CRCNS: Investigating Brain Dynamics through the Lens of Statistical Mechanics

突触功能障碍被认为是阿尔茨海默病最早的大脑变化之一 阿尔茨海默病(AD)，导致神经元回路过度兴奋。然而，网络的变化与年龄有关 性倾向于与疾病神经病理重叠，增加了分离的难度 与男性和女性正常衰老轨迹相关的疾病特异性改变。的确， AD对女性的影响不成比例，占所有确诊AD患者的三分之二 痴呆症。 利用静息状态fMRI连接体和扩散MRI衍生的结构连接体，我们将使用 用于研究激发-抑制平衡的新型混合静止态结构连接体(Rs-SC)。最近， 使用一组认知正常的APOE-ε4携带者和年龄/性别匹配的非携带者 表现出性别与年龄、表型的交互作用，随着年龄的增长表现出明显的高度兴奋 只在女性身上观察到，但在男性身上看不到。此外，在女性携带者中开始表现出高度兴奋。 年龄50岁，在扣带回前区、海马旁回和颞叶区域，以及 在空间学习中，过度兴奋与神经元资源的代偿性募集有关 记忆任务。 在这项建议中，我们将描述1)特定性别的兴奋-抑制平衡的规范轨迹 使用人类连接组计划(HCP)数据，以及2)改变了 使用阿尔茨海默病神经成像倡议(ADNI)数据以及3)进一步 在纵向阿尔茨海默病小鼠模型中测试和验证我们的高兴奋框架。 相关性(请参阅说明)： 在这项提议中，我们将开发新的计算工具来表征超激发模式 衰老和阿尔茨海默氏症，并验证我们基于人类数据的过度兴奋框架(ADNI和 Hcp)，以及纵向AD小鼠模型。这将大大提高我们对AD的理解 并有可能加速发现更强大的AD非侵入性成像生物标记物。

Synaptic dysfunction has been hypothesized to be one of the earliest brain changes in Alzheimer’s disease (AD), leading to hyper-excitation in neuronal circuits. However, network changes related to age and sex tend to overlap with disease neuropathology, increasing the difficulty of separating disease-specific alterations from those related to normal aging trajectories in males and females. Indeed, AD disproportionately affects women, who comprise two thirds of all persons diagnosed with AD dementia. Leveraging resting state fMRI connectome and diffusion MRI-derived structural connectome, we will use a novel hybrid resting-state structural connectome (rs-SC) to study excitation-inhibition balance. Recently, using a group of cognitively normal APOE-ε4 carriers and age/gender matched non-carriers we demonstrated a sex-by-age-by-phenotype interaction, with significant hyperexcitation with increasing age only observable in women, but not in men. Further, hyperexcitation in female carriers began to exhibit at age 50 in the anterior cingulate, parahippocampal gyrus and temporal lobe regions, and the degree of hyperexcitation is linked to compensatory recruitment of neuronal resources during a spatial learning memory task. In this proposal, we will characterize 1) sex-specific normative trajectories of excitation-inhibition balance using the Human Connectome Project (HCP) data, and 2) altered excitation-inhibition balance in abnormal aging using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, as well as 3) further test and validate our hyperexcitation framework in longitudinal mouse models of AD. RELEVANCE (See instructions): In this proposal, we will develop novel computational tools to characterize hyper-excitation patterns in aging and Alzheimer's Disease and validate our hyperexcitation framework on human data (ADNI and HCP) as well as longitudinal mouse models of AD. This will significantly improve our understanding of AD and potentially accelerate the discovery of more robust non-invasive imaging biomarkers of AD.