{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:10:58Z","timestamp":1791515458591,"version":"4.3.4"},"reference-count":217,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Traumatic brain injury (TBI) initiates a complex cascade of pathophysiological events that have far-reaching consequences beyond the initial injury. This review examines the current state of the literature on the mechanisms underlying neurotrauma and neuroinflammation, with particular emphasis on the molecular cross-talk between these disparate pathways that ultimately precipitates the development of chronic traumatic encephalopathy (CTE). We integrate this mechanistic knowledge with potential diagnostic biomarkers, such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and advances in neuroimaging and machine learning-based predictive tools. Finally, we discuss the current therapeutic approaches under investigation, and highlight which molecular targets have yet to be explored for potential therapeutic development.<\/jats:p>","DOI":"10.3390\/ijms26157191","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"7191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["From Acute Injury to Chronic Neurodegeneration: Molecular Mechanisms Linking Secondary Brain Injury to Long-Term Pathology"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8326-502X","authenticated-orcid":false,"given":"Julia K.","family":"Kaniuk","sequence":"first","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, 240 E Huron Street, Suite 1-200, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8434-7224","authenticated-orcid":false,"given":"Divy","family":"Kumar","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, 240 E Huron Street, Suite 1-200, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-7641","authenticated-orcid":false,"given":"Christopher","family":"Mazurek","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, 240 E Huron Street, Suite 1-200, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6161-1569","authenticated-orcid":false,"given":"Sepehr","family":"Khavari","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, 240 E Huron Street, Suite 1-200, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9091-5818","authenticated-orcid":false,"given":"Christopher","family":"Sollenberger","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8242-6020","authenticated-orcid":false,"given":"Arun","family":"Ahuja","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, 240 E Huron Street, Suite 1-200, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Mossner","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Northwestern Medicine, 676 N St Clair Street, Suite 2210, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9910-148X","authenticated-orcid":false,"given":"Christopher S.","family":"Ahuja","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Northwestern Medicine, 676 N St Clair Street, Suite 2210, Chicago, IL 60611, USA"},{"name":"Simpson-Querrey Research Institute, 303 E. Superior Street, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","unstructured":"CDC (2025, March 01). About Mild TBI and Concussion, Available online: https:\/\/www.cdc.gov\/traumatic-brain-injury\/about\/index.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.mcna.2019.11.001","article-title":"Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management","volume":"104","author":"Capizzi","year":"2020","journal-title":"Med. Clin. N. 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