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: 10474580
• 负责人: STEPHANIE Ruggiano JONES
• 金额: $ 23.65万
• 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/10474580
• 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; 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，人们对了解大脑的机制越来越感兴趣 在阿尔茨海默病(AD)的连续体中，大脑动态平衡的丧失是潜在的。动物 模型表明，这种现象的基础是兴奋性/抑制性(E/I)平衡的丧失 由于淀粉样寡聚体和斑块对抑制终末的毒性作用。这种极度兴奋是 被认为是观察到的阿尔法/贝塔的功率和区域间同步增加的基础 用脑电和脑磁图(M/EEG)测量人体的频率振荡。 健忘型轻度认知障碍(AMCI)患者在静息状态下(7-14赫兹)脑磁图功率增加 淀粉样蛋白沉积较高的脑区的阿尔法和(15-29赫兹)β波段。此外，aMCI 后来转为AD(COV)的患者与未转为AD(NOCONV)的患者相比，显示出增加的趋势 大脑前部和后部区域之间的同步性。虽然动物和人类的研究是高度 协同作用，尚不清楚在动物模型中发现的过度兴奋是否是 人类神经生理学中发现的超同步化。为了弥合这一差距，目前的提案将适用 最近开发了一个计算神经建模框架，该框架独特地设计用于将人类 宏观M/EEG信号到可被询问的潜在细胞和电路级动力学 使用有创动物记录或其他成像方式(例如，磁共振光谱学、纤维束造影术)，即 人脑皮质神经解算器(HNN)。我们将把新的分析方法应用于以前收集的 COV-和NOCONV-的纵向脑磁图、纤维束成像、容量测量和磁共振GABA波谱数据 AMCI患者和对照(目标1和3)，并将结果与HNN框架(目标2)相结合，以 建立新的早期诊断AD生物标志物并解释其详细的神经机制 这些生物标志物。 相关性(请参阅说明)： 越来越多的公众健康需要了解大脑机制在大脑中的缺失。 阿尔茨海默病(AD)过程中的脑内稳态。该项目旨在定义新的早期 阿尔茨海默病的诊断措施和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扇全新的窗口来抵消 并延缓随年龄增长的认知衰退，最终降低照顾者的成本并改善