Decoupling neural and vascular functional pathology in individuals at risk for Alzheimer's disease- U.S.-Japan Brain Research Cooperative Program (BRCP) Administrative Supplement

解耦阿尔茨海默病风险个体的神经和血管功能病理学 - 美日脑研究合作计划 (BRCP) 行政补充文件

• 批准号: 10020696
• 负责人: DAVID H SALAT
• 金额: $ 4.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020696
• 关键词: Address; Administrative Supplement; Aging; Alternative Therapies; Alzheimer' s Disease; Alzheimer' s disease risk; Award; Blood Vessels; Brain; Brain Pathology; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical; Cognitive; Data; Dementia; Dependence; Development; Disease; Disease Progression; Early Intervention; Exploratory/Developmental Grant; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Hospitals; Genetic Predisposition to Disease; Genetic Risk; Goals; Human; Hyperemia; Impaired cognition; Individual; Japan; Knowledge; Laboratories; Learning; Link; Magnetic Resonance Imaging; Magnetoencephalography; Maps; Massachusetts; Measurement; Measures; Metabolic; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Parents; Participant; Pathologic; Pathology; Physiological; Physiology; Preventive Intervention; Principal Investigator; Process; Public Health; Research Personnel; Research Project Grants; Research Proposals; Scanning; Senile Plaques; Signal Transduction; Site; Symptoms; Therapeutic; Therapeutic Intervention; Time; Training; United States National Institutes of Health; Universities; Vascular Diseases; aging brain; base; blood oxygen level dependent; brain research; comorbidity; data acquisition; experience; functional decline; hemodynamics; insight; neural correlate; neuroimaging; neurophysiology; new technology; novel; parent project; pre-clinical; programs; progressive neurodegeneration; quantitative imaging; relating to nervous system; response

Abstract of the funded parent award. Three major principles are at the forefront of current understanding about the pathology and potential therapeutic approach to addressing the massive public health burden of Alzheimer’s disease (AD). First, the clinical symptoms and functional dependence resulting from this disease are known to occur after potentially decades of degenerative brain changes linked to amyloid plaque and neurofibrillary tangle cortical pathologies; second, prevalent comorbid pathologies, particularly cerebrovascular dysfunction, contribute to a hastening of disease processes and clinical decline; third, any therapeutic intervention targeting either of these pathologic domains would need to be implemented at the earliest time possible, prior to evidence of cognitive decline given that dementia is only apparent after substantial irrecoverable neurodegeneration has transpired. Functional magnetic resonance imaging (fMRI) is used to measure brain activity and previously contributed extensively to the characterization of AD progression. Individuals at genetic risk of AD show altered fMRI indicators even prior to expression of cognitive impairment, and thus, fMRI has provided critical insights into pathophysiology of preclinical AD. The fMRI signal is an indirect correlate of neural activity based on the phenomenon of ‘functional hyperemia’ in which metabolic activity in the brain is followed by a nutritive increase in cerebral blood flow and this hemodynamic response can be measured through the blood oxygenation level dependent (BOLD) contrast mechanism. A critical barrier in the application of fMRI to the study of AD is the intricate entanglement of neural and vascular physiology at the basis of the BOLD signal resulting in an inability to differentiate between the effects of neural dysfunction and comorbid vascular pathology. The goal of this NIH R21 research proposal is to decouple neurophysiological from vasculo-physiological components of the fMRI BOLD signal and to apply this new technology to the study of brain pathology, associated with the genetic risk of AD, before any evidence of cognitive and functional decline. To this end, we will implement a cutting-edge scanning and analysis paradigm in cognitively healthy older participants at different levels of genetic risk of AD by [1] simultaneous recording of combinations between fMRI, electro-encephalographic, and magnetoencephalographic data, [2] quantifying transient intrinsic neurophysiological states of brain networks, and [3] using these states to anchor measurement of the neurally induced hemo-dynamic response. We emphasize that the R21 mechanism is exploratory/developmental, and in this spirit, we propose to explore optimal parameters to advance this novel technology. Successful implementation of this approach would provide novel insight into how genetic vulnerabilities are linked to distinct neural and vascular dysfunctions, which have been suggested to influence the plaque and tangle pathology in AD. Targeting specific neural and vascular pathophysiology by novel, alternative therapies in preclinical AD holds promise to make prevention and early intervention, to thwart or slow down progressive neurodegeneration, possible.

资助家长奖的摘要。 三个主要原则是目前对病理学和潜在治疗方法的最前沿理解。 这是解决阿尔茨海默病（AD）巨大公共卫生负担的一种方法。第一，临床 已知由这种疾病引起的症状和功能依赖性可能在几十年后发生， 与淀粉样斑块和神经纤维缠结皮质病理学有关的退行性脑变化;第二， 常见的共病病理，特别是脑血管功能障碍，有助于加速疾病 过程和临床下降;第三，任何针对这些病理领域的治疗干预 需要在认知能力下降的证据出现之前尽早实施， 痴呆症仅在发生了实质性的不可恢复的神经变性之后才明显。功能磁 核磁共振成像（fMRI）用于测量大脑活动，以前曾广泛用于 AD进展的特征。具有AD遗传风险的个体甚至在治疗前就显示出改变的fMRI指标。 表达的认知障碍，因此，功能磁共振成像提供了重要的见解的病理生理学， 临床前AD。功能磁共振成像信号是一种间接的相关神经活动的基础上的现象“的功能 “充血”，其中脑中的代谢活动之后是脑血流量的营养性增加， 这种血液动力学反应可以通过血氧水平依赖（BOLD）对比来测量 机制应用fMRI研究AD的一个关键障碍是神经元的复杂纠缠， 以及基于BOLD信号的血管生理学，导致无法区分 神经功能障碍和共病血管病理学的影响。这项NIH R21研究提案的目标是 将fMRI BOLD信号的神经生理学成分与血管生理学成分分离，并将其应用于 新技术的研究大脑病理学，与遗传风险的AD，之前的任何证据表明， 认知和功能下降。为此，我们将实施一种前沿的扫描和分析范式 在不同AD遗传风险水平的认知健康老年参与者中，[1]同时记录 功能磁共振成像、脑电图和脑磁图数据之间的组合，[2]量化 大脑网络的瞬时内在神经生理状态，[3]使用这些状态来锚测量 神经诱导的血液动力学反应。我们强调，R21机制是 探索性/发展性，本着这种精神，我们建议探索推进这部小说的最佳参数 技术.这种方法的成功实施将提供新的见解如何遗传 脆弱性与不同的神经和血管功能障碍有关，这被认为会影响 AD的斑块和缠结病理。靶向特定的神经和血管病理生理学， 临床前AD的替代疗法有望预防和早期干预， 可能是进行性神经退化