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This study aimed to identify underlying mechanisms contributing to decrements in fluid cognitive abilities in chronic (&gt;6 months) mild-to-moderate TBI. Specifically, the study focused on the relationships between cognitive performance, white matter integrity, TBI-related symptoms, and blood biomarkers, which are thought to be indicative of biological processes including neuronal injury (neurofilament light [NF-L], neurofilament heavy, ubiquitin C-terminal hydrolase-L1), vascular injury (vascular endothelial growth factor A), glial injury (glial fibrillary acidic protein [GFAP]), neurodegeneration (tau, phosphorylated-tau), immune response (GFAP immunoglobulin G), and inflammation (tumor necrosis factor-\u03b1, interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, interferon-\u03b3, and macrophage inflammatory protein-1\u03b1). The final study sample included 57 participants (42 males, 15 females) aged 19\u201359 with a history of chronic, remote mild-to-moderate TBI. Participants underwent cognitive and behavioral testing, neuroimaging, and a blood draw. Diffusion-weighted magnetic resonance imaging was used to assess white matter integrity in tracts connecting frontal and parietal regions with fractional anisotropy utilized as the metric. Blood samples were analyzed for TBI-related biomarkers. The study found that higher fluid cognition scores were associated with higher white matter integrity in frontal\u2013parietal networks, fewer reported TBI-related symptoms, and mixed biomarker and cytokine levels. Inflammatory processes were linked to lower fractional anisotropy in white matter pathways, more reported symptoms, and increased biomarkers of injury. Higher white matter integrity was also associated with fewer reported neurobehavioral symptoms. The findings provide evidence for a complex interplay of ongoing neuroinflammatory processes, white matter integrity, symptomology, and cognitive function in chronic mild-to-moderate TBI. The results underscore the importance of considering both structural brain changes and systemic responses in understanding the long-term effects of TBI. The observed correlations between cognitive deficits, white matter disruptions, and biomarker profiles suggest potential avenues for targeted interventions aimed at mitigating these effects in TBI patients.<\/jats:p>","DOI":"10.1089\/neu.2024.0566","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T09:42:39Z","timestamp":1750844559000},"page":"1732-1746","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Inflammatory, White Matter, and Neurodegenerative Mechanisms in Fluid Ability Decrements in Chronic Mild-to-Moderate Traumatic Brain Injury"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-7015","authenticated-orcid":false,"given":"Samantha H.","family":"Penhale","sequence":"first","affiliation":[{"name":"Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2732-5529","authenticated-orcid":false,"given":"Abigail B.","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA."},{"name":"Brain Rehabilitation Research Center, North Florida\/South Georgia VAMC, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoumi","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah E.","family":"McQuillan","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Maczuzak","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somnath","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon","family":"Lamb","sequence":"additional","affiliation":[{"name":"Brain Rehabilitation Research Center, North Florida\/South Georgia VAMC, Gainesville, Florida, USA."},{"name":"Department of Psychiatry, Center for OCD, Anxiety, and Related Disorders, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0577-6687","authenticated-orcid":false,"given":"Richard","family":"Rubenstein","sequence":"additional","affiliation":[{"name":"Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy K.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firas","family":"Kobeissy","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Center for Neurotrauma, Multiomics &amp; 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