Brain fluid clearance and misfolded protein dynamics following traumatic brain injury

创伤性脑损伤后脑液清除和错误折叠蛋白质动力学

• 批准号: 10740569
• 负责人: TRACY A. BUTLER
• 金额: $ 105.91万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740569
• 关键词: Abeta clearance; Acceleration; Accident and Emergency department; Acute; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Animals; Biological Markers; Blood; Blood Vessels; Brain; Cause of Death; Cerebrospinal Fluid; Clinical assessments; Cognition; Cognitive; Complex; Data; Deposition; Development; Diffusion; Disease Progression; Excision; Failure; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hour; Human; Impairment; Inflammation; Injury; Intercellular Fluid; Intervention; Lesion; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Metabolic Clearance Rate; Methods; Modality; Modeling; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathologic; Persons; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Process; Prognostic Factor; Protein Dynamics; Proteins; Publishing; Recovery; Reporting; Research; Risk; Risk Factors; Sleep; Sleep disturbances; Symptoms; System; Techniques; Time; Toxin; Traumatic Brain Injury; Traumatic Brain Injury recovery; Ventricular; abeta accumulation; abeta deposition; brain dysfunction; comparison control; critical period; design; disability; fluid flow; glymphatic clearance; glymphatic flow; glymphatic system; human model; insight; mild traumatic brain injury; misfolded protein; multimodality; neuroimaging; novel; prevent; primary outcome; prospective; radiotracer; recruit; secondary outcome; solute; standard measure; targeted treatment; tau Proteins; therapeutic target; ventricular system; wasting; water channel

PROJECT SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a leading cause of death and disability and a risk factor for later development of Alzheimer's Disease (AD.) This project focuses on brain cerebrospinal/interstitial fluid systems essential for clearing the brain of waste and toxins, including the glymphatic system, as important to the pathophysiology of both TBI and AD. We will use neuroimaging to measure brain fluid clearance after TBI. Our preliminary results suggest that TBI causes significant reduction in clearance. In this project, we will confirm these results using additional clearance measurement methods, and determine if lower post-injury clearance is associated with worse cognitive, functional and symptomatic recovery from TBI. We will also use neuroimaging (Positron Emission Tomography - PET) to measure brain amyloid-β (Aβ) – a hallmark pathologic feature of AD – as soon as possible after TBI. Studies in animals and our preliminary data in humans indicate that Aβ is released after TBI and deposits rapidly in the brain, but after a variable period of time, is usually no longer present. We hypothesize that the rate of brain fluid clearance will predict the change in brain Aβ over one year after TBI. Poor clearance and persistent Aβ may explain (in part) why TBI is a risk factor for AD. In addition, monitoring these processes after TBI will provide information relevant to understanding AD in general, since this same pathophysiology – poor clearance leading to Aβ deposition – occurs in AD, but slowly over decades, making it more difficult to study. We will conduct a five year longitudinal study which will recruit subjects within hours after moderate or complex-mild TBI from a network of busy NYC emergency rooms. Neuroimaging, blood draw for TBI biomarkers and detailed cognitive/clinical assessment will be performed as soon as possible (<14 days) after injury and repeated at one year. Because there is no current gold standard for measuring brain fluid clearance in humans, we use a panel of complementary PET and MRI neuroimaging methods to estimate fluid flow, mixing and clearance through interconnected fluid-filled spaces in the brain. This includes a PET method we developed that measures the rate of radiotracer egress from the ventricle. Integrating measures from these multimodal methods will provide greater insight into human fluid clearance than could be achieved with any single modality, and will also provide information about the relative accuracy/predictive ability of each measure that can inform design of future studies. Results from this project will provide novel information about brain fluid clearance after TBI that is also relevant to AD, and that can inform targeted therapies to enhance TBI recovery and reduce future risk of neurodegeneration.

项目概要/摘要 创伤性脑损伤 (TBI) 是导致死亡和残疾的主要原因，也是日后发生脑损伤的危险因素 阿尔茨海默氏病 (AD.) 该项目重点关注大脑、脑脊液/间质液系统，这些系统对于阿尔茨海默病至关重要 清除大脑中的废物和毒素，包括类淋巴系统，这对病理生理学很重要 TBI 和 AD 都将使用神经影像学来测量 TBI 后的脑液清除率。 结果表明，TBI 会导致清除率显着降低。在本项目中，我们将确认这些结果。 使用额外的间隙测量方法，并确定是否与受伤后间隙降低相关 TBI 后的认知、功能和症状恢复较差。 我们还将使用神经成像（正电子发射断层扫描 - PET）来测量大脑淀粉样蛋白-β (Aβ) – AD 的标志性病理特征——TBI 后尽快进行动物研究和我们的初步数据。 人类研究表明，Aβ 在 TBI 后释放并迅速沉积在大脑中，但经过一段可变的时间后 我们发现脑液清除率可以预测这种变化。 TBI 后一年内大脑中 Aβ 的清除率低下和持续存在的 Aβ 可能（部分）解释了为什么 TBI 是一种风险。 此外，在 TBI 后监测这些过程将提供与 AD 相关的信息。 了解 AD 的总体情况，因为同样的病理生理学——清除不良导致 Aβ 沉积—— 发生在 AD 中，但在几十年内缓慢发生，这使得研究变得更加困难。 我们将进行一项为期五年的纵向研究，该研究将在中等或中等程度后数小时内招募受试者。 来自繁忙的纽约市急诊室网络的复杂-轻度 TBI，TBI 抽血。 生物标志物和详细的认知/临床评估将在术后尽快（<14天）进行 因为目前没有测量脑液清除率的金标准。 在人类中，我们使用一组互补的 PET 和 MRI 神经成像方法来估计流体流量， 通过大脑中相互连接的充满液体的空间进行混合和清除，这包括我们的 PET 方法。 开发了测量放射性示踪剂从心室流出的速率的方法。 多模式方法将比任何方法更深入地了解人体体液清除情况 单一模式，还将提供有关每种措施的相对准确性/预测能力的信息 这可以为未来的研究设计提供信息。 该项目的结果将提供有关 TBI 后脑液清除的新信息，这也是相关的 AD，并且可以为靶向治疗提供信息，以促进 TBI 恢复并降低未来的风险 神经变性。