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.

资助父母奖的摘要。 三个主要原则是当前对病理和潜在疗法的理解的最前沿 解决阿尔茨海默氏病（AD）大规模公共卫生伯恩的方法。首先，临床 已知这种疾病导致的症状和功能依赖性在潜在的几十年后发生 与淀粉样斑块和神经纤维缠结皮质病理学有关的退化大脑变化。第二， 普遍的合并症病理，尤其是脑血管功能障碍，导致疾病加速 过程和临床下降；第三，针对这些病理领域的任何一种治疗干预措施 鉴于该认知能力下降的证据，需要尽早实施 仅在实质性不可恢复的神经退行性变化后，痴呆才明显。功能磁性 共振成像（fMRI）用于测量脑活动，并以前对 广告进展的表征。处于AD的遗传风险的人甚至在此之前都显示出更改的fMRI指标 认知障碍的表达，因此，fMRI为病理生物生物生理提供了关键的见解 临床前广告。 fMRI信号是基于功能现象的神经活动的间接相关性 充血的大脑中的代谢活性之后是脑血流的营养增加和 可以通过血液氧合水平（BOLD）对比度测量这种血液动力学反应 机制。 fMRI在AD研究中应用的关键障碍是神经的复杂纠缠 和基于大胆信号的血管生理学，导致无法区分 神经功能障碍和合并性血管病理的影响。这项NIH R21研究建议的目的是 从fMRI BOLD信号的Vasculo-Physiology组件中解脱出神经生理学 在任何证据的证据之前 认知和功能下降。为此，我们将实施尖端的扫描和分析范式 在认知健康的老年参与者中，以不同水平的AD遗传风险的参与者[1]简单记录 功能磁共振成像，电脑电图和磁性数据之间的组合，[2]量化 脑网络的瞬时内在神经生理状态，[3]使用这些状态锚定测量 神经诱导的血液动力反应。我们强调R21机制是 探索性/发展性，本着这种精神，我们建议探索最佳参数以推动这本小说 技术。成功实施这种方法将为遗传如何提供新的见解 脆弱性与独特的神经和血管功能障碍有关，这些神经和血管功能障碍被认为会影响 AD中的斑块和缠结病理学。通过新颖的靶向特定的神经元和血管病理生理学 临床前广告中的替代疗法有望进行预防和早期干预，以挫败或缓慢 向下进行性神经变性，可能。