{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T05:04:54Z","timestamp":1793509494363,"version":"4.5.0"},"reference-count":108,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ricerca Corrente 2024"},{"name":"Telethon","award":["GJC21131"],"award-info":[{"award-number":["GJC21131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to define a balanced review on the use of biomarkers in HSP. Methods: This review focuses on fluid biomarkers already available in clinical or research settings\u2014primarily validated in other neurodegenerative diseases\u2014and assesses their potential translation to the HSP context. Biomarkers such as neurofilament light chain, brain-derived tau, glial fibrillary acidic protein, and soluble TREM2 reflect key converging mechanisms of neurodegeneration, including axonal damage, neuronal loss, and glial activation. These shared downstream pathways represent promising targets for disease monitoring in HSP, independently of the underlying genetic mutation. Results: An integrative framework of fluid biomarkers could assist in defining disease progression and stratify patients in both clinical and research settings. Moreover, recent advances in ultrasensitive assays and remote sampling technologies, such as dried blood spot collection, offer concrete opportunities for minimally invasive, longitudinal monitoring. When combined with harmonized multicenter protocols and digital infrastructure, these tools could support scalable and patient-centered models of care. Conclusions: The integration of already available biomarkers into the HSP field may accelerate clinical translation and offer a feasible strategy to overcome the challenges posed by genetic and clinical heterogeneity.<\/jats:p>","DOI":"10.3390\/genes16101189","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:13:27Z","timestamp":1760361207000},"page":"1189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Fluid Biomarkers in Hereditary Spastic Paraplegia: A Narrative Review and Integrative Framework for Complex Neurodegenerative Mechanisms"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5651-4970","authenticated-orcid":false,"given":"Lorenzo","family":"Cipriano","sequence":"first","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnology, University Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzio","family":"Setola","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Barghigiani","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/S1474-4422(19)30235-2","article-title":"Hereditary Spastic Paraplegia: From Diagnosis to Emerging Therapeutic Approaches","volume":"18","author":"Shribman","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1093\/brain\/aww111","article-title":"Genetic and Phenotypic Characterization of Complex Hereditary Spastic Paraplegia","volume":"139","author":"Kara","year":"2016","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1186\/s13023-025-03849-3","article-title":"The Epidemiology of Hereditary Spastic Paraplegia and Associated Common Mental Health Outcomes in England and Northern Ireland","volume":"20","author":"Jeyakumar","year":"2025","journal-title":"Orphanet J. 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