Connecting late-life depression and cognition with statistical physics based connectomics and sparse Frechet regression

将晚年抑郁症和认知与基于统计物理学的连接组学和稀疏 Frechet 回归联系起来

• 批准号: 10190424
• 负责人: Alex Leow
• 金额: $ 126.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190424
• 关键词: Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Archives; Area; BRAIN initiative; Brain; Clinical; Cognition; Cognitive; Complement; Data; Data Set; Dementia; Demographic Factors; Depressed mood; Diagnosis; Disease; Elderly; Equilibrium; Exhibits; Female; Functional disorder; Gender; Genotype; Graph; Hippocampus (Brain); Hybrids; Impaired cognition; Individual; Intervention; Late Effects; Learning; Link; Mathematics; Measures; Mediating; Memory; Mental Depression; Modeling; Moods; Nature; Nerve Degeneration; Neurobiology; Neurocognitive; Neurons; Parietal Lobe; Persons; Physics; Pilot Projects; Prevention; Process; Regression Analysis; Reporting; Resources; Rest; Risk Factors; Role; Sampling; Secondary to; Statistical Data Interpretation; Structure; Synapses; Temporal Lobe; Testing; Time; Woman; base; cerebral atrophy; cognitive development; cognitive function; cognitive performance; comparison group; connectome; demographics; ferrite; follow-up; functional decline; functional outcomes; geriatric depression; indexing; male; men; morris water maze; multimodality; neuronal circuitry; neuropathology; normal aging; novel; prevent; prospective; recruit; secondary analysis; sex; tool; virtual; β-amyloid burden

Recently, several lines of evidence have supported that synaptic dysfunction represents one of the earliest brain changes in Alzheimer’s disease (AD), leading to hyper-excitation in neuronal circuits. However, network changes related to age, sex and other risk factors such as the apolipoprotein E (APOE) ε4 allele 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 (women comprise two thirds of all persons diagnosed with AD dementia, while female ε4 allele carriers are four times more likely to develop AD than men). Further compounding the challenges is the potential for psychiatric conditions to influence these relationships. Specifically, late life depression (LLD) has been proposed as a significant contributor to accelerated cognitive decline and progression to dementia. While it remains unclear which neurobiological aspects of LLD represent pathognomonic features, versus co- occurring aspects of AD, determining their impact on functional outcomes is a significant opportunity to disentangle the relationship between depression and neurodegenerative processes in late life. We will use multi-modal connectomics to analyze excitation-inhibition balance (E-I balance) in the well-characterized ADNI and ADNI-D samples to elucidate the relationship between late- life depression and neurodegeneration. Our pipeline will be based on a novel resting-state structural connectomics (rs-SC) approach that yields a hyperexcitation indicator (HI). Previously, in a group of cognitively normal APOE-ε4 carriers and age/gender matched non- carriers we demonstrated a sex-by-age-by-genotype interaction, with significant hyperexcitation with increasing age only observable in women, but not in men. In particular, results supported that hyperexcitation in female carriers began to exhibit at age 50 in the default mode network (DMN). Further, the degree of hyperexcitation was shown to be related to compensatory recruitment of neuronal resources during a spatial learning memory task (virtual Morris water maze task). Motivated by this pilot study, we will examine the links between mood (late-life depression) and subsequent cognitive decline and development of dementia in the context of synaptic dysfunction.

最近，多项证据支持突触功能障碍是其中之一 阿尔茨海默病 (AD) 中最早的大脑变化，导致神经元过度兴奋 然而，网络变化与年龄、性别和其他危险因素有关。 载脂蛋白 E (APOE) ε4 等位基因往往与疾病神经病理学重叠，增加了 难以将疾病特异性改变与正常衰老相关的改变区分开来 男性和女性的轨迹（女性占所有诊断患有 AD 的人的三分之二） 痴呆症，而女性 ε4 等位基因携带者患 AD 的可能性是男性的四倍）。 进一步加剧挑战的是精神疾病有可能影响这些 具体而言，晚年抑郁症（LLD）被认为是一种重要的人际关系。 加速认知能力下降和痴呆症进展的因素，但它仍然存在。 不清楚 LLD 的哪些神经生物学方面代表了病理特征，而不是共同的 AD 的各个方面，确定它们对功能结果的影响是一个重要的 有机会解开抑郁症和神经退行性疾病之间的关系 晚年的过程。 我们将使用多模态连接组学来分析兴奋-抑制平衡（E-I平衡） 在充分表征的 ADNI 和 ADNI-D 样本中，以阐明晚期之间的关系 我们的管道将基于一种新颖的静息状态。 结构连接组学 (rs-SC) 方法可产生超兴奋指标 (HI)。 此前，在一组认知正常的 APOE-ε4 携带者和年龄/性别匹配的非 我们证明了携带者的性别、年龄、基因型之间的相互作用，并具有显着的过度兴奋 随着年龄的增长，仅在女性中观察到这一现象，但在男性中则不然，这一结果得到了支持。 女性携带者的过度兴奋在 50 岁时开始在默认模式网络中表现出来 （DMN）此外，过度兴奋的程度被证明与代偿性有关。 在空间学习记忆任务期间招募神经资源（虚拟莫里斯水 受这项试点研究的启发，我们将研究情绪（晚年）之间的联系。 抑郁症）以及随后的认知能力下降和痴呆症的发展 突触功能障碍。