Tau, β-amyloid, and glucose metabolism following service-related Traumatic Brain Injury in Vietnam war veterans: The AIBL-VETS study

Abstract

Traumatic Brain Injury (TBI) is common amongst military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer′s disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 NIA–AA research framework, by measuring tau, β–amyloid and glucose metabolism using positron emission tomography (PET) in veterans with service–related TBI. Seventy male Vietnam war veterans — 40 with TBI (aged 68.0±2.5 years) and 30 controls (aged 70.1±5.3 years) — with no prior diagnosis of dementia or mild cognitive impairment underwent β–amyloid (18F–Florbetaben), tau (18F–Flortaucipir) and 18F–FDG PET. The TBI cohort included 15 participants with mild, 16 with moderate, and 9 with severe injury. β–amyloid level was calculated using the Centiloid (CL) method and tau was measured by Standardized Uptake Value Ratios (SUVR) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE–e4. The findings were validated in an independent cohort from the ADNI–DOD study. There were no significant nor trending differences in β–amyloid or tau levels or 18F–FDG uptake between the TBI and control groups before and after controlling for covariates. The β–amyloid and tau findings were replicated in the ADNI–DOD validation cohort and persisted when the AIBL–VETS and ADNI–DOD cohorts were combined (114 TBI vs 87 controls in total). These findings suggest that TBI is not associated with the later life accumulation of the neuropathological markers of AD.

Traumatic brain injury and Alzheimer’s Disease biomarkers: A systematic review of findings from amyloid and tau positron emission tomography (PET)

“…92 There were also no differences upon stratifying by injury severity (mTBI versus mild-to-moderate TBI). 92 Using the same three composite ROIs with the addition of a meta-temporal composite ROI, Hicks and colleagues (2022) similarly noted no association of TBI with elevated [ 18 F]-MK-6240 SUVR; intriguingly, control subjects actually demonstrated higher [ 18 F]-MK-6240 SUVRs. 93 Furthermore, Rowe and colleagues (2019) observed no evidence for increased tau pathology in similar temporoparietal and mesial-temporal composite ROIs in subjects with TBI compared to Aβ+ patients with AD, Aβ+ patients with MCI, or Aβ+ cognitively normal patients.…”

“…All ten papers analyzed at least one cortical and/or subcortical ROI, including cortical composite ROIs (mesial-temporal, temporoparietal, meta-temporal, and rest of neocortex composites), frontal, temporal, parietal, and occipital lobes, the cingulate gyrus, precuneus, insula, basal ganglia, and substantia nigra (Table 6). 92-95,97-102…”

“…94 In line with those findings, Dore et al (2022) also found no difference in Florbetaben uptake between TBI and non-TBI veteran subjects. 92 There were still no significant differences in amyloid levels when the TBI group was subdivided into mTBI (n=15) and moderate-to-severe TBI (n=25). 92 As this study only examined cognitively normal subjects, the validity of the previously-observed association between TBI + PTSD and worsened cognitive performance cannot be assessed, but the lack of evidence for increased amyloid in TBI patients is congruent with both studies from Weiner and colleagues.…”

“…These ROIs included measures of global amyloid status and/or burden, as well as the frontal, parietal, temporal, and occipital lobes, the corpus callosum and/or fornix, the anterior and the posterior cingulate, and the cuneus or precuneus (Table 4). [74][75][76][77][78][79][80][85][86][87][88][89][90][91][92][93][94][95] Global amyloid status and/or burden Schneider and colleagues (2019) found history of TBI to be associated with increased global cortical Florbetapir SUVRs in cognitively normal individuals. 89 Mielke and colleagues (2014) similarly observed no association between TBI and amyloid deposition in cognitively normal individuals via [ 11 C]-PiB, but amongst individuals with mild cognitive impairment (MCI), those with TBI had ~18% higher global amyloid and 5-fold higher odds of increased amyloid compared to those without TBI.…”

“…Evidence for cortical and/or subcortical tau deposition All ten papers analyzed at least one cortical and/or subcortical ROI, including cortical composite ROIs (mesial-temporal, temporoparietal, meta-temporal, and rest of neocortex composites), frontal, temporal, parietal, and occipital lobes, the cingulate gyrus, precuneus, insula, basal ganglia, and substantia nigra (Table 6). [92][93][94][95][97][98][99][100][101][102] Cortical composite ROIs Dore and colleagues (2022) saw no difference in Flortaucipir uptake between TBI and non-TBI subjects in any of three composite ROIs (mesial-temporal, temporoparietal, and rest of neocortex). 92 There were also no differences upon stratifying by injury severity (mTBI versus mild-to-moderate TBI).…”