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

项目摘要 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 阿尔茨海默病患者的行为症状体会阿尔茨海默病患者将经历 痴呆症的行为症状(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。这使得开发变得有效 阿尔茨海默病的治疗和症状管理方法极具挑战性。我们的试点数据显示 在BSD的日常报告中，个体内部的异质性在症状类型和发生频率上都是如此。 其他人则报告了3个月内BSD变化率的显著个体内异质性。它是 目前尚不清楚是什么机制导致了人内和人与人之间的BSD差异。而当 BSD亚型已经被提出，目前还不清楚BSD在亚型中的类型是什么 时间上相互依赖的或彼此不同的。正如应用于AD，修订后的症状管理模型， 指向环境(即未满足的需求、压力源)、个人(即遗传、微生物群、种族)和疾病 (例如，HSV1感染、全身炎症)因素是BSD的机制途径。我们假设 跨多个系统的这些因素促成了BSD的机械性发展，从而导致了可变性 在单独的BSD表达中。跨多个系统阐明这些因素将有助于创建个性化的 治疗BSD的方法从照顾行为训练到药物干预。 共同居住的照顾者和AD或混合型AD(有血管受累)患者的二元体(N=162) 二人)将被招募。同样数量的高加索人和非裔美国人将被录取，这样 可以考察种族差异的贡献作用。使用微纵向设计，照顾者将 完成为期30天的每日日记，报告他们观察到的环境暴露情况，包括类型、 BSD的频率、持续时间和严重程度。在注册和每个新的一周日记开始时，双胞胎将 访问研究诊所，在那里将从AD患者身上收集血液和粪便样本(5个样本 总计)。BSD将在每日日记条目中报告，BSD类型以存在或不存在22 17个领域的症状。我们将使用多层次模型分析框架来检验假设 在研究战略中概述，以完成以下目标：(1)确定环境(即， 未满足的需求、应激源)、个人(即基因、微生物群、种族)和疾病(即HSV1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，以及 (2)识别BSD的亚症候群和预测组成员资格的因素。影响：通过竞争性测试领先 BSD的假设，这个项目将阐明区分无法解决的BSD患者的标准 通过适当关注他们未得到满足的需求。该项目的调查结果将为有针对性的干预提供信息 支持阿尔茨海默病患者及其家庭照顾者。 H：\CNR Secure\Grant应用程序-按教师名称\Pickering，Carol\NIH\r01 NIMH\Grant 组件\抽象\项目摘要_最终传输.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