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

Abstract

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 (n = 107) and without (n = 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 APOE genotype (higher in participants with one or more APOE ε4 allele). However, no differences in PHF-tau or Aβ1−42 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.

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank

“…In the Sydney Brain Bank, of the 636 cases screened, only five were identified as having CTE-NC, illustrating a strikingly low prevalence (0.79%). This is consistent with a recent study reporting a low frequency of CTE-NC (0.6%) in 532 individuals from a similar community-based cohort of ageing and neurodegeneration in the USA 29 and a large-scale study reporting no CTE-NC in 310 cases from Europe. 30 There was not a single case of CTE-NC in individuals with a documented history of a TBI alone; rather, three of the cases had TBI in addition to high exposure to repetitive head impacts in collision and combat sports and two cases had no known history of neurotrauma (TBI or repetitive head impacts in sports).…”

“… 29 additionally quantified the levels of paired helical filament tau, ß-amyloid 1–42, α-synuclein, phosphorylated TDP-43 as well as markers of inflammation (Iba1 and glial fibrillary acidic protein) in various brain regions of a large post-mortem cohort and found no association between TBI and these measures. However, in a subset of cases with more carefully matched control samples and more detailed analysis, higher levels of hippocampal tau were found in individuals with a history of TBI with loss of consciousness, 29 which is more consistent with the findings from our study. Other post-mortem studies also report that TBI is associated with greater tau and ß-amyloid pathology and greater phosphorylation-independent TDP-43.…”

“…Another limitation was our approach to screening. First, similar to past studies that screened large populations of cases, 26 , 29 , 30 we examined tissue from the small number of cortical regions considered to be most valuable to detect CTE-NC. 18 , 19 Given that CTE-NC can be sparse, isolated, and located nearly anywhere in the cortex, it is possible that some cases harboring this pathology were not detected.…”

“… 28 In a large community-based sample of 532 cases, only three cases (0.6%) had CTE-NC and none of these cases had a known history of head injury with loss of consciousness or participation in contact sports. 29 Another community-based study found no evidence of CTE-NC, using a strict definition of CTE-NC, in their cases. 30 …”

Applying the Bradford Hill Criteria for Causation to Repetitive Head Impacts and Chronic Traumatic Encephalopathy

“…Another larger post-mortem study of 310 older individuals found that while ARTAG was frequently found in the general aging population (incidence of 38%), there was no evidence of CTE neuropathology in any individual (46). Postupna et al reviewed 532 consecutive autopsy cases from the Adult Changes in Thought (ACT) study which consisted mostly of individuals with no TBI history and found only three cases of CTE (75). Two cases had a history of falls later in life and the third case had a history of military service.…”