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的兴趣越来越大 在阿尔茨海默氏病（AD）的连续体中，大脑体内平衡的丧失是基本的。动物 模型表明，这种现象的底物是兴奋/抑制（E/I）平衡的丧失 由于淀粉样蛋白低聚物和斑块对抑制末端的毒性作用。这种过度兴奋的是 假定是为了奠定了观察到的α/beta的功率和跨区域内同步的增加 具有电磁和磁摄影（M/EEG）的人类测量的频率振荡。 失忆性轻度认知受损（AMCI）患者（7-14Hz）的静息状态升高（AMCI）患者增加 淀粉样蛋白沉积较高的大脑区域中的Alpha和（15-29Hz）β带。另外，AMCI 与非转换器（Noconv）相比，后来转换为AD（CORS）的患者显示出增加 前脑区域和后脑区域之间的同步。而动物和人类研究很高 协同作用，尚不清楚动物模型中的过度兴奋性是否是 在人类神经生理学中发现的高超同步。为了弥合这一差距，当前的建议将适用 最近开发的计算神经建模框架独特而设计，旨在将人类联系起来 宏观M/EEG信号可以质疑潜在的细胞和电路水平动力学 具有侵入性动物记录或其他成像方式（例如MR光谱，拖拉术），即 人类新皮层神经溶剂剂（HNN）。我们将向先前收集的新分析方法应用新的分析方法 纵向MEG，拖拉术，体积和MR GABA光谱数据在交流和noconv-中 AMCI患者和对照（目标1和3），并将结果与​​HNN框架（目标2）整合到 建立新的早期诊断AD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（请参阅说明）： 公共卫生越来越需要了解损失的大脑机制 阿尔茨海默氏病（AD）连续体的大脑体内平衡。该项目旨在提早定义新的 基于确定的AD和针对性治疗策略的诊断措施和针对性的治疗策略 神经回路异常。该项目有可能打开一个全新的窗口以抵消 随着衰老的延迟认知能力下降，最终降低了护理人员的成本并改善