Abstract
Single and repeated sports-related mild traumatic brain injury (mTBI), also referred to as concussion, can result in chronic post-concussive syndrome (PCS), neuropsychological and cognitive deficits, or chronic traumatic encephalopathy (CTE). However PCS is often difficult to diagnose using routine clinical, neuroimaging or laboratory evaluations, while CTE currently only can be definitively diagnosed postmortem. We sought to develop an animal model to simulate human repetitive concussive head injury for systematic study. In this study, mice received single or multiple head impacts by a stereotaxic impact device with a custom-made rubber tip-fitted impactor. Dynamic changes in MRI, neurobiochemical markers (Tau hyperphosphorylation and glia activation in brain tissues) and neurobehavioral functions such as anxiety, depression, motor function and cognitive function at various acute/subacute (1-7 day post-injury) and chronic (14-60 days post-injury) time points were examined. To explore the potential biomarkers of rCHI, serum levels of total Tau (T-Tau) and phosphorylated Tau (P-Tau) were also monitored at various time points. Our results show temporal dynamics of MRI consistent with structural perturbation in the acute phase and neurobiochemical changes (P-Tau and GFAP induction) in the subacute and chronic phase as well as development of chronic neurobehavioral changes, which resemble those observed in mTBI patients.
Highlights
Single and repeated sports-related mild traumatic brain injury, referred to as concussion, can result in chronic post-concussive syndrome (PCS), neuropsychological and cognitive deficits, or chronic traumatic encephalopathy (CTE)
We sought to address this through the use of a single (s) and repetitive (r) mild closed head injury (mCHI) mouse model with the purpose of making it as clinically relevant as possible, in which no remarkable tissue disorganization, or subdural or interstitial hemorrhage in cortex, hippocampus, cerebellum and brain stem was found by histological examination
The results indicate that repetitive mild closed head injury (rmCHI) showed an initial lowering of apparent diffusion coefficient (ADC) values (0.4– 0.6 × 10−3 mm2/s) below that shown by the other two conditions
Summary
Single and repeated sports-related mild traumatic brain injury (mTBI), referred to as concussion, can result in chronic post-concussive syndrome (PCS), neuropsychological and cognitive deficits, or chronic traumatic encephalopathy (CTE). Gross pathological changes of rmTBI have been reported, including long-term persistent brain volume loss, as well as histological changes, including Tau-immunoreactive neurofibrillary tangles, the hallmark of CTE, in the brain found in athletes (and others) with a history of repetitive brain trauma[4] These changes in the brain can begin months, years, or even decades after the last concussion or end of active athletic involvement. In CHI models, the injury is induced through the intact skull by direct impact (e.g. dropping a weight on the intact skull or striking the intact skull with a piston), non-impact (e.g. blast) or inertial loading (by rapid rotation of head in the sagittal, coronal or oblique planes)[6] These models have demonstrated some degree of behavioral deficits and some histological changes, no systematic study was reported to establish the dynamic correlation between brain morphology or biochemical changes and the development of functional deficits. The levels of T-Tau and P-Tau in serum were dynamically detected using a novel ultrasensitive assay as we previous reported[7]
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