Janice Stewart

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 Alzheimers 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 Alzheimers 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.

Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes

Concussion or mild traumatic brain injury (mTBI) represents the most common type of brain injury. However, in contrast with moderate or severe injury, there are currently few non-invasive experimental studies that investigate the cumulative effects of repetitive mTBI using rodent models. Here we describe and compare the behavioral and pathological consequences in a mouse model of single (s-mTBI) or repetitive injury (r-mTBI, five injuries given at 48 h intervals) administered by an electromagnetic controlled impactor. Our results reveal that a single mTBI is associated with transient motor and cognitive deficits as demonstrated by rotarod and the Barnes Maze respectively, whereas r-mTBI results in more significant deficits in both paradigms. Histology revealed no overt cell loss in the hippocampus, although a reactive gliosis did emerge in hippocampal sector CA1 and in the deeper cortical layers beneath the injury site in repetitively injured animals, where evidence of focal injury also was observed in the brainstem and cerebellum. Axonal injury, manifest as amyloid precursor protein immunoreactive axonal profiles, was present in the corpus callosum of both injury groups, though more evident in the r-mTBI animals. Our data demonstrate that this mouse model of mTBI is reproducible, simple, and noninvasive, with behavioral impairment after a single injury and increasing deficits after multiple injuries accompanied by increased focal and diffuse pathology. As such, this model may serve as a suitable platform with which to explore repetitive mTBI relevant to human brain injury.

4-Hydroxynonenal Immunoreactivity is Increased in Human Hippocampus After Global Ischemia

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimers disease (AD) and cerebral ischemia. 4‐Hydroxynonenal (4‐HNE) is a toxic byproduct of lipid peroxidation, and immunoreactivity to 4‐HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4‐HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) ε4 allele influenced the extent of 4‐HNE immunoreactivity. 4‐HNE immunoreactivity was assessed semi‐quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42days). There was minimal cellular 4‐HNE immunoreactivity in the control group. However, compared to controls, 4‐HNE immunoreactivity was significantly increased in neurons (p<0.0002) and glia (p<0.0001) in the hippocampal formation after global ischemia. Possession of an APOEε4 allele did not influence the extent of neuronal or glial 4‐HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4‐HNE immunoreactivity with survival period after global ischemia (r2= 0.0801; p<0.036) and a significant positive correlation between the extent of glial 4‐HNE immunoreactivity and survival after global ischemia (r2= 0.2958; p<0.0001). The data indicate a marked increase in neuronal and glial 4‐HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4‐HNE immunoreactivity.

Influence of Apolipoprotein E Genotype on Neuronal Damage and ApoE Immunoreactivity in Human Hippocampus Following Global Ischemia

Apolipoprotein E (apoE) influences the response to and outcome from brain injury possibly through alterations in neuronal repair mechanisms. This study aimed to determine alterations in neuronal and glial apoE after brain injury in patients and sought to determine whether possession of an apoE-epsilon4 allele influences the degree of apoE immunoreactivity or the degree of neuronal damage following brain injury. ApoE immunoreactivity and neuronal damage were semiquantitatively assessed in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia and subsequently died (n = 58, survival ranged from 1 hour to 3 months). There was a significant degree of neuronal damage in all hippocampal sectors and in the neocortex of the global ischemia group compared with controls (p < 0.0001). Glial apoE immunoreactivity was significantly increased in hippocampal sectors (CA1, CA2, CA3/CA4, dentate fascia) in the global ischemia group compared with controls (p < 0.01). Neuronal apoE immunoreactivity was significantly increased in all hippocampal sectors (CA1, CA2, CA3/CA4, dentate fascia) and in the neocortex of the global ischemia group compared with controls (p < 0.0001). There was a significant and positive association between the degree of neuronal apoE immunoreactivity and the degree of neuronal damage in the global ischemia cases (r2 = 0.691, p < 0.001) and there was not an association in the control group. Possession of an apoE-epsilon4 allele did not influence the degree of neuronal or glial apoE immunoreactivity or the degree of neuronal damage in the global ischemia cases or the controls. The data indicate apoE is markedly increased in neurons and glia following brain injury. In this study, apoE genotype did not appear to influence neuronal damage, glial apoE or intraneuronal apoE following injury

Association of APOE e4 and cerebrovascular pathology in traumatic brain injury

Background: Previous studies have found the e4 allele of the apolipoprotein E gene (APOE e4) is associated with an unfavourable outcome after head injury, but this has not been related to specific pathological features. Objectives: This study tested the postulate that head injured patients with APOE e4, amounting to approximately a third of the population, are selectively predisposed to one or more of the different pathological features that constitute the response to traumatic brain injury (TBI), and that this underlies the association of APOE e4 with poor clinical outcome. Methods: Included in the study were 239 fatal cases of TBI (1987–1999) for which APOE genotypes were determined from archival tissue. For each case, specific pathological features of trauma were recorded by researchers blinded to the APOE e4 status. Of the 239 cases examined, 83 (35%) were APOE e4 carriers and 156 (65%) were non-carriers. Results: Possession of APOE e4 was associated with a greater incidence of moderate or severe contusions (42% v 30% for carriers versus e4 non-carriers; p =  0.05) and there was a trend towards a greater incidence of severe ischaemic brain damage (54% v 42%; p =  0.08). Significant differences were not noted between the other pathological features examined. Conclusions: Possession of APOE e4 is associated with a greater incidence of moderate/severe contusional injury and severe ischaemic brain damage in fatal cases of TBI. This may be relevant to the relatively poor outcome from traumatic brain injury in patients with APOE e4 identified in clinical studies.

Cytokine Gene Polymorphisms and Outcome after Traumatic Brain Injury

Clinical outcome after traumatic brain injury (TBI) is variable and cannot easily be predicted. There is increasing evidence to suggest that there may be genetic influences on outcome. Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6 months after head injury. A prospectively identified cohort of patients (n=1096, age range 0-93 years, mean age 37) was used. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome (TNFA -238 and -308, IL6 -174, -572 and -597, IL1A -889, IL1B -31, -511 and +3953, and TGFB -509 and -800), TNFA -308 was identified as having a likely association. The TNFA -308 SNP was further evaluated, and a significant association was identified, with 39% of allele 2 carriers having an unfavorable outcome compared with 31% of non-carriers (adjusted odds ratio 1.67, confidence interval 1.19-2.35, p=0.003). These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that tumor necrosis factor alpha plays an important role in this process.

Association between APOE genotype, neuropathology and dementia in the older population of England and Wales.

J. A. R. Nicoll, G. M. Savva, J. Stewart, F. E. Matthews, C. Brayne and P. Ince (2011) Neuropathology and Applied Neurobiology37, 285–294
Association between APOE genotype, neuropathology and dementia in the older population of England and Wales

Amyloid β-protein length and cerebral amyloid angiopathy-related haemorrhage

The relationship between amyloid β-protein (Aβ) length and the apolipoprotein E (APOE) ε2 allele, which is over-represented in cerebral amyloid angiopathy-related haemorrhage (CAAH), has not previously been examined. Of 57 CAA patients studied, 37 had CAAH. All patients, particularly those with CAAH had more blood vessels immunoreactive for Aβ40 than Aβ42 in both the leptomeninges and cerebral cortex. CAAH patients had more Aβ40-immunoreactive blood vessels in the leptomeninges (p < 0.001) and cortex (p = 0.027) than had non-haemorrhage patients. Cortical blood vessels, the usual source of haemorrhage in CAAH, were more frequently Aβ42 immunoreactive in APOE ε2 carriers than in non-ε2 carriers (p = 0.022). The APOE ε2 allele may predispose to CAAH by increasing the seeding of cortical blood vessels by Aβ42.

Involvement of apolipoprotein E in herpes simplex encephalitis

APOE polymorphism may influence risk for cold sores and, by interacting with latent HSV-1, risk for Alzheimers disease (AD). APOE genotype also influences outcome after brain injury. We sought to determine whether APOE genotype influences risk for herpes simplex encephalitis (HSE), whether apoE is involved in the response to HSE and if APOE genotype influences outcome from HSE. There was increased immunoreactivity of neurons, neuropil and glia for apoE areas of brain damaged by HSE. APOE genotypes for cases of HSE (n = 57) were similar to those of controls (n = 41). APOE genotypes for survivors of HSE were similar to those of patients who died. We conclude that apoE is involved in the response to damage associated with HSE, as in other forms of brain injury. However, APOE genotype does not appear to influence either the risk of developing HSE or subsequent mortality.

A Neprilysin Polymorphism and Amyloid-β Plaques Following Traumatic Brain Injury

Traumatic brain injury (TBI) induces the rapid formation of Alzheimers 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.