Simultaneous EEG/fMRI to disentangle neural and vascular mechanisms of Alzheimer's disease pathology

同步脑电图/功能磁共振成像可解开阿尔茨海默病病理学的神经和血管机制

• 批准号: 10525421
• 负责人: Tatiana Sitnikova
• 金额: $ 59.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525421
• 关键词: Address; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Area; Attention; Biological Markers; Biological Process; Blood; Blood Vessels; Brain; Brain region; Cells; Cerebrovascular Circulation; Clinical; Cognition; Cognitive; Cognitive deficits; Complex; Coupling; Data; Dementia; Deposition; Disease; Dorsal; Early Intervention; Elderly; Electroencephalography; Enrollment; Episodic memory; Event; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Future; Hematological Disease; High Prevalence; Homeostasis; Human; Image; Imaging Techniques; Imaging technology; Impaired cognition; Individual; Investigation; Link; Longitudinal cohort; Machine Learning; Maintenance; Measurement; Measures; Mediating; Memory; Metabolic; Metabolism; Methods; Multivariate Analysis; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurophysiology - biologic function; Pathologic; Pathology; Patients; Performance; Pharmacology; Physiological; Population; Predisposition; Preventive therapy; Process; Property; Proteins; Public Health; Records; Recurrence; Regulation; Reporting; Rest; Scanning; Senile Plaques; Signal Transduction; Structure; Symptoms; System; Techniques; Technology; Testing; Time; Work; base; blood oxygen level dependent; blood oxygenation level dependent response; brain abnormalities; brain cell; cohort; cost effective; cost estimate; density; effective therapy; executive function; follow-up; functional magnetic resonance imaging/electroencephalography; genetic risk factor; imaging modality; in vivo; interest; invention; mild cognitive impairment; neural network; neural patterning; neurophysiology; neurovascular; neurovascular coupling; novel; prevent; relating to nervous system; response; source localization; tau Proteins

Abstract. Alzheimer’s disease (AD) is presently an untreatable neurodegenerative disorder with a massive public health burden. With invention of biomarker technologies for imaging β-amyloid (Aβ) plaques and neurofibrillary tangles in the living human brain, it became clear that these pathologies that define AD begin decades prior to overt dementia symptoms resulting from this disease. This prolonged pre-dementia period offers opportunities for early interventions. However, much is currently unknown about the complex AD pathophysiology in these early stages. One intriguing observation is that the early Aβ pathology is often localized to highly metabolic regions of the brain. These regions, also known as ‘cortical hubs’ due to their high functional interconnectivity with other brain areas, may display activity related susceptibility. Animal models show that, in functionally active brain regions, disrupted rapid temporal structure of intrinsic neural activity and neurovascular dysregulation can influence Aβ homeostasis. It is possible that these pathophysiological mechanisms hold true in the aging human brain. However, precise measurement of rapid neural activity and neurovascular regulation in the higher-order brain areas most vulnerable to AD has been challenging. Currently available imaging techniques, when used alone, have severe limitations. The signal measured by functional magnetic resonance imaging (fMRI) reflects coupling between metabolic demand of active brain cells and a nutritive increase in cerebral blood flow and cannot differentiate between dysfunctions in neural activity itself and this neurovascular coupling (NVC). Techniques, such as electroencephalography (EEG), cannot unambiguously localize the recorded neurophysiological signal to specific neural networks. To overcome this critical barrier, we developed a cutting-edge scanning and analysis paradigm that [1] simultaneously records EEG and fMRI data, [2] detects and quantifies short timescale structure of transient events of intrinsic neurophysiological activity in cortical networks, and [3] uses these neural network events to anchor assessment of capacity to adjust vascular energy delivery in response to activity demands. Such selective measurements in unique neural networks will be used in the current project to test if disrupted rapid neural function and NVC in the active ‘cortical hubs’ are associated and show temporal precedence to Aβ pathology and the linked deficits in higher-order cognitive domains in a longitudinal cohort of older adults without clinical dementia. We will quantify Aβ pathology by leveraging novel ultra-sensitive blood biomarkers. Successful implementation of this approach would suggest that, in the aging human brain, abnormal fast neural dynamics and NVC in specific cortical regions are disease states predisposing to Aβ pathological changes. If such disease states are an upstream process to Aβ pathology, then in future studies, it may be possible to regulate Aβ homeostasis through pharmacological or brain stimulation approaches that target fast neural dynamics and NVC, and consequently, prevent progressive pathology and cognitive decline.

抽象的。阿尔茨海默氏病（AD）呈现出一种不可治疗的神经退行性疾病 公共卫生伯恩。有意成像成像β-淀粉样蛋白（Aβ）斑块的生物标志物技术和 神经原纤维缠结在活着的人脑中，很明显这些定义AD的病理 由于这种疾病引起的明显痴呆症状之前的几十年。这个长时间的止动期 提供早期干预的机会。但是，目前对复杂的广告未知 在这些早期阶段的病理生理。一个有趣的观察是，早期的Aβ病理通常是 位于大脑的高度代谢区域。这些区域，也称为“皮质枢纽” 与其他大脑区域的功能互连性可能显示与活动相关的敏感性。动物模型 表明，在功能活跃的大脑区域中，内在神经元活性的快速临时结构中断了 神经血管失调会影响Aβ稳态。这些病理生理可能 机制在衰老的人脑中成立。但是，精确测量快速神经活动和 在最容易受到AD的高阶大脑区域中的神经血管调节受到挑战。 目前可用的成像技术在单独使用时会受到严重限制。信号由 功能磁共振成像（fMRI）反映了活性大脑代谢需求之间的耦合 细胞和脑血流的营养增加，无法区分神经元功能障碍 活动本身和这种神经血管耦合（NVC）。技术，例如脑电图（EEG）， 无法明确将记录的神经生理信号定位到特定的神经元网络。到 克服了这一关键障碍，我们开发了一种尖端的扫描和分析范式[1] 类似地记录了脑电图和fMRI数据，[2]检测和量化瞬态的短时间结构 皮质网络中内在神经生理活性的事件，[3]使用这些神经元网络事件进行 根据活动需求响应调节血管能量输送的能力的锚评估。 当前项目中将使用独特神经网络中的选择性测量，以测试是否破坏了快速 主动“皮质中心”中的神经功能和NVC是关联的，并且显示出暂时的Aβ 在纵向老年人的纵向认知领域中的病理和连接的缺陷 没有临床痴呆。我们将利用新型的超敏感血液生物标志物来量化Aβ病理。 这种方法的成功实施将表明，在人类衰老的大脑中，异常快速 特定皮质区域中的神经动力学和NVC是疾病状态，易于Aβ病理学 更改。如果这种疾病状态是Aβ病理学的上游过程，那么在以后的研究中，可能是 可以通过药物或脑刺激方法来调节Aβ体内稳态，以快速靶向 神经动力学和NVC，因此可以预防渐进的病理和认知能力下降。