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: 9260704
• 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/9260704
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Area; Astrocytes; Attenuated; Autopsy; 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 tests; Diffuse; Diffusion Magnetic Resonance Imaging; Encephalitis; Enzymes; Experimental Models; FDA approved; Future; Goals; Health; Healthcare Systems; Image; Imaging Techniques; Impaired cognition; Impairment; Injury; Intervention; Investigation; Iowa; Laboratories; Life; Long-Term Effects; Measurement; Medical Research; Microglia; Military Personnel; Modeling; Motor; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neurological status; Onset of illness; Oxidoreductase; Pathologic; 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; 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; axon injury; chronic traumatic encephalopathy; cognitive function; cognitive recovery; density; early onset; emerging adult; functional disability; hypercholesterolemia; imaging biomarker; immunoreactivity; improved; improved outcome; in vivo; inhibitor/antagonist; injured; motor recovery; mouse model; nervous system disorder; neuropathology; neurotrophic factor; neurotropin; novel therapeutics; prevent; prognostic assays; prognostic value; public health relevance; research clinical testing; spatial memory; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutic evaluation; visual memory

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）： 爆炸引起的创伤性脑损伤（爆炸 TBI）被认为是当前军事冲突的标志性损伤。遭受爆炸性脑外伤的退伍军人会遭受脑震荡和神经功能缺损，并且患慢性神经系统疾病（包括慢性创伤性脑病和阿尔茨海默病（AD））的风险增加。爆炸受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，因为爆炸性创伤性脑损伤的长期影响目前尚不清楚，并且没有改善爆炸性创伤性脑损伤后长期功能恢复的治疗方法。我们的初步研究表明，小鼠实验性脑损伤会损害认知、前庭运动和感觉（视觉）功能，并且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,PSEN1dE9 小鼠模型（该模型概括了年龄和损伤引起的 A¿ 病理学的几个方面）来检验以下假设：重复性轻度爆炸损伤会加速 A¿ 积累的发生和/或加剧 A¿ 积累的发生和进展，并诱导过度的 tau 磷酸化 (p-tau)，从而加剧突触损失和功能损伤。这些变化将在冲击波创伤性脑损伤后的慢性康复期间与空间记忆和前庭运动任务的表现相关进行检查。我们还假设爆炸损伤会损害视网膜功能，并建议评估这种缺陷是否可以作为爆炸引起的大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弥散张量成像 (DTI) 以及脑脊液 (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，即测试辛伐他汀的治疗价值，辛伐他汀是一种 FDA 批准的药物，目前用于治疗高胆固醇血症，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 APPswe、PSEN1dE9 和 C57Bl/6 野生型小鼠在单次或重复轻度 (20 psi) 级爆炸暴露后慢性恢复阶段（3、6、9 和 12 个月）期间的 A¿ 和 p-tau 病理学和功能（视觉、前庭运动、认知）缺陷（目标 1）。第二个主要目标是评估 APPswe、PSEN1dE9 小鼠与损伤后 3、6、9 和 12 个月评估的 C57Bl/6 野生型小鼠相比，每日给予辛伐他汀是否会预防急性、短暂（3 个月）或持续慢性（生存期持续时间）早期发作和/或减少 A¿ 和 p-tau 病理学并改善爆炸损伤后的功能恢复（目标 2）。第三，我们将确定冲击波损伤的慢性后遗症，无论有或没有辛伐他汀干预，如何与轴突病理学和脑连通性变化（通过 DTI）以及脑脊液和血浆中 A¿ 和 p-tau 水平相关，从而提供有价值的诊断和/或预后测试，与冲击波 TBI 中视觉和记忆功能的评估一起使用（目标 3）。前庭运动和视觉功能的纵向评估将在爆炸损伤后 3、6、9 和 12 个月进行。认知功能将是 在 DTI 成像、脑脊液和血浆收集以及处死之前的每个时间点进行测试，然后进行 Ab、p-tau、APP、BDNF 和其他神经营养素分子分析，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的量化。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，并将确定所提出的功能诊断和治疗方法转化为爆炸伤退伍军人的临床评估和治疗的潜在价值。