Understanding the Pathway to Functional Disability in Alzheimer's disease

描述（由申请人提供）：残疾在老年人中很常见，是一个主要的公共卫生问题，因为它与生活质量下降和服务利用率增加有关。阿尔茨海默病（AD）是致残的主要原因。尽管它很重要，但相对较少的研究已经完成，以了解AD功能下降的过程，或驱动个人日常功能下降轨迹的机制。在发展中的退行性痴呆，如阿尔茨海默氏症，日常能力的丧失是一个渐进的过程。也就是说，与认知能力类似，功能能力是连续下降的，反映了潜在疾病的进展。这项研究的重点是更好地理解功能衰退的完整连续性，特别是在残疾之前和预测残疾的早期和微妙问题（残疾被定义为对主要生活领域的依赖，如日常生活的工具和基本活动）。残疾的发展是许多因素复杂相互作用的结果。在AD中，很明显认知能力下降是主要的决定因素；该项目的一个重点是更好地了解特定的认知障碍如何导致日常功能的特定领域的缺陷。然而，除了认知之外，可能还有大量其他因素进一步促进和帮助解释下降速度和模式的个体差异。在NIA之前的支持下（AG021511），我们开发了一种新颖而敏感的方法来测量“功能限制”-可能先于直接残疾发展的功能问题。使用这种方法，我们已经证明轻度认知障碍（MCI）与中度到正常衰老和痴呆的功能限制有关。采用前瞻性的纵向研究设计，本项目的目的1侧重于描述正常功能和残疾之间的中间阶段和过渡点。目的2-4试图通过检查这种可变性的潜在来源来理解我们在个体功能轨迹中看到的异质性。具体来说，我们将研究神经心理、神经精神和运动障碍如何影响残疾途径。此外，我们将研究如何相关的风险因素，如一般健康状况和教育，修改功能下降的轨迹。更好地了解功能衰退的轨迹，以及导致个体发病率和衰退模式的因素，将对早期诊断和预后具有重要的临床意义；治疗发展和早期实施支持性服务和护理规划；以及疾病进展的测量以及潜在疾病治疗的效果。公共卫生相关性：阿尔茨海默病（AD）是残疾的主要原因（现实生活能力下降，如管理个人财务或药物、驾驶等），这直接降低了患者及其照顾者的生活质量，并导致经济负担增加。尽管它们很重要，但我们并不清楚与AD相关的功能问题是如何发生和发展的，也不清楚导致进行性残疾的具体因素。了解阿尔茨海默病的残疾是如何发展的，将对公共卫生、预防医学和治疗发展产生深远的影响，也将对患者的个性化护理产生重要影响。

DESCRIPTION (provided by applicant): Disability is common in the elderly and is a major public health concern because it is associated with reduced quality of life and increased service utilization. Alzheimer's Disease (AD) is a major cause of disability. Despite its importance, relatively little research has been done to understand the course of functional decline in AD, or the mechanisms that drive individual trajectories of declines in everyday function. The loss of everyday abilities in the setting of a developing degenerative dementia such as AD is a progressive process. That is, functional abilities decline along a continuum, similar to cognition, reflecting progression of the underlying disease. A major emphasis of the proposed study is to better understand the full continuum of functional decline, particularly early and subtle problems that precede and predict disability (disability being defined as dependency in major life domains such as instrumental and basic activities of daily living). The development of disability results from a complex interplay between numerous factors. In AD, clearly cognitive decline is a major determinant; a focus of this project is to better understand how specific cognitive impairments contribute to deficits in specific domains of everyday function. In addition to cognition, however, there are likely a large number of other factors that further contribute to and help explain individual variability in rates and patterns of decline. With previous NIA support (AG021511) we developed a novel and sensitive approach to measuring `functional limitations' - functional problems that likely precede the development of frank disability. Using this approach we have demonstrated that Mild Cognitive Impairment (MCI) is associated with functional limitations intermediate to normal aging and dementia. Using a prospective, longitudinal research design, Aim 1 of this project focuses on characterizing the intermediate stages and transition points between normal function and disability. Aims 2-4 seek to understand the heterogeneity we see in individual functional trajectories by examining potential sources of this variability. Specifically, we will examine how neuropsychological, neuropsychiatric, and motor impairments influence the disability pathway. In addition, we will examine how associated risk factors, such as general health status and education, modify the trajectories of functional decline. An improved understanding of trajectories of functional decline, and the factors that contribute to individual rates and patterns of decline, will have important clinical relevance for: early diagnosis and prognosis; treatment development and the early implementation of supportive services and care planning; and the measurement of disease progression and the effects of potential disease modifying treatments. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is a major cause of disability (declines in real-world abilities such as manage one's finances or medications, driving, etc.), which directly reduced quality of life for patients and their caregivers, and lead to increased economic burden. Despite their importance, we do not clearly understand how functional problems develop and progress in association with AD, nor do we understand the specific factors that contribute to progressive disability. Understanding how disability develops in AD will have far reaching applications to public health, preventative medicine, and treatment development, and will also have important implications for the individualized care of patients.