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: 10677683
• 负责人: Tatiana Sitnikova
• 金额: $ 59.03万
• 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/10677683
• 关键词: Address; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; 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; Physiological; Population; Predisposition; Preventive therapy; Process; Property; Proteins; Public Health; Records; Recurrence; Regional Disease; Regulation; Reporting; Rest; Scanning; Senile Plaques; Signal Transduction; Structure; Symptoms; System; Techniques; Technology; Testing; Time; Work; beta amyloid pathology; blood oxygen level dependent; blood oxygenation level dependent response; 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; neural network; neural patterning; neurophysiology; neurovascular; neurovascular coupling; novel; pharmacologic; prevent; 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）是目前无法治疗的神经退行性疾病，具有大量的 公共卫生负担。随着用于β-淀粉样蛋白（Aβ）斑块成像的生物标志物技术的发明， 在活体人脑中的神经元缠结，很明显，这些病理定义的AD开始 在这种疾病导致的明显痴呆症状之前的几十年。这段长时间的痴呆前期 提供了早期干预的机会。然而，目前对复杂的AD有很多未知之处， 在这些早期阶段的病理生理。一个有趣的观察是，早期Aβ病理学通常是 位于大脑的高代谢区域。这些区域，也被称为“皮质枢纽”，因为它们的高密度， 与其他脑区的功能互连性可以显示与活动相关的易感性。动物模型 表明，在功能活跃的大脑区域，内在神经活动的快速时间结构被破坏， 神经血管失调可影响Aβ稳态。可能这些病理生理学的 在衰老的人脑中也是如此。然而，快速神经活动的精确测量和 最容易受到AD影响的高级大脑区域的神经血管调节一直具有挑战性。 当前可用的成像技术在单独使用时具有严重的局限性。测量的信号 功能性磁共振成像（fMRI）反映了活跃大脑的代谢需求之间的耦合 细胞和脑血流量的营养性增加，不能区分神经功能障碍， 活动本身和这种神经血管耦合（NVC）。技术，如脑电图（EEG）， 不能明确地将记录的神经生理信号定位到特定的神经网络。到 为了克服这一关键障碍，我们开发了一种尖端的扫描和分析范式，[1] 同时记录EEG和fMRI数据，[2]检测和量化瞬态的短时间尺度结构， 皮质网络中的内在神经生理活动事件，并[3]使用这些神经网络事件， 锚评估根据活动需求调整血管能量输送的能力。等 在当前的项目中，将使用独特的神经网络中的选择性测量，以测试是否快速中断 神经功能和NVC在活跃的“皮层枢纽”是相关的，并显示出时间优先于Aβ 老年人纵向队列中高阶认知领域的病理学和相关缺陷 没有临床痴呆。我们将通过利用新型超敏感血液生物标志物来量化Aβ病理学。 这种方法的成功实施将表明，在衰老的人脑中， 特定皮质区域的神经动力学和NVC是诱发Aβ病理性的疾病状态 变化如果这种疾病状态是Aβ病理学的上游过程，那么在未来的研究中， 可能通过药理学或脑刺激方法调节Aβ稳态， 神经动力学和NVC，并因此预防进行性病理学和认知衰退。