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Progressive neuopathological changes following traumatic brain injury

Johnson, Victoria E. (2012) Progressive neuopathological changes following traumatic brain injury. PhD thesis, University of Glasgow.

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Abstract

Whilst the acute effects of traumatic brain injury (TBI) may be devastating, growing evidence suggests TBI may initiate long-term neurodegenerative processes. Indeed, an epidemiological association between TBI and Alzheimer’s disease (AD) has been demonstrated. Here the link between TBI and chronic neurodegeneration is explored by examining associated pathologies in material from patients surviving TBI for varying intervals. Furthermore, the Aβ clearing enzyme, neprilysin, has emerged as important with regards to Aβ dynamics in AD and thus may be relevant to Aβ-plaque formation in TBI. Its influence on Aβ dynamics in TBI was explored in an animal model of TBI and in human TBI material. First, a potential association between acute-Aβ plaques post-TBI and a GT repeat polymorphism of the Aβ-degrading enzyme, neprilysin was investigated using DNA fragment sizing analysis (n=81). Results show there was an increased risk of Aβ plaques for patients with greater 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 Aβ plaques (p=0.003). These data suggest a genetically linked mechanism that determines which TBI patients will rapidly form Aβ plaques. The role of neprilysin in TBI was further examined using immunohistochemistry (IHC) to evaluate plaque formation in neprilysin knock-out mice at 2h, 48h and 4mo following a single controlled cortical impact in mice. Young (2mo) and older (8mo) mice were examined at each time point and compared to age-matched injured and uninjured wild-type mice (n=4 for all groups). No plaques were observed at any time point or in age group indicating that neprilysin deficiency alone is insufficient to recapitulate the plaque pathology observed in humans using this model. Next, post-mortem brains from long-term survivors of just a single TBI (1 to 47 years survival; n=39) versus uninjured, age-matched controls (n=47) were examined for hallmark AD pathologies, neurofibrillary tangles (NFTs) and Aβ plaques using IHC and thioflavin-S staining. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one third of TBI cases. Moreover, thioflavin-S staining revealed that while plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases, displayed predominantly thioflavin-S positive plaques or a mixed positive / diffuse pattern. These data indicate that TBI may induce or accelerate the presence of neurodegeneration-associated pathologies many years following just a single injury. To explore potential mechanisms driving plaque formation post-TBI, IHC was used to examine amyloid-β’s precursor, APP in TBI cases with acute survival (10h to 1 week; n=20), moderate survival (1 week to 1 year; n=17) and long-term survival (>1 year; n=33), versus uninjured controls (n=47). Following TBI, increased somatic APP immunoreactivity (IR) was observed in all TBI cases (n=70; 100%) versus (n=47; 70%) of controls (Chi Sq; p=0.00001). Moreover, increased APP IR was present in all survival intervals examined, (10h to 10 days, p=0.001; 10 days to 1 year, p=0.0001; > 1 year; p=0.001; all Chi Sq) versus controls, and an increased extent / distribution of pathology was demonstrated in the TBI group regardless of survival time. Interestingly, APP IR was not associated with the presence of plaques suggesting increased APP alone is insufficient to drive post-traumatic plaque formation. The Tar-DNA binding protein, TDP-43 has emerged as an important pathological feature in various chronic neurodegenerative diseases including frontotemporal lobe dementia, and more recently in dementia pugilistica caused by repetitive TBI. Here we examined survivors of a single TBI using IHC specific for TDP-43. TBI cases were acute (n=23: Survival <2 weeks) and long-term (n=39; 1-47 years survival) and were compared to uninjured controls (n=47). No association was found between single TBI and pathological TDP-43 inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, IR to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival, potentially as part of a normal stress-response. Finally, acute and chronic inflammation was evaluated in the corpus callosum following TBI, a region highly susceptibility to injury. IHC specific for CR3/43 and CD68 was analysed using digital quantitation to determine the percentage area of positive staining in acute TBI cases (survival < 14 days; n=18) and compared to age-matched controls (n=18). Long-term survivors of TBI (surv >1 year; n=23) were compared to controls (n=23) and a further subset of acute TBI cases (survival < 10 days; n=12) compared to age-matched long-term survivors of TBI (survival >1 year; n=12). While no quantitative difference was demonstrated between groups, 44% of long-term survival TBI cases displayed extensive amoeboid cells versus 0% of controls (Chi Sq; p=0.0004), indicating a percentage of TBI patients may develop a chronic inflammatory response in a time-frame consistent with epidemiological associations linking TBI with AD.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: traumatic brain injury, alzheimer's diseease, amyloid beta, tau, neurofibrillary tangles, amyloid precursor protein, tar-DNA binding protein, inflammation
Subjects: R Medicine > RB Pathology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Supervisor's Name: Stewart, Dr. William
Date of Award: 2012
Depositing User: Dr Victoria E. Johnson
Unique ID: glathesis:2012-3162
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 21 Feb 2012
Last Modified: 10 Dec 2012 14:04
URI: http://theses.gla.ac.uk/id/eprint/3162

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