AUTHOR=Postupna Nadia , Rose Shannon E. , Gibbons Laura E. , Coleman Natalie M. , Hellstern Leanne L. , Ritchie Kayla , Wilson Angela M. , Cudaback Eiron , Li Xianwu , Melief Erica J. , Beller Allison E. , Miller Jeremy A. , Nolan Amber L. , Marshall Desiree A. , Walker Rod , Montine Thomas J. , Larson Eric B. , Crane Paul K. , Ellenbogen Richard G. , Lein Edward S. , Dams-O'Connor Kristen , Keene C. Dirk 

TITLE=The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample

JOURNAL=Frontiers in Neurology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.624696

DOI=10.3389/fneur.2021.624696

ISSN=1664-2295

ABSTRACT=<p>The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) β in brains from ACT participants with (<italic>n</italic> = 107) and without (<italic>n</italic> = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for α-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%–none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Aβ showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and <italic>APOE</italic> genotype (higher in participants with one or more <italic>APOE</italic> ε4 allele). However, no differences in PHF-tau or Aβ<sub>1−42</sub> were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Aβ, α-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.</p>