Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat Rev Neurosci

University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
Nature Reviews Neuroscience (Impact Factor: 31.38). 03/2010; 11(5):361-70. DOI: 10.1038/nrn2808
Source: PubMed

ABSTRACT Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.

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Available from: William Stewart, Sep 15, 2014
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    • "Characteristic features of AD are the formation of β-amyloid (Aβ) plaques, neurofi brillary tangles and the loss of connections between neurons. AD and TBI share several common gene expression changes such as amyloid precursor proteins (APP), BACE1, ApoE4 and tau (Johnson et al., 2010; Liliang et al., 2010a,b; Sivanandam and Thakur, 2012). Post mortem analyses of severe TBI patients showed Aβ deposits in the cortical area of the brain in about 30% of patients (Roberts et al., 1994). "
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    • "Diffuse injuries include hypoxia/ischemia, vascular damage, and diffuse macro-/ microstructural axonal injury. Numerous epidemiologic studies have linked TBI to AD (reviewed in [6] [7] [8] [9] [10] [11] [12]). A history of TBI may be associated with earlier onset of AD [1,6,7,13–16] and the apolipoprotein E ε4 (APOE ε4) allele may worsen outcome [13,17–28]. "
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    ABSTRACT: Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans.
    Alzheimer's and Dementia 06/2014; 10(3):S226–S235. DOI:10.1016/j.jalz.2014.04.005 · 17.47 Impact Factor
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    • "After a traumatic brain injury, there is an acute phase of calcium dyshomeostasis due to cellular responses to injury which includes glutamatergic excitotoxicity and lasts minutes to hours. Subsequently, there is often a sustained pattern of calcium dysregulation that includes ER mechanisms and can last days to weeks, and is associated with amyloid accumulation, tau pathology, cell death, and cognitive deficits (Deshpande et al., 2008; Johnson et al., 2010; Shively et al., 2012; Weber, 2004, 2012). This pattern of degenerative pathology and memory impairment is not dissimilar to that observed in clinical AD and in AD mouse models, thus serving as a potential common factor driving the increased incidence of aggressive dementia in traumatic brain injury patients. "
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    ABSTRACT: Calcium ions are versatile and universal biological signaling factors that regulate numerous cellular processes ranging from cell fertilization, to neuronal plasticity that underlies learning and memory, to cell death. For these functions to be properly executed, calcium signaling requires precise regulation, and failure of this regulation may tip the scales from a signal for life to a signal for death. Disruptions in calcium channel function can generate complex multi-system disorders collectively referred to as "calciumopathies" that can target essentially any cell type or organ. In this review, we focus on the multifaceted involvement of calcium signaling in the pathophysiology of Alzheimer's disease, and summarize the various therapeutic options currently available to combat this disease. Detailing the series of disappointing AD clinical trial results on cognitive outcomes, we emphasize the urgency to design alternative therapeutic strategies if synaptic and memory functions are to be preserved. One such approach is to target early calcium channelopathies centrally linked to AD pathogenesis.
    European journal of pharmacology 12/2013; DOI:10.1016/j.ejphar.2013.11.012 · 2.68 Impact Factor
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