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) 与加速的神经退行性疾病有关，是晚年痴呆症（阿尔茨海默病相关痴呆症 (ADRD) 的一种）的公认原因，尽管其驱动病理机制尚不完全清楚，但临床前证据越来越多地表明微血管损伤是导致老年痴呆症的原因。 TBI 神经病理学的一个关键组成部分，表明 TBI 相关神经变性 (TreND) 与其他 ADRD 具有共同的重要特征，包括血管导致认知障碍和痴呆 (VCID)。迄今为止，TBI 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，但仍然需要描述人类 TBI 后微血管功能障碍的演变，并建立对 TBI 相关 VCID 的作用的进一步了解。微血管损伤导致长期神经退行性变，有可能改善患者的预后预测，并有助于克服开发有效疗法以改善这种疾病过程的持续障碍，因此，非常需要开发可靠的成像生物标志物。 TBI 相关的 VCID 可以更好地告知预后、对损伤内表型进行分类、监测长期恢复并确定治疗目标。该提案的中心假设是，TBI 导致的慢性微血管功能障碍代表了 VCID 的一种类型，并将其与最初的大脑联系起来。损伤导致随后数月至数年发生的缓慢进展的神经元损失，最终导致脑萎缩和长期认知能力下降。为了检验这一假设，我们提出了一项多时间点神经影像学研究来确定微血管的自然史。 TBI 后前 3 年的功能障碍，其中我们将建立基于 MRI 的微血管功能测量的纵向变化模式，包括脑血流量、脑血管反应性、血脑屏障功能障碍和细胞外游离水与我们预计 TBI 患者会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。损伤后早期将预测 TBI 后头 3 年内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，TBI 是一种可能可治疗但尚未得到充分研究的内表型。