CRCNS: US-Spain Research Proposal: Interpreting MEG Biomarkers of Alzheimer's Progression with Human Neocortical Neurosolver

CRCNS：美国-西班牙研究提案：用人类新皮质神经解算器解释阿尔茨海默病进展的 MEG 生物标志物

• 批准号: 10616791
• 负责人: STEPHANIE Ruggiano JONES
• 金额: $ 23.66万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616791
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease diagnostic; Alzheimer’s disease biomarker; Amyloid; Amyloid deposition; Animal Model; Animals; Anisotropy; Anterior; Area; Biological Markers; Brain; Brain region; Caregivers; Cells; Characteristics; Collaborations; Data; Demyelinations; Diagnostic; Diffusion Magnetic Resonance Imaging; Early Intervention; Education; Equilibrium; Event; Frequencies; Homeostasis; Human; Impaired cognition; Instruction; Interdisciplinary Study; Link; Magnetic Resonance Spectroscopy; Magnetoencephalography; Measures; Mentorship; Methods; Neocortex; Patients; Phase; Public Health; Quality of life; Research Proposals; Rest; Shapes; Signal Transduction; Spain; Spectrum Analysis; Speed; Synapses; Testing; Thalamic structure; Thick; Toxic effect; Underrepresented Populations; care costs; cingulate cortex; design; excitatory neuron; gamma-Aminobutyric Acid; imaging modality; improved; interest; mild cognitive impairment; neocortical; neural circuit; neural model; neuromechanism; neurophysiology; predictive modeling; programs; targeted treatment; tractography; treatment strategy; white matter

Over the last decade, there has been a growing interest in understanding the brain mechanisms underlying the loss of the brain homeostasis in the continuum of Alzheimer's Disease (AD). Animal models suggest that the substrate for this phenomenon is the loss of the excitatory/inhibitory (E/I) balance due to the toxic effects of amyloid oligomers and plaques on inhibitory terminals. This hyperexcitability is presumed to underlie the observed increases in power and interarea synchronization of alpha/beta frequency oscillations measured in humans with electro- and magneto-encephalography (M/EEG). Amnesic mild cognitively impaired (aMCI) patients present increased resting-state MEG power in (7-14Hz) alpha and (15-29Hz) beta bands in brain regions with higher amyloid deposition. Additionally, aMCI patients who later converted to AD (CONV), compared to non-converters (NOCONV), showed increased synchrony between anterior and posterior brain regions. While animal and human studies are highly synergistic, it is unknown if the hyperexcitability found in animal models is the origin of the hypersynchronization found in human neurophysiology. To bridge this gap, the current proposal will apply a recently developed a computational neural modeling framework uniquely designed to link human macroscale M/EEG signals to the underlying cellular and circuit level dynamics that can be interrogated with invasive animal recordings or other imaging modalities (e.g., MR spectroscopy, tractography), namely Human Neocortical Neurosolver (HNN). We will apply new analysis methods to previously collected longitudinal MEG, tractography, volumetry, and MR GABA spectroscopy data in CONV- and NOCONV- aMCI patients and controls (Aims 1 and 3) and integrate the results with the HNN framework (Aim 2) to establish new early diagnostic AD biomarkers and to interpret the detailed neural mechanisms underlying these biomarkers. RELEVANCE (See instructions): There is a growing public health need to understanding the brain mechanisms underlying the loss of the brain homeostasis in the continuum of Alzheimer's Disease (AD). This project aims to define new early diagnostic measures for AD and targeted treatment strategies for early intervention based on identified neural circuit abnormalities. The project has the potential to open a completely new window to counteract and delay cognitive decline with aging, ultimately reducing the cost for caregivers and improving the

在过去的十年中，人们对了解大脑机制越来越感兴趣 阿尔茨海默病（AD）连续体中大脑稳态丧失的潜在原因。动物 模型表明，这种现象的根源是兴奋/抑制 (E/I) 平衡的丧失 由于淀粉样蛋白寡聚体和斑块对抑制性末端的毒性作用。这种过度兴奋是 推测是观察到的α/β功率和区域间同步增加的基础 通过脑电图和脑磁图（M/EEG）测量人体的频率振荡。 遗忘症轻度认知障碍 (aMCI) 患者在 (7-14Hz) 时表现出静息态 MEG 功率增加 淀粉样蛋白沉积较高的大脑区域中的 α 和 (15-29Hz) β 带。此外，aMCI 与未转化的患者 (NOCONV) 相比，后来转化为 AD (CONV) 的患者表现出增加 前脑区和后脑区之间的同步性。虽然动物和人类研究高度 协同作用，目前尚不清楚动物模型中发现的过度兴奋是否是协同作用的根源 人类神经生理学中发现的超同步。为了弥补这一差距，当前的提案将适用 最近开发的计算神经建模框架独特设计用于连接人类 宏观 M/EEG 信号发送至可被询问的底层细胞和电路级动态 使用侵入性动物记录或其他成像方式（例如，MR 光谱、纤维束成像），即 人类新皮质神经解算器（HNN）。我们将对之前收集的数据应用新的分析方法 CONV- 和 NOCONV- 中的纵向 MEG、纤维束成像、体积测定和 MR GABA 光谱数据 aMCI 患者和对照（目标 1 和 3）并将结果与​​ HNN 框架（目标 2）整合 建立新的早期诊断 AD 生物标志物并解释潜在的详细神经机制 这些生物标志物。 相关性（参见说明）： 公共卫生部门越来越需要了解大脑功能丧失背后的机制。 阿尔茨海默病（AD）连续体中的大脑稳态。该项目旨在定义新的早期 AD的诊断措施和基于已确定的早期干预的针对性治疗策略 神经回路异常。该项目有可能打开一个全新的窗口来抵消 并延缓衰老带来的认知能力下降，最终降低护理人员的成本并改善