Assess Neural Circuits and Subtypes Underlying Dimensions of Neuropsychiatric Symptoms in Alzheimer's Disease

项目摘要 神经精神症状（Neuropsychiatric symptoms，缩写为CNS）通常见于轻度认知障碍或 阿尔茨海默病（AD）痴呆。这些症状影响高达97%的AD患者， 可能导致认知功能加速下降并转化为痴呆症。虽然许多努力 一直致力于研究阿尔茨海默病的病因学，阿尔茨海默病痴呆的神经生物学基础 仍不清楚迫切需要推进对这些症状的机械理解， 对于早期发现和及时干预以预防AD进展至关重要。越来越多的证据表明 这种差异性的神经网络基本上是重叠的，并且与独特的大脑网络的功能障碍有关。 因此，从三维角度评估其相关的电路水平功能障碍将提供重要的 有助于加深我们对参与表达的神经回路的理解。响应于 根据PAR-20-159的指导方针，该项目的总体目标是评估神经回路并确定 神经生理亚型（即，亚型）的潜在维度。我们假设 神经回路的不同模式将反映从临床前到 严重AD痴呆，并相互作用以确定预测临床症状的神经生理学亚型 和AD进展的速率。在目标1中，我们将识别可解释的神经回路和相关的潜在神经回路。 使用稀疏多变量相关性分析来确定多个域的维数。在目标2中，我们将确定 神经生理学亚型使用统计聚类与指导下，从三维相关 电路特性我们将进一步评估和解释神经生物学意义和临床 这些维度和子类型的相关性。将制定拟议的办法， 通过评估两个独立队列（OASIS-3和ADNI）的静息状态功能MRI进行评价， 总共有1,800多个主题。该项目的成功成果将使人们更好地了解 潜在的神经生物学机制及其临床相关性，形成了一个有前途的新途径， 潜在地指导AD的干预和更好地管理AD进展，从而为 AD痴呆症的精准医疗

Project Abstract Neuropsychiatric symptoms (NPS) are commonly observed in individuals with mild cognitive impairment or Alzheimer’s disease (AD) dementia. These symptoms affect up to 97% of patients during the course of AD and may cause accelerated declines in cognitive functions and conversion to dementia. Though numerous efforts have been devoted to investigating the etiology of NPS, the neurobiological basis underlying NPS in AD dementia remains unclear. There is an urgent need to advance the mechanistic understanding of these symptoms, which is crucial for early detection and timely intervention to prevent AD progression. Increasing evidence has indicated that differential NPS overlap substantially and are relevant to dysfunctions in distinctive brain networks. Assessing NPS dimensionally and their associated circuit-level dysfunctions would therefore provide significant benefits to deepen our understanding of neural circuits involved in the expression of NPS. In response to the guidelines of the PAR-20-159, the overall objective of the project is to assess neural circuits and identify neurophysiological subtypes (i.e., subtypes) underlying dimensions of NPS in dementia. We hypothesize that distinct patterns of neural circuits will reflect latent dimensions of NPS domains that span from preclinical to severe AD dementia, and interact to define neurophysiological subtypes that are predictive of clinical symptoms and the rate of AD progression. In Aim 1, we will identify interpretable neural circuits and the linked latent dimensions of NPS domains using a sparse multivariate correlation analysis. In Aim 2, we will identify neurophysiological subtypes using statistical clustering with guidance from the NPS dimension-associated circuitry characteristics. We will further evaluate and interpret the neurobiological meanings and clinical relevance underlying these dimensions and subtypes. The proposed approaches will be developed and evaluated by assessing resting-state functional MRI from two independent cohorts (OASIS-3 and ADNI) with more than 1,800 subjects in total. Successful outcomes of the project will lead to an improved understanding of the neurobiological mechanism underlying NPS and its clinical relevance, form a promising new avenue to potentially guide the intervention of NPS and better the management of AD progression, and hence pave the way towards precision medicine of AD dementia.