Chronic neurodegenerative and neurophysiological sequela of closed-head TBI

闭合性头颅脑损伤的慢性神经退行性和神经生理学后遗症

• 批准号: 8398487
• 负责人: JOHN Eric DUDA
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398487
• 关键词: AD pathology; Acceleration; Acute; Affect; Afghanistan; Alzheimer like pathology; Alzheimer' s Disease; Amyloidosis; Animal Model; Animals; Automobile Driving; Blast Cell; Brain Pathology; Cerebral cortex; Chronic; Control Animal; Demyelinations; Diffuse; Diffuse Axonal Injury; Electrophysiology (science); Evaluation; Family suidae; Functional disorder; Head; Health; Hippocampus (Brain); Injury; Iraq; Lateral; Learning; Link; Liquid substance; Long-Term Effects; Measurement; Memory; Military Personnel; Modeling; Motor; Mus; Nerve Degeneration; Nervous System Physiology; Network-based; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Pathology; Percussion; Population; Problem Solving; Proteins; Research Personnel; Rodent; Role; Soldier; Sports; Structure-Activity Relationship; Synapses; System; Tauopathies; Techniques; Testing; Time; Transgenic Mice; Traumatic Brain Injury; Unconscious State; Veterans; War; Work; alpha synuclein; axonal degeneration; clinically relevant; early onset; mild traumatic brain injury; mouse model; neurobehavior; neurobehavioral; neurobehavioral test; neuroinflammation; neuropathology; neurophysiology; nigrostriatal system; public health relevance; relating to nervous system; synaptic function; synuclein, alpha (non A4 component of amyloid precursor) protein, human; therapeutic target; white matter

DESCRIPTION (provided by applicant): Military traumatic brain injury (TBI) has risen markedly in the current wars in Iraq and Afghanistan, and may occur in isolation or as a component of severe battlefield polytrauma. Recently, there have been estimates of 15-20% of warfighters (over 300,000 soldiers) having served in Iraq or Afghanistan having sustained at least mild TBI. These staggering numbers of afflicted warfighters make the chronic effects of TBI one of the most pressing issues affecting our Veterans. Accordingly, the overall objective of this proposal is to identify the mechanism(s) and progressive changes underlying the transition from acute to chronic pathology following closed-head TBI. Our central hypothesis is that a single severe or repeated mild closed-head TBI induces slowly progressive neurodegenerative changes over months to years post-insult. We believe these long-term neurodegenerative changes will be most apparent in the hippocampus, nigrostriatal system, aspects of the cerebral cortex, and diffuse white matter. Moreover, we hypothesize that a driving mechanism for these neurodegenerative changes is the gradual intra-axonal accumulation (and concomitant pre-synaptic depletion) of alpha-synuclein - an amyloidogenic protein - that eventually leads to more widespread axonal dysfunction, loss of synaptic efficacy, and neuronal degeneration. Initially, this will manifest as neurophysiological deficits affecting axonal efficacy and synaptic function, and will underlie a gradual neurobehavioral decline in learning, problem-solving, and motor function. To test these hypotheses, we have assembled a multi-faceted team of investigators with expertise in neurodegenerative pathologies, rodent and porcine models of TBI, and neural systems electrophysiology. We will use a pro-amyloidogenic transgenic mouse model of TBI and a swine model of closed-head rotational acceleration-induced TBI to mechanistically evaluate the pathophysiological progression from 1 month to 2 years post-injury. Importantly, the transgenic mouse studies (expressing human alpha-synuclein) will be used to directly compare the pathophysiology and neurodegenerative mechanisms in blast-TBI versus impact-TBI. In both mice and pigs, we will employ a comprehensive battery of tests including: (1) assessment of evolving neurodegenerative changes including diffuse axonal injury (DAI), Parkinson's-like Lewy pathology, Alzheimer's-like amyloidosis and tauopathies, synaptic loss, and neuroinflammation; (2) neurobehavior testing of learning, memory, motor, and problem solving; and (3) neurophysiological measurements using electrophysiological techniques sensitive to axonal loss/dysfunction, synaptic changes, and excitability changes. The evaluation of TBI-induced chronic neurodegeneration, neurobehavior, and neurophysiology in the same animals is a unique and powerful experimental platform to detect subtle neurological changes, investigate precipitating pathophysiology, and establish specific structure-function relationships. Importantly, these will be evaluated following either a single moderate or severe injury, or following repeated mild injuries. Although there is mounting evidence for links between TBI and early onset of neurodegenerative pathologies, the mechanisms of these progressive neuropathological changes following militarily relevant single or repetitive closed-head TBI are unknown. However, establishing the pathophysiological links is critical for the long-term health and neurological function of our Veterans, and thus underscores the importance and relevance of the current proposal. PUBLIC HEALTH RELEVANCE: RELEVANCE This proposal will investigate the long-term neurological consequences of traumatic brain injury (TBI), one of the most important issues facing our Veterans. TBI is considered the "signature injury" of Iraq and Afghanistan wars, with over 300,000 warfighters having been afflicted with at least mild-bTBI. While TBI in contact sports may induce brain pathology and predispose for neurodegenerative diseases, little is known about the pathophysiological progression following militarily relevant TBI. This proposal will use controlled animal models to investigate the relationship between blast and non-blast TBI and chronic neurodegenerative changes.

描述（由申请人提供）： 军事创伤性脑损伤（TBI）在目前的伊拉克和阿富汗战争中显著上升，可能单独发生或作为严重战场多发性创伤的一部分。最近，估计有15-20%的战士（超过300，000名士兵）在伊拉克或阿富汗服役，至少有轻微的TBI。这些数量惊人的受影响的战士使TBI的慢性影响成为影响我们退伍军人的最紧迫问题之一。因此，本提案的总体目标是确定闭头TBI后从急性病理学转变为慢性病理学的机制和渐进性变化。我们的中心假设是，一个单一的严重或反复轻度闭头TBI诱导缓慢进行性神经退行性变化在数月至数年后的侮辱。我们相信这些长期的神经退行性变化在海马体、黑质纹状体系统、大脑皮质和弥漫性白色物质中最为明显。此外，我们假设这些神经退行性变化的驱动机制是α-突触核蛋白（一种淀粉样蛋白）的逐渐轴突内积累（以及伴随的突触前耗竭），最终导致更广泛的轴突功能障碍，突触功效丧失和神经元变性。最初，这将表现为 神经生理学缺陷影响轴突功效和突触功能，并且将成为学习、解决问题和运动功能的逐渐神经行为下降的基础。为了验证这些假设，我们组建了一个多方面的研究团队，他们具有神经退行性病变、啮齿动物和猪TBI模型以及神经系统电生理学方面的专业知识。我们将使用促淀粉样蛋白生成转基因小鼠TBI模型和闭合头旋转加速度诱导TBI的猪模型，从机械上评估损伤后1个月至2年的病理生理学进展。重要的是，转基因小鼠研究（表达人α-突触核蛋白）将用于直接比较冲击性TBI与冲击性TBI的病理生理学和神经退行性机制。在小鼠和猪中，我们将采用一组全面的测试，包括：（1）评估神经退行性变化，包括弥漫性轴索损伤（DAI）、帕金森样Lewy病理学、阿尔茨海默样淀粉样变性和tau蛋白病、突触丢失和神经炎症;（2）学习、记忆、运动和解决问题的神经行为测试;和（3）使用对轴突损失/功能障碍、突触变化和兴奋性变化敏感的电生理学技术的神经生理学测量。在同一动物中评价TBI诱导的慢性神经退行性变、神经行为和神经生理学是一个独特而强大的实验平台，可以检测细微的神经变化，研究诱发的病理生理学，并建立特定的结构-功能关系。重要的是，这些将在单次中度或重度损伤或重复轻度损伤后进行评估。虽然有越来越多的证据表明TBI和神经退行性病变的早期发作之间的联系，这些渐进性神经病理学变化的机制，军事相关的单一或重复的闭头TBI是未知的。然而，建立病理生理学联系对我们退伍军人的长期健康和神经功能至关重要，因此强调了当前提案的重要性和相关性。 公共卫生关系： 该提案将调查创伤性脑损伤（TBI）的长期神经系统后果，这是我们退伍军人面临的最重要的问题之一。TBI被认为是伊拉克和阿富汗战争的“标志性损伤”，超过30万名战士患有至少轻度的bTBI。虽然接触性运动中的TBI可能诱发脑病理学和易患神经退行性疾病，但对军事相关TBI后的病理生理学进展知之甚少。该提案将使用受控 动物模型，以研究急性和非急性TBI与慢性神经退行性变化之间的关系。