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

最近，一些证据支持突触功能障碍代表了 阿尔茨海默病（AD）最早的大脑变化，导致神经元过度兴奋， 电路.然而，网络变化与年龄、性别等危险因素有关， 载脂蛋白E（APOE）ε4等位基因倾向于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分开 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可能影响这些 关系。特别是，晚年抑郁症（LLD）已被提出作为一个重要的 加速认知能力下降并进展为痴呆症。这个问题仍然没有 不清楚LLD的哪些神经生物学方面代表了特异性特征，而共同特征 AD的发生方面，确定其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 生命后期的过程。 我们将使用多通道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样品中，以阐明晚期- 生活抑郁症和神经退化。我们的管道将基于一种新的静止状态 结构连接组学（rs-SC）方法，其产生过兴奋指标（HI）。 以前，在一组认知正常的APOE-ε4携带者和年龄/性别匹配的非- 携带者，我们证明了性别，年龄，基因型的相互作用，与显着的兴奋过度 随着年龄的增长，只在女性中观察到，而在男性中则没有。特别是，结果支持 在默认模式网络中，女性携带者在50岁时开始表现出过度兴奋， （DMN）。此外，过度兴奋的程度被证明与代偿性相关。 在空间学习记忆任务期间神经元资源的募集（虚拟Morris水 迷宫任务）。受这项初步研究的启发，我们将研究情绪（晚年生活） 抑郁症）和随后的认知下降和痴呆症的发展， 突触功能障碍

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.