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

项目摘要 该项目将调查不同的环境，个人和疾病相关因素如何影响 阿尔茨海默病（AD）患者的行为症状的经验。AD患者将经历 痴呆症（BSD）的行为症状在他们患病期间的某个时候，虽然大多数患者不会 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 AD的治疗和症状管理方法极具挑战性。我们的飞行员数据显示 BSD每日报告的症状类型和发生频率的个体内异质性。 其他人报告了3个月内BSD变化率的显着个体内异质性。是 目前还不清楚是什么机制导致了BSD中的这些人内和人与人之间的变化。而 BSD子综合征已经被提出，但还不清楚子综合征中的BSD类型是如何定义的。 在时间上相互依赖或不同。当应用于AD时，修订的症状管理模型， 指向环境（即，未满足的需求，压力源），个人的（即，遗传、微生物组、种族）和疾病 (i.e., HSV 1感染、全身性炎症）因素作为BSD的机制途径。我们假设 跨多个系统的这些因素有助于BSD的机械式开发，因此也就导致了BSD的可变性 在单独的BSD表达式中。在多个系统中阐明这些因素将有助于创建个性化的 从行为训练到药物干预的BSD治疗方法。 共同居住的照顾者和AD或混合型AD（血管受累）患者的成对组（N=162 将被招募。将入组相同数量的高加索人和非洲裔美国人二联体， 种族差异的作用可以研究。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。在登记时和每个新的日记周开始时， 访问研究诊所，从AD患者身上采集血液和粪便样本（5份样本 共计）。BSD将在每日日记条目中报告，BSD类型以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 概述了研究战略，以完成以下目标：（1）确定如何环境（即， 未满足的需求，压力源），个人的（即，遗传、微生物组、种族）和疾病（即HSV 1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)确定BSD的子综合征和群体成员的预测因子。影响：通过竞争性测试， BSD的假设，这个项目将阐明区分BSD患者的标准，这些患者无法解决 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，Pickering，Pickering\NIH\R01 NIMH\Grant 组件\摘要\项目摘要_最终转移. 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