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

抽象的。阿尔茨海默病(AD)是一种目前无法治愈的神经退行性疾病，具有巨大的 公共卫生负担。随着β-淀粉样蛋白(Aβ)斑块成像生物标记物技术的发明 在活着的人脑中，神经原纤维缠绕在一起，很明显，这些定义阿尔茨海默病的病理开始 在这种疾病引起的明显痴呆症症状之前几十年。这段漫长的痴呆症前期 为早期干预提供了机会。然而，目前对复杂的AD有很多未知之处 这些早期阶段的病理生理学。一个有趣的观察是，早期的Aβ病理通常是 位于大脑的高度新陈代谢区域。这些区域，也被称为‘皮质中枢’，因为它们的高密度 与其他脑区的功能互连，可能表现出活动相关的易感性。动物模型 研究表明，在功能活跃的大脑区域，扰乱了固有神经活动的快速时间结构 神经血管失调会影响Aβ的动态平衡。有可能这些病理生理学 这种机制在老化的人脑中也是成立的。然而，准确测量快速神经活动和 最易受AD影响的高阶大脑区域的神经血管调节一直具有挑战性。 目前可用的成像技术，当单独使用时，具有严重的局限性。测量的信号 功能磁共振成像(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，无法区分神经功能障碍 活动本身和这种神经血管偶联(NVC)。技术，如脑电(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。至 克服了这一关键障碍，我们开发了一种尖端扫描和分析范式，[1] 同时记录EEG和fMRI数据，[2]检测并量化瞬变的短时间尺度结构 皮层网络中固有神经生理活动的事件，[3]利用这些神经网络事件 根据活动需求调整血管能量输送的能力的锚定评估。是这样的 在目前的项目中，将使用独特神经网络中的选择性测量来测试是否快速中断 活跃的“皮质中枢”中的神经功能和NVC是相关的，并且在时间上优先于β 老年人纵向队列中高阶认知域的病理学和相关缺陷 没有临床痴呆症。我们将通过利用新的超敏感血液生物标记物来量化Aβ病理。 这一方法的成功实施将表明，在老化的人脑中，速度异常快 神经动力学和特定皮质区域的NVC是易患β病理的疾病状态 改变。如果这种疾病状态是β病理的上游过程，那么在未来的研究中，它可能是 可能通过快速靶向的药物或脑刺激方法调节β动态平衡 神经动力学和NVC，从而防止进行性病理和认知能力下降。

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.