In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury

Abstract

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.

Network diffusion modeling predicts neurodegeneration in traumatic brain injury

“…NDM applies to any first‐order diffusive process on a graph. Therefore, NDM may also be able to model the effect of progressive deafferentation and atrophy resulting from a traumatic brain injury (likely driven either by Wallerian degeneration of the white matter connections or, similar to the neurodegenerative conditions, via abnormal protein aggregation and transmission as suggested by recent findings) . In the present study, we used NDM to achieve precisely this in a cohort of TBI patients.…”

“…Therefore, NDM may also be able to model the effect of progressive deafferentation and atrophy resulting from a traumatic brain injury (likely driven either by Wallerian degeneration of the white matter connections or, similar to the neurodegenerative conditions, via abnormal protein aggregation and transmission as suggested by recent findings). 16,17 In the present study, we used NDM to achieve precisely this in a cohort of TBI patients. Moreover, we implemented a novel automated inference method to identify several injury epicenters from which neurodegenerative pathology most likely originates in each individual patient.…”

Toward a Global and Reproducible Science for Brain Imaging in Neurotrauma: The ENIGMA Adult Moderate/Severe Traumatic Brain Injury Working Group

“…With metabolic imaging this hypothesis can be evaluated directly. Tau deposition has more recently been observed in mixed TBI samples (see Gorgoraptis et al, 2019;Wooten et al, 2019). In the work by Wooten and colleagues, these findings where spatially co-localized with sites showing the greatest network connectivity established using fMRI.…”

Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy

“…[27][28][29] In humans, CTE Tau pathology also has a distinctly different distribution in the brain than that found in Alzheimer's disease. 30 At present, there is no therapy for CTE. 31,32 Systemic anti-pTau antibody therapy has been successful in treating a murine model of CTE, 33,34 but this strategy is unlikely to be successful in humans, as has been found with systemic administration of anti-pTau in clinical studies of Alzheimer's disease [35][36][37] ; the blood/brain barrier limits the amount of systemically administered antibodies reaching the brain to <0.5% of the administered dose.…”