Longitudinal MRI Investigation of Traumatic Microvascular Injury

创伤性微血管损伤的纵向 MRI 研究

基本信息

批准号：
10571853
负责人：
Jeffrey B Ware
金额：
$ 78.04万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10571853
关键词：
Acceleration Affect Aging Alzheimer&apos s disease related dementia Atrophic Automobile Driving Axon Blood Blood Vessels Blood brain barrier dysfunction Brain Brain Injuries Cerebrovascular Circulation Chronic Classification Clinical Clinical Research Cognitive Control Groups Dementia Deterioration Development Diffusion Magnetic Resonance Imaging Disease Elderly Evolution Exhibits Functional disorder Hospitalization Human Humanities Image Impaired cognition Impairment Individual Injury Investigation Link Magnetic Resonance Imaging Measures Microvascular Dysfunction Modeling Monitor Morbidity - disease rate Myelin Myelin Water Imaging Natural History Nature Nerve Degeneration Neurodegenerative Disorders Neurons Neuropsychology Outcome Participant Pathologic Pathology Patient Recruitments Patient-Focused Outcomes Pattern Perfusion Predictive Value Process Prognosis Research Risk Factors Role Survivors TBI Patients Techniques Testing Thick Tissues Traumatic Brain Injury Water Work axon injury blood-brain barrier permeabilization 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 long term recovery 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 vascular injury white matter

项目摘要

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）与加速神经变性有关，是后期痴呆症的公认原因，这是一种阿尔茨海默氏病有关的痴呆症（ADRD）。尽管驾驶病理机制尚不完全理解，但临床前的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，表明与TBI相关的神经变性（趋势）份额重要特征包括对认知障碍和痴呆症（VCID）的血管贡献。尽管迄今为止对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害上，但仍未满足地表征人类中微血管功能障碍的演变，并确定与TBI相关的VCID的作用。对微血管损伤如何有助于长期神经退行性的有助于改善患者预测的潜力，并有助于克服有效疗法改善这种疾病过程的持续障碍。这是非常需要开发与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标。该提议的中心假设是，TBI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在几个月至数年的执法中逐渐缓慢进行性神经元丧失联系起来，最终导致脑部萎缩和长期认知。为了检验这一假设，我们提出了一项多时间神经影像学研究，以确定TBI的头三年的微血管功能障碍的自然历史，在该研究中，我们将在基于MRI的微血管功能测量中建立纵向变化的模式。我们预计TBI患者将提取脑萎缩和微血管功能障碍超过正常衰老，这将通过与纵向检查的健康对照组相比确定。我们还假设，在伤亡后初期评估的微血管成像措施将预测随后在TBI之后的头三年随后的脑萎缩和认知能力下降的幅度。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，TBI病理生理学是一种可能治疗但可以理解的TBI内表型。