Positron emission tomography of tau in Iraq and Afghanistan Veterans with blast neurotrauma

Abstract

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25-69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any associations with clinical symptoms.

Keywords: Blast; Positron emission tomography; Tau; Traumatic brain injury; Veteran.

Fig. 1

SUVR (using isthmus cingulate as reference) of two representative participants. Note high uptake in skin and eyes, similar to that reported in older adults, but strong nonspecific binding in midbrain is not observed. Representative participants with low score (A) and a high score (B) on Factor 1- Blast Exposure. Uptake for the participant in (A) is generally consistent with that presented for participants aged 20–26 by Schöll et al. (2016).

Fig. 2

SUVR was sampled in the cortex and evaluated for associations with the head trauma factors. Of the 66 cortical regions defined, 47 were correlated with Factor 1- Blast Exposure. Significant regions are displayed, with colors indicating significance level.

Fig. 3

Vertex-wise (A and B) and Voxel-wise (C) correlations between T807 uptake and Factor 1 – Blast Exposure. Images displayed are t-statistics thresholded at q = 0.05 (FDR correction). Maximum (yellow) values are 5.0 for all images. Minimum values are as follows: left hemisphere = 2.239; right hemisphere = 2.149; volume = 3.010. For the remaining two factors (Factor 2 – Symptom Duration and Factor 3 – Blunt Concussion) no voxels/vertices survived the correction for multiple comparisons.

Fig. 4

Results of Independent Components Analysis (ICA). After denoising, four components were an ideal fit for the data. The first component and its significant associations are shown here. Results indicate that, with increasing beta weight on Factor 1 – Blast Exposure, tracer uptake appears more like the map shown (e.g., with increasing numbers of blasts, more tracer uptake is expected in the inferior cerebellum and lateral occipital regions, but less in the anterior lobe of the cerebellum). Panel B shows a scatter plot of ICA component scores and beta weights for Factor 1 – Blast Exposure. The remaining three components from the ICA analysis and the remaining 11 scatter plots comparing component scores to factor beta weights are included in the supplemental materials. Note: The scatter plot displays the unranked factor beta weights, although statistics were completed using rank transforms.