Longitudinal MRI Investigation of Traumatic Microvascular Injury

创伤性脑损伤（TBI）与加速的神经退行性变性有关，是老年痴呆（一种阿尔茨海默病相关痴呆（ADRD））的公认原因。尽管驱动病理机制尚不完全清楚，但临床前证据越来越多地指出微血管损伤是TBI神经病理学的关键组成部分，表明TBI相关神经变性（TreND）与其他adrd具有重要特征，包括血管对认知障碍和痴呆（VCID）的贡献。虽然迄今为止对脑外伤的神经影像学研究主要集中在神经元细胞体和轴突的结构损伤上，但在描述人类脑外伤后微血管功能障碍的演变以及确定脑外伤相关VCID的作用方面，仍存在未满足的需求。对微血管损伤如何导致长期神经退行性变的更好理解，具有改善患者预后预测的潜力，并有助于克服开发有效治疗方法以改善这种疾病过程的持续障碍。因此，有必要开发可靠的tbi相关VCID的成像生物标志物，以更好地告知预后，分类损伤内表型，监测长期恢复，并确定治疗目标。该建议的中心假设是，创伤性脑损伤导致的慢性微血管功能障碍代表了一种VCID，并将最初的脑损伤与随后数月至数年缓慢进行性神经元丧失联系起来，最终导致脑萎缩和长期认知能力下降。为了验证这一假设，我们提出了一项多时间点神经影像学研究，以确定tbi后头3年微血管功能障碍的自然历史，在该研究中，我们将建立基于mri的微血管功能测量的纵向变化模式，包括脑血流、脑血管反应性、血脑屏障功能障碍和与脑萎缩有关的细胞外自由水。我们预计，创伤性脑损伤患者将表现出脑萎缩和微血管功能障碍，这将通过与纵向检查的健康对照组进行比较来确定。此外，我们假设损伤后早期评估的微血管成像测量将预测TBI后头3年脑萎缩和认知能力下降的程度。最终，该项目将对VCID在TBI病理生理学中的作用产生新的见解，这是一种潜在的可治疗但尚未充分研究的TBI内表型。

Traumatic Brain Injury (TBI) is associated with accelerated neurodegeneration and is a recognized cause of late-life dementia, a type of Alzheimer’s Disease Related Dementia (ADRD). Although the driving pathological mechanisms are incompletely understood, preclinical evidence increasingly points to microvascular injury as a key component of TBI neuropathology, indicating that TBI-related Neurodegeneration (TreND) shares important features including a vascular contribution to cognitive impairment and dementia (VCID) with other ADRDs. While neuroimaging investigations of TBI to date have primarily focused on structural damage to neuronal cell bodies and axons, there remains an unmet need to characterize the evolution of microvascular dysfunction after TBI in humans and establish the role of TBI-related VCID. An improved understanding of how microvascular injury contributes to long-term neurodegeneration holds potential to improve patient outcome prediction and help overcome persistent barriers to the development of effective therapies to ameliorate this disease process. Thus, there is a great need to develop reliable imaging biomarkers of TBI-related VCID to better inform prognosis, classify injury endophenotypes, monitor long-term recovery, and identify treatment targets. The central hypothesis of this proposal is that chronic microvascular dysfunction as a consequence of TBI represents a type of VCID and links the initial brain injury to subsequent slowly progressive neuronal loss occurring in the ensuing months to years, ultimately contributing to brain atrophy and long-term cognitive decline. To test this hypothesis, we propose a multi-timepoint neuroimaging study to determine the natural history of microvascular dysfunction over the first 3 years post-TBI, in which we will establishing the pattern of longitudinal change in MRI-based measures of microvascular function including cerebral blood flow, cerebrovascular reactivity, blood-brain-barrier dysfunction, and extracellular free water in relation to brain atrophy. We expect that TBI patients will exhibit brain atrophy and microvascular dysfunction in excess of that associated with normal aging, which will be determined by comparison to a longitudinally examined healthy control group. We additionally hypothesize that microvascular imaging measures assessed in the early postinjury period will predict the magnitude of subsequent brain atrophy and cognitive decline during the first 3 years after TBI. Ultimately, this project will yield novel insights into the role of VCID in TBI pathophysiology, a potentially treatable yet understudied endophenotype of TBI.