Comparison of [18F]AV-1451 PET with HDFT in chronic TBI subjects

Objectives: Traumatic brain injury (TBI) subjects are more likely to have dementia characterized by increased hyperphosphorylated tau at an early age, relative to sporadic Alzheimer’s disease subjects. It has been hypothesized that this may be related to axonal injury, possibly decades before the manifestation of dementia, and that this could result in tau buildup in the brain. We undertook a study to investigate the relationship between tau burden and white matter tract integrity relative to the frequency of TBI. Methods: We studied a cohort of 27 TBI subjects (21-61 yrs) and 7 cognitively normal controls (age 21-59 yrs) scanned with [18F]AV-1451 PET for tau deposition assessment and high-definition fiber tracking (HDFT) MRI for white matter tract integrity assessment. [18F]AV-1451 PET images were classified as positive (AV1451+) if tau deposition was visually apparent, or negative (AV1451-) if not. HDFT MRI images were also classified as positive (HDFT+) or negative (HDFT-) based on tractography analyses. All TBI subjects and normal controls underwent neuropsychological testing which included measures of memory, executive function, and information processing speed. All TBI subjects were impaired on at least one measure of memory and executive function and on all variables measuring information processing speed. TBI subjects were classified based on trauma exposure frequency into three categories: few (less than 4 exposures), intermediate (4-10 exposures), or numerous (greater than 10 exposures). Results: HDFT was positive for white matter changes in 16 TBI patients (7 few, 2 intermediate, 7 numerous). Three patients in the numerous exposure category had positive [18F]AV-1451 scans, showing substantially higher uptake in several cortical grey matter regions, including occipital, parietal, posterior cingulate, and precuneus. Figure below compares an [18F]AV-1451 positive subject with controls. In summary (table), all subjects who exhibited neurodegeneration in tau PET and white matter degradation in HDFT MRI were TBI patients with numerous TBI exposures.

Conclusions: These data are consistent with the hypothesis that axonal injury resulting from numerous repetitive TBI episodes may lead to increased tau deposition.

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Figure: PET scans of a representative [18F]AV-1451-positive subject compared to similar age controls. Columns show matched axial, coronal, and sagittal slices respectively. Rows A and B show T1 MR and [18F]AV-1451 images respectively averaged over two control subjects (aged 58 and 59). Row C shows [18F]AV-1451 images for a chronic TBI subject (age 54) with axonal injury on HDFT. PET scans were warped to a common space (MNI). SUVR scale is indicated by the color bar. This patient is a military veteran with a history of numerous blast exposures and frank deficits in attention, working memory, and processing speed.