CRCNS: Investigating Brain Dynamics through the Lens of Statistical Mechanics

CRCNS：通过统计力学的视角研究大脑动力学

基本信息

批准号：
10401891
负责人：
Alex Leow
金额：
$ 29.05万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401891
关键词：
Achievement Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer’s disease biomarker Amyloid beta-42 Amyloid deposition Anterior Apolipoprotein E Back Brain Clinical Cognitive Complex DNA Sequence Alteration Data Data Set Diagnosis Diffusion Magnetic Resonance Imaging Disease Dose Elderly Equilibrium Exhibits Family Female Functional Magnetic Resonance Imaging Functional disorder Gender Graph Human Hybrids Image Impairment Instruction Knock-in Learning Link Longevity Mathematics Measures Medical Imaging Memory Modeling Modernization Mus Nature Neurons Onset of illness Parahippocampal Gyrus Pattern Performance Persons Phase Transition Phenotype Physics Property Resources Rest Risk Statistical Mechanics Structure Synapses System Techniques Temporal Lobe Testing Thermodynamics Time Transgenic Mice Woman base computerized tools connectome deep learning design disease classification ferrite genetic risk factor graph neural network human data improved lens male men mouse model multimodality neuroimaging neuronal circuitry neuropathology non-invasive imaging normal aging novel outcome prediction recruit sex tau Proteins theories tool

项目摘要

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.

突触功能障碍已成为阿尔茨海默氏症最早的大脑变化之一疾病（AD），导致神经回路过度兴奋然而，网络变化与年龄有关。性别往往与疾病神经病理学重叠，增加了分离的难度事实上，与男性和女性正常衰老轨迹相关的疾病特异性改变。 AD 对女性的影响尤为严重，她们占所有被诊断患有 AD 的人的三分之二失智。利用静息态 fMRI 连接组和扩散 MRI 衍生的结构连接组，我们将使用最近，新型混合静息态结构连接体（rs-SC）用于研究兴奋-抑制平衡。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，我们表现出性别、年龄、表型之间的相互作用，随着年龄的增加，显着的过度兴奋仅在女性中观察到，但在男性中观察不到。此外，女性携带者开始表现出过度兴奋。 50岁前扣带回、海马旁回和颞叶区域，以及过度兴奋与空间学习期间神经资源的补偿性招募有关记忆任务。在本提案中，我们将描述 1) 兴奋-抑制平衡的性别特异性规范轨迹使用人类连接组计划 (HCP) 数据，以及 2) 改变兴奋-抑制平衡使用阿尔茨海默病神经影像倡议 (ADNI) 数据发现异常衰老，以及 3) 进一步在 AD 纵向小鼠模型中测试和验证我们的超兴奋框架。相关性（参见说明）：在本提案中，我们将开发新颖的计算工具来表征超激励模式衰老和阿尔茨海默病，并验证我们的人类数据超兴奋框架（ADNI 和 HCP）以及 AD 纵向小鼠模型，这将显着提高我们对 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志物。