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（BLAST TBI）被认为是当前军事冲突的签名伤害。暴露于BLAST TBI患者咨询和神经系统缺陷的退伍军人，并且患有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氏病（AD）。对爆炸造成的退伍军人的康复和预防慢性神经病理学是需要大量投资的医学研究领域，因为爆炸TBI的长期影响目前尚不清楚，并且在BLAST TBI后没有改善长期功能恢复的治疗方法。我们的初步研究表明，小鼠的实验性爆炸TBI会影响认知，前庭运动和感觉（视觉）功能，这些缺陷是通过淀粉样蛋白（A a。）和tau蛋白的变化来实现的，这些蛋白包含AD的标志性神经病理学。 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 induced excessive tau phosphorylation (p-tau), exacerbating synaptic loss and functional impairment.这些变化将在爆炸TBI后的慢性康复期内与在空间记忆和前庭任务上的性能有关。我们还假设爆炸损伤会损害残留功能，并提议评估这种缺陷是否可以作为爆炸引起的大脑损害的早期诊断指标。对诊断和潜在预后值的其他生物标志物分析将包括扩散张量成像（DTI）以及脑脊液（CSF）和血浆中A检测和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FDA批准的药物目前用于治疗高胆固醇血症的药物，并在几种脑损伤模型中明显有效地改善结果。我们首先将在单次或重复的轻度（20 psi）级爆炸后，在慢性恢复阶段（3、6、9和12个月）在AppSwe，PSEN1DE9和C57BL/6野生型MICE（AIL类型MICE 1）之后，我们将在慢性恢复阶段（3、6、9和12个月）中表征A？和P-TAU病理学和功能（视觉，前庭，认知）缺陷。第二个主要目标是评估急性，瞬态（3个月）或每日二伐他汀的持续慢性（生存期）是否会防止早期发作和/或减少和/或减少，A a a和P-TAU病理学，并改善AppSwe，PSEN1DE9小鼠的爆炸损伤后的功能恢复，与C57BL/6野生型小鼠相比，与3、6、6、9、9、9、9、9、9、9、9、9、9、9、9、9、9、9、9，均为12个月，2个月。第三，我们将确定在CSF和Plasma中A轴突病理和大脑连接性的变化（通过DTI）以及CSF和Plasma中A和P-TAU的水平与大脑连接性的变化相关的慢性后遗症如何与CSF和PLASMA中的A和P-TAU水平相关，从而提供了有价值的诊断和/或预后测试，可与视觉和记忆的评估相关。前庭运动和视觉功能的纵向评估将在爆炸损伤后的3、6、9和12个月进行。认知功能将是 在进行DTI成像，CSF和血浆收集和牺牲之前的每个时间点进行测试，然后是AB，P-TAU，APP，BDNF和其他神经营养蛋白分子分析，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BLAST TBI是否可以加速和加剧AD和CTE的典型慢性神经退行性变化，并将确定提出的功能性诊断和治疗方法的潜在价值，以转化为临床评估和治疗爆炸性退伍军人的临床评估。