Chronic effects of blast injury: analyses of Alzheimer related pathology

爆炸伤的慢性影响：阿尔茨海默病相关病理学分析

• 批准号: 8591118
• 负责人: Matthew M. Harper
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591118
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Amyloid; Area; Astrocytes; Attenuated; Axon; Behavioral; Biochemical; Biological Markers; Blast Cell; Blast Injuries; Blindness; Brain; Brain Concussion; Brain Injuries; Brain-Derived Neurotrophic Factor; Cell Count; Cerebrospinal Fluid; Cholesterol; Chronic; Cities; Clinical; Clinical Treatment; Coenzyme A; Cognitive; Cognitive deficits; Collection; Conflict (Psychology); Development; Diagnostic; Diagnostic or Prognostic Tests; Diffuse; Diffusion Magnetic Resonance Imaging; Encephalitis; Enzymes; Experimental Models; FDA approved; Future; Goals; Health; Healthcare Systems; Image; Imaging Techniques; Injury; Intervention; Investigation; Iowa; Laboratories; Life; Long-Term Effects; Measurement; Medical Research; Memory; Microglia; Military Personnel; Modeling; Motor; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurological status; Onset of illness; Outcome; Oxidoreductase; Pathology; Pathway interactions; Performance; Peripheral; Pharmaceutical Preparations; Phase; Plasma; Population; Prevention; Quality of life; Recovery; Recovery of Function; Rehabilitation therapy; Retinal; Risk; Sampling; Sensory; Severities; Simvastatin; Site; Staging; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Transgenic Organisms; Translating; Translations; Traumatic Brain Injury; Treatment Protocols; Veterans; Vision; Visual; Wild Type Mouse; age related; cognitive function; density; early onset; emerging adult; functional disability; hypercholesterolemia; immunoreactivity; improved; in vivo; inhibitor/antagonist; injured; mouse model; nervous system disorder; neuropathology; neurotrophic factor; novel; prevent; prognostic; public health relevance; research clinical testing; tau Proteins; tau aggregation; tau phosphorylation; tau-1; visual memory; visual motor

DESCRIPTION (provided by applicant): Blast-induced traumatic brain injury (blast TBI) is considered the signature injury of current military conflicts. Veterans exposed to blast TBI suffer concussions and neurological deficits, and are at increased risk for developing chronic neurological disorders including chronic traumatic encephalopathy and Alzheimer's disease (AD). Rehabilitation of blast-injured Veterans and prevention of chronic neuropathology is an area of medical research in need of intensive investigation because long-term effects of blast TBI are currently unknown and there are no treatments for improving long-term functional recovery after blast TBI. Our preliminary studies demonstrate that experimental blast TBI in mice impairs cognitive, vestibulomotor and sensory (visual) function, and these deficits are accompanied by changes in amyloid-¿ (A¿) and tau proteins which comprise the hallmark neuropathology of AD. We propose to use the transgenic APPswe,PSEN1dE9 mouse model, which recapitulates several aspects of age- and injury-induced A¿ pathology, to test the hypothesis that repetitive mild blast injury accelerates the onset and/or aggravates the onset and progression of A¿ accumulation and induces excessive tau phosphorylation (p-tau), exacerbating synaptic loss and functional impairment. These changes will be examined in relation to performance on spatial memory and vestibulomotor tasks during the chronic rehabilitation period after blast TBI. We also hypothesize that blast injury impairs retinal function, and propose to evaluate if such deficit could serve as an early diagnostic indicator of blast-induced damage to the brain. Additional biomarker analyses of diagnostic and potential prognostic values will include diffusion tensor imaging (DTI) and measurements of A¿ and p-tau concentration in cerebrospinal fluid (csf) and plasma. These studies will provide the framework for another major goal of this proposal, which is to test the therapeutic value of simvastatin, an FDA- approved drug currently in use for treatment of hypercholesterolemia and markedly effective in improving outcome in several models of brain injury. We will first characterize A¿ and p-tau pathology and functional (visual, vestibulomotor, cognitive) deficits during the chronic recovery phase (3, 6, 9, and 12 months) after single or repetitive mild (20 psi) grade blast exposure in the APPswe,PSEN1dE9 and C57Bl/6 wild type mice (Aim 1). The second major goal is to assess whether acute, transient (3 month) or continuous chronic (duration of survival period) daily simvastatin administration will prevent early onset of, and/or reduce, A¿ and p-tau pathology and improve functional recovery after blast injury in APPswe,PSEN1dE9 mice compared to C57Bl/6 wild type mice evaluated 3, 6, 9, and 12 months after injury (Aim 2). Thirdly, we will determine how chronic sequelae of blast injury, with or without simvastatin intervention, correlate with axonal pathology and changes in brain connectivity (by DTI) and levels of A¿ and p-tau in csf and plasma, thus providing valuable diagnostic and/or prognostic tests to be used together with the assessments of visual and memory function in blast TBI (Aim 3). Longitudinal assessments of vestibulomotor and visual function will be performed at 3, 6, 9, and 12 months after blast injury. Cognitive function will be tested at each time point prior to DTI imaging, csf and plasma collection, and sacrifice, followed by Ab, p-tau, APP, BDNF and other neurotrophin molecule analyses, quantification of plaque load, cell number, synapse density, and microglia/astrocyte reactivity. Collectively, these studies will determine whether blast TBI can accelerate and exacerbated chronic neurodegenerative changes typical of AD and CTE, and will determine the potential value of the proposed functional diagnostic and therapy approaches for their translation into clinical evaluation and treatment of blast-injured Veterans.

描述（由申请人提供）： 爆炸性脑损伤（blast induced traumatic brain injury，简称BBI）被认为是当前军事冲突的标志性损伤。暴露于爆炸性TBI的退伍军人遭受脑震荡和神经缺陷，并且患慢性神经系统疾病的风险增加，包括慢性创伤性脑病和阿尔茨海默病（AD）。爆炸伤退伍军人的康复和慢性神经病理学的预防是一个需要深入研究的医学研究领域，因为爆炸TBI的长期影响目前尚不清楚，也没有改善爆炸TBI后长期功能恢复的治疗方法。我们的初步研究表明，小鼠实验性冲击波TBI损害认知，前庭和感觉（视觉）功能，这些缺陷伴随着淀粉样蛋白（A）和tau蛋白的变化，这些蛋白构成了AD的标志性神经病理学。我们建议使用转基因APPswe，PSEN 1dE 9小鼠模型，该模型概括了年龄和损伤诱导的A？病理学的几个方面，以测试以下假设：重复性轻度冲击伤加速A？积累的发作和/或加速A？积累的发作和进展，并诱导过度的tau磷酸化（p-tau），加剧突触丢失和功能障碍。这些变化将在冲击波TBI后的慢性康复期间与空间记忆和前庭任务的表现相关。我们还假设爆炸伤损害视网膜功能，并建议评估这种缺陷是否可以作为爆炸引起的脑损伤的早期诊断指标。诊断和潜在预后价值的其他生物标志物分析将包括扩散张量成像（DTI）和脑脊液（csf）和血浆中A？和p-tau浓度的测量。这些研究将为该提案的另一个主要目标提供框架，该目标是测试辛伐他汀的治疗价值，辛伐他汀是FDA批准的药物，目前用于治疗高胆固醇血症，并且在改善几种脑损伤模型的结果方面显着有效。我们将首先描述A？以及在APPswe、PSEN 1dE 9和C57 B1/6野生型小鼠中在单次或重复轻度（20 psi）等级冲击波暴露后慢性恢复期（3、6、9和12个月）期间的p-tau病理学和功能（视觉、前庭、认知）缺陷（Aim 1）。第二个主要目标是评估急性、短暂（3个月）或连续慢性（生存期持续时间）每日辛伐他汀给药是否会预防APPswe、PSEN 1dE 9小鼠冲击伤后A？和p-tau病理的早期发作和/或减少，并改善损伤后3、6、9和12个月评估的C57 Bl/6野生型小鼠的功能恢复（目标2）。第三，我们将确定冲击伤的慢性后遗症，有或没有辛伐他汀干预，如何与轴突病理学和脑连接的变化（通过DTI）以及CSF和血浆中A？和p-tau水平相关，从而提供有价值的诊断和/或预后测试，与冲击伤TBI的视觉和记忆功能评估一起使用（目的3）。在冲击伤后3、6、9和12个月进行前庭和视觉功能的纵向评估。认知功能将是 在DTI成像、CSF和血浆收集和处死之前的每个时间点进行测试，然后进行Ab、p-tau、APP、BDNF和其他神经营养因子分子分析，定量斑块负荷、细胞数量、突触密度和小胶质细胞/星形胶质细胞反应性。总的来说，这些研究 将确定爆炸性TBI是否会加速和加剧AD和CTE典型的慢性神经退行性变化，并将确定拟议的功能诊断和治疗方法的潜在价值，将其转化为爆炸伤退伍军人的临床评估和治疗。