Longitudinal MRI Investigation of Traumatic Microvascular Injury

创伤性微血管损伤的纵向 MRI 研究

• 批准号: 10345147
• 负责人: Jeffrey B Ware
• 金额: $ 81.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345147
• 关键词: Affect; Aging; Alzheimer' s disease related dementia; Atrophic; Automobile Driving; Axon; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Cerebrovascular Circulation; Chronic; Clinical; Clinical Research; Cognitive; Control Groups; Core-Binding Factor; Dementia; Deterioration; Development; Diffusion Magnetic Resonance Imaging; Disease; Elderly; Evolution; Exhibits; Functional disorder; Hospitalization; Human; Image; Impaired cognition; Impairment; Individual; Injury; Investigation; Link; Magnetic Resonance Imaging; Measures; Microvascular Dysfunction; Modeling; Monitor; Morbidity - disease rate; Myelin; Natural History; Nature; Nerve Degeneration; Neurons; Neuropsychology; Outcome; Pathologic; Pathology; Patient Recruitments; Patient-Focused Outcomes; Patients; Pattern; Perfusion; Permeability; Predictive Value; Process; Prognosis; Recovery; Research; Risk Factors; Role; Survivors; TBI Patients; Techniques; Testing; Thick; Tissues; Traumatic Brain Injury; Water; Work; axon injury; base; brain magnetic resonance imaging; brain tissue; brain volume; cerebral atrophy; cerebrovascular; disability burden; effective therapy; endophenotype; extracellular; follow-up; functional decline; gray matter; hypoperfusion; imaging biomarker; improved; indexing; injury-related death; insight; morphometry; mortality; neuroimaging; neuron loss; neuronal cell body; neuropathology; new therapeutic target; normal aging; novel; outcome prediction; pre-clinical; pre-clinical research; prognostic significance; prognostic value; programs; progressive neurodegeneration; therapy development; time interval; vascular cognitive impairment and dementia; white matter

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.

创伤性脑损伤（TBI）与加速的神经变性相关，并且是老年痴呆症（一种阿尔茨海默病相关痴呆症（ADRD））的公认原因。尽管驱动病理机制尚未完全了解，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TBI的神经影像学研究主要集中在对神经元细胞体和轴突的结构损伤上，但仍然需要表征人类TBI后微血管功能障碍的演变并确定TBI相关VCID的作用。对微血管损伤如何促进长期神经退行性变的更好理解有可能改善患者结局预测，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，非常需要开发TBI相关VCID的可靠成像生物标志物，以更好地告知预后，对损伤内表型进行分类，监测长期恢复，并确定治疗靶点。该建议的中心假设是，TBI导致的慢性微血管功能障碍代表一种VCID，并将初始脑损伤与随后数月至数年内发生的随后缓慢进行性神经元损失联系起来，最终导致脑萎缩和长期认知能力下降。为了验证这一假设，我们提出了一个多时间点的神经影像学研究，以确定在TBI后的第一个3年的微血管功能障碍的自然史，我们将建立在MRI为基础的措施，包括脑血流量，脑血管反应性，血脑屏障功能障碍，和细胞外游离水与脑萎缩的微血管功能的纵向变化模式。我们预计TBI患者将表现出超过正常衰老相关的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。我们还假设，在创伤后早期评估的微血管成像措施将预测随后的脑萎缩和认知能力下降的幅度在TBI后的前3年。最终，该项目将产生新的见解VCID在TBI病理生理学中的作用，TBI的一个潜在的可治疗的，但研究不足的内在表型。