Biological and environmental factors driving behavioral symptoms in Alzheimer's disease

项目总结 这个项目将调查不同的环境、个人和疾病相关因素是如何影响的 阿尔茨海默病（AD）患者行为症状的经验。阿尔茨海默病患者会经历 痴呆的行为症状（BSD），尽管大多数患者不会 体验所有类型的BSD或以可预测的模式体验它们。这使得发展有效 阿尔茨海默病的治疗和症状管理方法极具挑战性。我们的试验数据显示高度 每日报告中BSD的症状类型和发生频率的个体异质性。 其他报告在3个月内BSD的变化率存在显著的个体异质性。是的 目前尚不清楚是什么机制导致了BSD中这些人与人之间和人与人之间的差异。而 BSD亚综合征已被提出，但尚不清楚这些亚综合征中的BSD类型是如何的 暂时地相互依赖的或不同的应用于AD，修订症状管理模型， 指向环境（即未满足的需求、压力源）、个人（即遗传、微生物组、种族）和疾病 （即HSV1感染，全身性炎症）因素作为BSD的机制途径。我们假设 这些跨多个系统的因素促成了BSD的机械性开发，从而导致了可变性 在个体BSD表达中。跨多个系统阐明这些因素将有助于创建个性化 治疗BSD的方法从护理行为训练到药物干预。 共同居住的照顾者和阿尔茨海默病患者或混合型阿尔茨海默病患者（伴血管受累）（N=162） 二人组将被招募。同样数量的白人和非裔美国人将被录取，这样 种族差异的作用是可以检验的。使用微纵向设计，护理人员将 完成30天的每日日记，报告他们对环境暴露的观察，包括类型， BSD的频率、持续时间和严重程度。在入学和每一个新的日记周开始时，两个人将 前往研究诊所，收集AD患者的血液和粪便样本（共5份样本） 总)。BSD将在每日日志条目中报告，BSD类型以存在或不存在为22进行测量 症状跨越17个域。我们将使用一个多层次的模型分析框架来检验假设 概述研究策略，以完成以下目标：(1)确定环境(即， 未满足的需求、压力源)、个人（即遗传、微生物组、种族）和疾病（即1型单纯疱疹病毒感染）； 全身性炎症)因素直接或通过相互作用影响每日BSD的概率 (2)确定BSD的亚综合征，以及群体成员的预测因子。影响：通过竞争性测试领先 假设BSD，这个项目将阐明区分BSD患者的标准，这些患者是无法解决的 通过适当关注他们未被满足的需求。该项目的研究结果将为有针对性的干预措施提供信息 支持阿尔茨海默病患者及其家庭照顾者。 H: \CNR Secure \Grant Applications‐by Faculty Name \Pickering, Carol \NIH\R 01 NIMH \Grant 组件\Abstract\Project Summary＿Final TRANSFER.docx

Project Summary This project will investigate how different environmental, personal and disease related factors contribute to the experience of behavioral symptoms of patients with Alzheimer's disease (AD). Patients with AD will experience behavioral symptoms of dementia (BSD) at some point during their illness, though most patients will not experience all types of BSD or experience them in a predictable pattern. This has made development of effective treatments and symptom management approaches for AD highly challenging. Our pilot data shows a high degree of intraindividual heterogeneity in daily reports of BSD both in type of symptom and frequency of occurrence. Others report significant intraindividual heterogeneity in the rate of change in BSD over a 3-month period. It is currently unclear what mechanisms contribute to these within- and between-person variations in BSD. While BSD subsyndromes have been proposed it is unclear how the types of BSD within the subsyndromes are temporally dependent or distinct from each other. As applied to AD, the Revised Symptom Management Model, points to environmental (i.e., unmet needs, stressors), personal (i.e., genetic, microbiome, ethnicity), and disease (i.e., HSV1 infection, systemic inflammation) factors as mechanistic pathways for BSD. We hypothesize that these factors across multiple systems contribute to the mechanistic development of BSD, and thus the variability in individual BSD expression. Elucidation of these factors across multiple systems will help create personalized approaches to treatment of BSD spanning from caregiving behavioral training to pharmacological interventions. Dyads of co-residing caregivers and persons with AD or mixed-type AD (with vascular involvement) (N=162 dyads) will be recruited. Equal numbers of Caucasian and African American dyads will be enrolled so that the contributing role of racial differences can be examined. Using a micro-longitudinal design, caregivers will complete daily diaries for 30 days reporting on their observations of environmental exposures, including type, frequency, duration, and severity of BSD. At enrollment and at the start of each new week of diaries, dyads will visit the research clinic where blood and stool samples will be collected from the person with AD (for 5 samples total). BSD will be reported in the daily diary entries, with BSD type measured as presence or absence of 22 symptoms across 17 domains. We will use a multi-level model analytic framework to examine hypotheses outlines in the research strategy in order to complete the following aims: (1) Determine how environmental (i.e., unmet needs, stressors), personal (i.e., genetic, microbiome, ethnicity) and disease (i.e. HSV1 infection, systemic inflammation) factors impact probability of daily BSD, either directly or through interaction effects, and (2) Identify subsyndromes of BSD, and predictors of group membership. Impact: By competitively testing leading hypotheses for BSD, this project will elucidate criteria for distinguishing patients with BSD that are not resolvable via appropriate attention to their unmet needs. Findings from this project will inform targeted interventions to support persons with Alzheimer's disease and their family caregivers. H:\CNR Secure\Grant Applications‐by Faculty Name\Pickering, Carol\NIH\R01 NIMH\Grant Components\Abstract\Project Summary_Final TRANSFER.docx