Understanding mechanisms of sub-acute neurodegeneration in moderate to severe traumatic brain injury

了解中度至重度创伤性脑损伤中亚急性神经变性的机制

• 批准号: 312338-2011
• 负责人: Green, Robin
• 金额: $ 1.75万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=506289
• 关键词: Understanding; mechanisms; sub; acute; neurodegeneration

Prevailing scientific and clinical assumptions hold that the cognitive and neurological status of people with moderate to severe TBI remains largely stable once a plateau in recovery has been achieved. Findings from our lab and a handful of others have demonstrated, however, that deleterious changes occur sub-acutely and that TBI may be a progressive, degenerative disorder. We have observed robust atrophy in our lab in the hippocampus (head, body and tail), corpus callosum (genu, body, splenium) and fornix from 5 to 24 post-injury and in a smaller sample, from 5 to 12 months post injury. These findings were revealed in volumetric MRI and diffusion tensor imaging (DTI) studies. At the same time points, we have also shown whole brain atrophy (ventricle to brain ratio) and loss of white matter integrity in a variety of regions. Critically, we have also demonstrated cognitive and functional associations with these neural changes. Based on these findings, the primary global aims of the proposed research are twofold: The first is to more fully characterize sub-acute atrophy, for example, understanding timelines of atrophy, which brain regions are most and least vulnerable, and what subject and environmental factors moderate deterioration. The second objective is to better understand mechanisms of this second wave of damage after brain injury. In particular, our prior findings suggest "transneuronal degeneration" (caused by disuse-induced delayed apoptosis) as a strong candidate mechanism. These aims will be approached through serial, longitudinal MRI analyses (structural, DTI and MR-spectroscopy) of discrete regions of the brains of patients with moderate to severe TBI, neuropsychological assessment, and mixed-effects growth curve modelling to allow individual recovery curves and impact of moderators to be assessed. We hope that the novel research questions examined in the proposed research will better elucidate the acute and chronic natural history of moderate-severe TBI, and the neuropathology that underlies it.

流行的科学和临床假设认为，一旦达到恢复平台期，中度至重度TBI患者的认知和神经系统状态基本保持稳定。然而，我们实验室和其他一些实验室的研究结果表明，有害的变化发生在亚急性期，TBI可能是一种进行性的退行性疾病。 我们在实验室中观察到损伤后5 - 24个月海马体（头、体和尾）、胼胝体（胼胝体、体、压部）和穹窿以及损伤后5 - 12个月的较小样本出现了强烈的萎缩。这些结果显示在体积MRI和扩散张量成像（DTI）研究。在同一时间点，我们还显示了全脑萎缩（脑室与脑的比例）和多个区域的白色物质完整性丧失。重要的是，我们还证明了认知和功能与这些神经变化的关联。基于这些发现，拟议研究的主要全球目标有两个：第一个是更全面地描述亚急性萎缩，例如，了解萎缩的时间表，哪些大脑区域最脆弱和最不脆弱，以及哪些主题和环境因素缓和恶化。第二个目标是更好地了解脑损伤后第二波损伤的机制。特别是，我们以前的研究结果表明，“跨神经元变性”（废用诱导的延迟凋亡）作为一个强有力的候选机制。这些目标将通过对中度至重度TBI患者大脑离散区域的系列纵向MRI分析（结构、DTI和MR光谱）、神经心理学评估和混合效应生长曲线建模来实现，以评估个体恢复曲线和调节剂的影响。我们希望在拟议的研究中检查的新的研究问题将更好地阐明中重度TBI的急性和慢性自然史，以及其背后的神经病理学。