Abstract
Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [18F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [18F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.
Highlights
We identified biomarker signatures in human veterans exposed to improvised explosive devices (IEDs) blasts in theater and rats exposed to repetitive low-level blasts in a shock tube
The rat model was developed to mimic a level of blast exposure that would be associated with human mild TBI (mTBI) or a subclinical blast exposure [34]
Rats exposed to this blast protocol exhibit a range of chronic anxiety and posttraumatic-stress disorder (PTSD)-like behavioral traits [26, 29, 31] and PTSD-related symptoms were prominent in the clinical presentations of the human veterans
Summary
Symptoms of post-traumatic neurodegeneration are variable but often include memory loss along with alterations in mood or personality, as well as poor impulse control and aggression The pathology underlying these symptoms may represent Alzheimer’s disease (AD)-type dementia or another clinical entity known as chronic traumatic encephalopathy (CTE). Describe a novel astroglial pathology, wherein scar-like changes involved the subpial glial plate, penetrating cortical blood vessels, white/gray matter junction, and structures lining the ventricles In another postmortem study, axonal pathology without demonstrable tauopathy was observed [24]. Axonal pathology without demonstrable tauopathy was observed [24] The prevalence of these pathological subtypes in veterans with chronic cognitive/behavioral syndromes following blast or other types of TBI remains to be determined. The results here indicate that NfL might be an informative parameter to include in a biomarker panel aimed at enabling the diagnosis of CTE during life
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