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

流行的科学和临床假设认为，中度至重度脑外伤患者的认知和神经状态在恢复达到平台期后基本保持稳定。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可能是一种进行性退行性疾病。我们在实验室观察到损伤后5至24个月海马（头部、身体和尾巴）、胼胝体（膝、身体、脾）和穹窿的严重萎缩，在一个较小的样本中，损伤后5至12个月。这些发现是在体积MRI和弥散张量成像（DTI）研究中发现的。在同一时间点，我们也显示了全脑萎缩（脑室与脑的比例）和多个区域白质完整性的丧失。重要的是，我们还证明了这些神经变化与认知和功能的联系。基于这些发现，提出的研究的主要全球目标有两个：首先是更全面地表征亚急性萎缩，例如，了解萎缩的时间线，哪些大脑区域最脆弱和最不脆弱，以及哪些主体和环境因素缓和了退化。第二个目标是更好地理解脑损伤后第二波损伤的机制。特别是，我们先前的研究结果表明“跨神经元变性”（由废用诱导的延迟凋亡引起）是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连续、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，从而评估个体恢复曲线和调节因子的影响。我们希望在提出的研究中检验的新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。

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.