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：
10222567
负责人：
Alex Leow
金额：
$ 28.87万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222567
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 convolutional neural network deep learning design disease classification ferrite genetic risk factor 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.

突触功能障碍已被认为是阿尔茨海默氏症最早的大脑变化之一疾病（AD），导致神经元电路过度兴奋。但是，网络变化与年龄有关性倾向于与疾病神经病理学重叠，增加了分离的困难与男性和女性正常衰老轨迹相关的疾病特异性变化。的确，广告不成比例地影响妇女，这些妇女构成了被诊断为广告的所有人中的三分之二失智。利用静止状态fMRI Connectome和扩散MRI衍生的结构连接组，我们将使用一个新型杂交静止状态结构连接组（RS-SC）研究兴奋抑制平衡。最近，使用一组认知正常的APOE-ε4载体和年龄/性别匹配的非携带者我们表现出逐年的性别相互作用，年龄增长显着过度过度过度过度仅在女性中可观察到，但在男性中不可观察。此外，女性承运人的过度激光开始暴露于 50岁的前扣带回，parahippocampal回和临时叶区域以及程度过度刺激与空间学习过程中神经元资源的补偿性募集有关内存任务。在此提案中，我们将表征1）特定于性别的刺激抑制平衡的正常轨迹使用人类连接项目（HCP）数据，2）改变了兴奋的抑制平衡使用阿尔茨海默氏病神经成像倡议（ADNI）数据以及3）的异常老化以及3）进一步在AD的纵向小鼠模型中测试和验证我们的过度刺激框架。相关性（请参阅说明）：在此提案中，我们将开发新颖的计算工具来表征在衰老和阿尔茨海默氏病，并验证我们在人类数据上的过度刺激框架（ADNI和 HCP）以及AD的纵向小鼠模型。这将大大提高我们对广告的理解并有可能加速AD的更强大的非侵入性成像生物标志物。