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: 9701844
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9701844
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Area; Astrocytes; Attenuated; Autopsy; Axon; Behavioral; Biochemical; Biological Markers; 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; Exposure to; 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; Retina; 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; density; early onset; emerging adult; functional disability; hypercholesterolemia; imaging biomarker; immunoreactivity; improved; improved outcome; in vivo; inhibitor/antagonist; motor recovery; mouse model; nervous system disorder; neuropathology; neurotrophic factor; novel therapeutics; preservation; prevent; 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（爆炸性脑损伤）被认为是当前军事冲突的标志性损伤，遭受爆炸性脑损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）的风险增加。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，并且没有改善的治疗方法。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的变化。 (A¿) 和 tau 蛋白构成 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诱导的 A¿病理学，检验重复性轻度冲击波损伤加速发作和/或加剧 A¿ 的发作和进展的假设累积并诱导过度的 tau 磷酸化 (p-tau)，加剧突触损失和功能损伤，我们将在爆炸性 TBI 后的慢性康复期间检查这些变化与空间记忆和前庭运动任务的表现。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，对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 A¿ 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 批准的一种目前用于治疗高胆固醇血症的药物。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¿ APPswe、PSEN1dE9 和 C57Bl 中单次或重复轻度 (20 psi) 级爆炸暴露后慢性恢复期（3、6、9 和 12 个月）期间的 p-tau 病理学和功能（视觉、前庭运动、认知）缺陷/6 野生型小鼠（目标 1）第二个主要目标是每天评估是否为急性、短暂（3 个月）或持续慢性（生存期持续时间）。辛伐他汀给药将预防 A¿ 的早期发作和/或减少 A¿与 C57Bl/6 野生型小鼠相比，在损伤后 3、6、9 和 12 个月评估了 APPswe、PSEN1dE9 小鼠爆炸损伤后的 p-tau 病理学和功能恢复（目标 2）。爆炸损伤的发生率，无论有或没有辛伐他汀干预，都与轴突病理学和大脑连接的变化（通过 DTI）和 A¿ 水平相关脑脊液和血浆中的 p-tau 蛋白，从而提供有价值的诊断和/或预后测试，与急变 TBI 中的视觉和记忆功能评估一起使用（目标 3）将在 3 时进行前庭运动和视觉功能的纵向评估。爆炸损伤后 6、9 和 12 个月的认知功能将受到影响。 在 DTI 成像、脑脊液和血浆采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。

项目成果

Brain injury-induced dysfunction of the blood brain barrier as a risk for dementia.

脑损伤引起的血脑屏障功能障碍是痴呆的风险。

• 发表时间: 2020
• 影响因子: 5.3
• 作者: Abrahamson, Eric E;Ikonomovic, Milos D
• 通讯作者: Ikonomovic, Milos D

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice.

爆炸介导的创伤性脑损伤后，急性轴突变性导致小鼠认知、运动和视觉缺陷的发展。

• 发表时间: 2016
• 影响因子: 3.4
• 作者: Yin, Terry C;Voorhees, Jaymie R;Genova, Rachel M;Davis, Kevin C;Madison, Ashley M;Britt, Jeremiah K;Cintrón;McDaniel, Latisha;Harper, Matthew M;Pieper, Andrew A
• 通讯作者: Pieper, Andrew A

Development of a PET radioligand selective for cerebral amyloid angiopathy.

开发针对脑淀粉样血管病选择性 PET 放射性配体。

• DOI: 10.1016/j.nucmedbio.2020.05.001
• 发表时间: 2021-01
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Abrahamson EE;Stehouwer JS;Vazquez AL;Huang GF;Mason NS;Lopresti BJ;Klunk WE;Mathis CA;Ikonomovic MD
• 通讯作者: Ikonomovic MD