglielmino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Forcina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ceccanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Inghilleri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiore","family":"Manganelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Tozza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ausilia","family":"Sciarrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vitali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sabino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Righi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Stufano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Stromillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"De Stefano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Calabresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Primiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"13072_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41582-019-0210-4","volume":"15","author":"D Adams","year":"2019","unstructured":"Adams D, Koike H, Slama M, Coelho T (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. 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Angela Romano received financial grants (honoraria and speaking) from Akcea, and travel grants to attend scientific meetings from Akcea, Alnylam, Pfizer, and Csl Behring. Fiore Manganelli received personal fees for scientific events from Alfa-Sigma, Alnylam Pharmaceuticals, and Akcea Therapeutics, and received a travel grant to attend scientific meetings from CSL Behring. Stefano Tozza received personal fees for scientific events from Alnylam Pharmaceuticals and Amicus Therapeutics, and travel grants to attend scientific meetings from Akcea Therapeutics. Maria Ausilia Sciarrone received travel grants to attend scientific meetings from Sobi. Francesca Vitali received travel grants to attend scientific meetings from Alnylam. All other authors declare that there are no disclosures.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The study was approved by the local ethics committee of \u201cComitato Etico Territoriale Lazio Area 3\u201d at the Fondazione Policlinico Agostino Gemelli IRCCS (protocol ID 5470), and all subjects provided written informed consent prior to participation in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"340"}}