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: 10396139
• 负责人: STEPHANIE Ruggiano JONES
• 金额: $ 24.38万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396139
• 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; Electroencephalography; Equilibrium; Event; Frequencies; Homeostasis; Human; Impaired cognition; Instruction; Interdisciplinary Study; Link; Magnetic Resonance Spectroscopy; Measures; Mentorship; Methods; Patients; Phase; Public Health; Quality of life; Research Proposals; Rest; Shapes; Signal Transduction; Spain; Spectrum Analysis; Speed; Structure; Synapses; Testing; Thalamic structure; Thick; Toxic effect; Underrepresented Populations; base; cingulate cortex; cost; design; encephalography; 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

在过去的十年里，人们对理解大脑机制的兴趣越来越大， 在阿尔茨海默病（AD）的连续体中，脑内稳态的丧失是潜在的。动物 模型表明，这种现象的基质是兴奋/抑制（E/I）平衡的丧失 这是由于淀粉样蛋白低聚物和斑块对抑制性末端的毒性作用。这种过度兴奋是 据推测，这是观察到的α/β能量增加和区域间同步的基础。 用脑电图和脑磁图（M/EEG）测量人类的频率振荡。 慢性轻度认知功能障碍（aMCI）患者在（7- 14 Hz）的静息态MEG功率增加 α和（15- 29 Hz）β带在大脑区域具有较高的淀粉样蛋白沉积。此外，aMCI 与非转换者（NOCONV）相比，后来转换为AD（CONV）的患者显示出增加的 大脑前部和后部区域之间的同步。虽然动物和人类研究是高度 尽管存在协同作用，但尚不清楚在动物模型中发现的过度兴奋是否是 在人类神经生理学中发现的超同步。为了弥补这一差距，将适用目前的建议， 最近开发了一种计算神经建模框架，该框架被独特地设计成将人类 宏观尺度M/EEG信号到可以被询问的底层细胞和电路水平动态 利用侵入性动物记录或其它成像模态（例如，磁共振波谱，纤维束成像），即 人类新皮质神经求解器（HNN）。我们将采用新的分析方法， CONV和NOCONV中的纵向MEG、纤维束成像、容量测定和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的生物标志物，并解释详细的神经机制， 这些生物标志物。 相关性（参见说明）： 越来越多的公共卫生需要了解大脑机制的损失， 阿尔茨海默病（AD）的连续体中的脑内稳态。该项目旨在定义新的早期 AD的诊断措施和基于确定的早期干预的靶向治疗策略 神经回路异常该项目有可能打开一个全新的窗口，以抵消 并延缓随着年龄增长而出现的认知能力下降，最终降低护理人员的成本，