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.

资助家长奖摘要。 目前对病理学和潜在治疗的理解最前沿的三个主要原则 解决阿尔茨海默病（AD）巨大的公共卫生负担的方法首先是临床。 据了解，这种疾病引起的症状和功能依赖性可能会在几十年后出现 与淀粉样斑块和神经原纤维缠结皮质病理相关的退行性大脑变化； 普遍存在的合并症，特别是脑血管功能障碍，会加速疾病的进展 过程和临床衰退；第三，针对这些病理领域的任何治疗干预 需要在认知能力下降的证据出现之前尽早实施，因为 痴呆症只有在发生严重的不可恢复的神经退行性变后才会显现出来。 磁共振成像（fMRI）用于测量大脑活动，以前主要用于 AD 进展的特征，具有 AD 遗传风险的个体甚至在发生之前就表现出改变的功能磁共振成像指标。 认知障碍的表达，因此，功能磁共振成像为认知障碍的病理生理学提供了重要的见解 临床前 AD。功能磁共振成像信号是基于“功能性”现象的神经活动的间接关联。 充血”，其中大脑的代谢活动随之而来的是脑血流量的营养增加和 这种血流动力学反应可以通过血氧水平依赖（BOLD）对比度来测量 应用功能磁共振成像研究 AD 的一个关键障碍是复杂的神经纠缠。 和血管生理学在 BOLD 信号的基础上导致无法区分 神经功能障碍和共病血管病理学的影响 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应用 在任何证据出现之前，研究与 AD 遗传风险相关的大脑病理学的新技术 为此，我们将实施尖端的扫描和分析范式。 通过 [1] 同时记录，在认知健康、处于不同 AD 遗传风险水平的老年参与者中 fMRI、脑电图和脑磁图数据的组合，[2] 量化 大脑网络的瞬时内在神经生理状态，以及[3]使用这些状态来锚定测量 我们强调 R21 机制是神经诱导的血液动力学反应。 探索性/发展性，本着这种精神，我们建议探索最佳参数来推进这部小说 这种方法的成功实施将为遗传如何发生提供新的见解。 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 通过新颖的、针对特定神经和血管病理生理学的斑块和缠结病理学。 临床前 AD 的替代疗法有望进行预防和早期干预，以阻止或减缓 降低进行性神经变性是可能的。