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

项目摘要

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.