Mechanistic role of vascular dysfunction in TBI-mediated cognitive dysfunction

血管功能障碍在 TBI 介导的认知功能障碍中的机制作用

• 批准号: 10610367
• 负责人: JONATHAN LIFSHITZ
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610367
• 关键词: Acute; Aerobic Exercise; Affect; Afghanistan; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Attenuated; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Carbon Dioxide; Cardiac; Cardiovascular system; Cerebrovascular Disorders; Cerebrum; Chronic; Coronary artery; Data; Dementia; Development; Diffuse; Disease; Echocardiography; Endothelium; Exposure to; Genetic Predisposition to Disease; Goals; Histopathology; Homeostasis; Hypertension; Impaired cognition; Impairment; Inbred SHR Rats; Injury; Iraq; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Neurons; Organ; Outcome; Outcome Measure; Pathologic; Pathway interactions; Perfusion; Physiological; Rattus; Regulation; Reporting; Rest; Role; Soldier; Sprague-Dawley Rats; Structure; Testing; Traumatic Brain Injury; Vascular Dementia; Vascular Diseases; Vascular blood supply; Veterans; Work; Youth; base; cardiovascular effects; cardiovascular risk factor; cerebral artery; cerebrovascular; chronic traumatic encephalopathy; cognitive function; disorder risk; early onset; exercise training; fluid percussion injury; hypertensive; improved; in vivo; insight; mild traumatic brain injury; military veteran; mortality; neurovascular; neurovascular coupling; normotensive; novel; object recognition; persistent symptom; pressure; prevent; rehabilitation strategy; response; service member; sham surgery; stressor; synergism

Abstract Mild traumatic brain injury (mTBI) is a major cause of mortality and morbidity especially among service- members and veterans. mTBI is linked to long-term development of dementia conditions such as Alzheimer's disease and related disorders, but the exact pathophysiologic mechanisms remain poorly-defined. Vascular disease and cardiovascular risk factors are strongly linked with dementia. We propose to test the hypothesis that long-term mTBI-induced cognitive dysfunction is due to, at least in part, persistent cerebrovascular dysfunction. We will also test the hypothesis that early onset mTBI and later development of hypertension will have synergistic effects on cerebrovascular and cognitive dysfunction compared to hypertension or mTBI alone. In Aim 1, we will measure the temporal changes (subacute and chronic) in cerebrovascular and cognitive function in a rat model of mTBI while establishing the mechanistic role of cerebrovascular dysfunction in mTBI-induce cognitive impairment. Following midline fluid percussion injury or sham surgery in Sprague-Dawley rats, we will measure subacute (8 weeks) and chronic (12 months) cerebrovascular function (in-vivo by brain contrast MRI and ex-vivo by measuring cerebral artery vasoreactivity) and cognitive function and establish their relationship. We will also determine if early (starting at 2 weeks post-injury) or late (starting at 10 months post-injury) aerobic exercise training will improve cerebrovascular function leading to improvement in cognitive function. We will identify molecular mechanisms by which cerebrovascular function modulates cognitive function in mTBI by investigating the role of endothelial function in the regulation of brain-derived neurotrophic factor. In Aim 2, we will probe the interaction between early onset mTBI and later development of hypertension in chronic cerebrovascular and cognitive dysfunction. Here we will use rats genetically prone to develop hypertension (spontaneously hypertensive rats) to determine the effects of early onset mTBI in modulating chronic cerebrovascular and cognitive function. We will also have an exploratory aim to look at effects of mTBI in Sprague-Dawley and hypertensive rats on cardiac structure and function and coronary artery function. The proposal could provide critical and novel insights on the mechanisms underlying vascular dysfunction in TBI and their role in the development of cognitive dysfunction.

抽象的 轻度创伤性脑损伤（mTBI）是死亡和发病的主要原因，尤其是在服役人员中 会员和退伍军人。 mTBI 与阿尔茨海默病等痴呆症的长期发展有关 疾病和相关疾病，但确切的病理生理机制仍不清楚。血管 疾病和心血管危险因素与痴呆症密切相关。我们建议检验以下假设： 长期 mTBI 引起的认知功能障碍至少部分是由于持续性脑血管功能障碍所致。 我们还将检验以下假设：早期发生的 mTBI 和后期发生的高血压具有协同作用 与单独使用高血压或 mTBI 相比，对脑血管和认知功能障碍的影响。在目标 1 中，我们将 测量大鼠模型中脑血管和认知功能的时间变化（亚急性和慢性） mTBI 的影响，同时建立脑血管功能障碍在 mTBI 诱发认知中的机制作用 损害。对 Sprague-Dawley 大鼠进行中线液体冲击损伤或假手术后，我们将测量 亚急性（8 周）和慢性（12 个月）脑血管功能（体内脑对比 MRI 和离体 通过测量脑动脉血管反应性）和认知功能并建立它们的关系。我们也会 确定是早期（从受伤后 2 周开始）还是晚期（从受伤后 10 个月开始）进行有氧运动 训练将改善脑血管功能，从而改善认知功能。我们将确定 通过研究脑血管功能调节 mTBI 认知功能的分子机制 内皮功能在脑源性神经营养因子调节中的作用。在目标 2 中，我们将探讨 慢性脑血管病患者早发型 mTBI 与后期高血压发展之间的相互作用 认知功能障碍。在这里，我们将使用遗传上容易患高血压（自发性 高血压大鼠）以确定早发型 mTBI 在调节慢性脑血管和 认知功能。我们还将探索性目标是观察 mTBI 对 Sprague-Dawley 和 高血压大鼠对心脏结构和功能以及冠状动脉功能的影响。该提案可以提供 关于 TBI 血管功能障碍的机制及其在 认知功能障碍的发展。