Inflammation and white matter degeneration persist for years after a single traumatic brain injury.

A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer's disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer's disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ≥3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.

Stereology of cerebral cortex after traumatic brain injury matched to the Glasgow outcome score.

Magnetic resonance imaging provides evidence for loss of both white and grey matter, in terms of tissue volume, from the cerebral hemispheres after traumatic brain injury. However, quantitative histopathological data are lacking. From the archive of the Department of Neuropathology at Glasgow, the cerebral cortex of 48 patients was investigated using stereology. Patients had survived 3 months after traumatic brain injury and were classified using the Glasgow Outcome Scale as follows: moderately disabled (n = 13), severely disabled (n = 12) and vegetative state (n = 12); and controls. Some patients from the archive were diagnosed with diffuse axonal injury post-mortem. Comparisons of changes in cortical neuron population across Glasgow Outcome Scale groups between diffuse axonal injury and non-diffuse axonal injury patients were undertaken using effect size analyses. The hypotheses tested were that (i) thinning of the cerebral cortex occurred after traumatic brain injury; (ii) changes in thickness of cortical layers in Brodmann areas 11, 10, 24a and 4 differed; and (iii) different changes occurred for neuronal number, their size and nearest neighbour index across Glasgow Outcome Scale groups. There was a greater loss of large pyramidal and large non-pyramidal neurons with a more severe score on the Glasgow Outcome Scale from all four cortical regions, with the greatest loss of neurons from the prefrontal cortex of patients with diffuse axonal injury. There were differences in the changes of number of medium and small pyramidal and non-pyramidal neurons between different cortical regions, and between patients with and without diffuse axonal injury. Generally, a decrease in the somatic diameter of pyramidal and non-pyramidal neurons was associated with a more severe clinical outcome. However, in the motor cortex a more severe Glasgow Outcome Scale was associated with an increased diameter of medium pyramidal neurons and small non-pyramidal cells. Pyramidal and non-pyramidal neurons did not follow a Poisson distribution within the neuropil of control patients. Pyramidal neurons were usually scattered while medium and small non-pyramidal neurons were clustered. An increased spacing between remaining neurons usually occurred across Glasgow Outcome Scale groups. It is concluded that loss of neurons resulted in reduced executive and integrative capability in patients after traumatic head injury.

A neprilysin polymorphism and amyloid-beta plaques after traumatic brain injury.

Traumatic brain injury (TBI) induces the rapid formation of Alzheimer's disease (AD)-like amyloid-beta (AB) plaques in about 30% of patients. However, the mechanisms behind this selective plaque formation are unclear. We investigated a potential association between amyloid deposition acutely after TBI and a genetic polymorphism of the AB-degrading enzyme, neprilysin (n = 81). We found that the length of the GT repeats in AB-accumulators was longer than in non-accumulators. Specifically, there was an increased risk of AB plaques for patients with more than 41 total repeats (p < 0.0001; OR: 10.1). In addition, the presence of 22 repeats in at least one allele was independently associated with plaque deposition (p = 0.03; OR: 5.2). In contrast, the presence of 20 GT repeats in one allele was independently associated with a reduced incidence of AB deposition (p = 0.003). These data suggest a genetically linked mechanism that determines which TBI patients will rapidly form AB plaques. Moreover, these findings provide a potential genetic screening test for individuals at high risk of TBI, such as participants in contact sports and military personnel.