Intraindividual Cognitive Variability as an Early Marker of Alzheimer's Disease

摘要 阿尔茨海默病(AD)是痴呆症最常见的形式，有神经病理，如贝塔-1。 淀粉样蛋白(Aβ)沉积和海马体体积缩小发生在临床认知障碍的前几年。 早期识别这些临床前AD阶段对于改进预防和治疗工作至关重要。 不幸的是，用传统神经心理学很难捕捉到最早的细微认知变化。 测试，其中1)是为了检测明显的临床认知障碍，2)是为了测量峰值表现 在受控良好的环境中的单个时间点，该时间点可能不具有代表性 日常生活。这些限制突显了对有效评估工具的需求，这些工具不仅可以涵盖 日常认知，也包括日常生活的方方面面，如心理社会因素，这些因素表明对阿尔茨海默病的恢复能力 临床症状学。利用常见智能手机技术的移动健康(MHealth)评估 可能有助于克服这些限制，因为在整个课程中，每天都会对行为进行多次实时采样 好几天了。重复采样能够表征一个人的行为的时间过程，在 他们的认知条件和他们的心理社会背景。 这项建议的目标是检查mHealth计划检测AD早期标记的效用 认知脆弱性。具体目标是检查随时间变化对mHealth认知性的影响 测量(即个体内认知变异性)是1)AD神经病理风险的标志，以及2)预测 传统神经心理学测验中的纵向认知衰退。一个探索性的目标是建议检查 阿尔茨海默病神经病变较多的个体是否表现出更强的同步性 心理社会背景(人际互动、情绪、孤独感)和日常认知表现。 参与者将是认知正常的Aβ阳性和阴性个体，从正在进行的纵向招募 收集阿尔茨海默病神经病理的神经心理学和神经成像(PET、MRI)标志物的研究。 参与者将接受为期14天的移动健康计划，两年内两次，对心理社会因素进行抽样 和认知能力。拟议的培训目标包括1)建立基本的移动健康技能和 在使用mHealth测量认知和心理社会因素方面的专门知识，2)获得高级 在有助于抵抗和恢复AD症状的心理社会因素方面的专业知识，以及3) 深入了解AD神经病理危险因素的正电子发射计算机断层扫描和核磁共振成像。 总而言之，这项拟议的K23奖为了解个人是否在 高AD神经病理风险在mHealth评估中显示出认知脆弱性的早期标志。这个 这项研究的结果将为PI作为独立机构的发展奠定必要的基础 神经心理学家-使用尖端方法早期识别风险和复原力的研究人员 影响AD症状发展的因素，最终影响AD的治疗。

ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia, with neuropathology such as beta- amyloid (Aβ) deposits and reduced hippocampal volume developing years before clinical cognitive impairment. Early identification of these preclinical AD stages is imperative for improving prevention and treatment efforts. Unfortunately, capturing the earliest subtle cognitive changes is difficult with traditional neuropsychological tests, which 1) were developed to detect overt clinical cognitive impairment, and 2) measure peak performance at a single, and potentially non-representative, time point in a well-controlled environment that is detached from daily life. These limitations underscore the need for valid assessment tools that capture not only the range of everyday cognition but also aspects of daily life, such as psychosocial factors, that signal resilience to AD clinical symptomatology. Mobile health (mHealth) assessments that utilize common smartphone technology may help overcome these limitations by sampling behavior multiple times per day in ‘real-time’, over the course of several days. Repeated sampling enables characterization of the time-course of a person’s behavior, both in terms of their cognition and their psychosocial context. The goal of this proposal is to examine the utility of a mHealth program to detect early markers of AD cognitive vulnerability. The specific aims are to examine whether variability over time on mHealth cognitive measures (i.e., intraindividual cognitive variability) is 1) a signature of AD neuropathologic risk, and 2) predicts longitudinal cognitive decline on traditional neuropsychological tests. An exploratory aim proposes to examine whether individuals with more AD neuropathology show stronger synchrony between their everyday psychosocial context (interpersonal interactions, mood, loneliness) and everyday cognitive performance. Participants will be cognitively normal Aβ positive and negative individuals recruited from ongoing longitudinal studies that gather neuropsychological and neuroimaging (PET, MRI) markers of AD neuropathology. Participants will undergo a 14-day mHealth protocol, twice over two years, that samples psychosocial factors and cognitive performance. The proposed training aims include 1) building foundational mHealth skills and specific expertise in using mHealth to measure cognition and psychosocial factors, 2) acquiring advanced expertise in psychosocial factors that contribute to resistance and resilience to AD symptoms, and 3) developing in-depth knowledge of PET and MRI imaging of AD neuropathologic risk factors. In summary, this proposed K23 award sets the foundation toward understanding whether individuals at high AD neuropathologic risk show early markers of cognitive vulnerability on mHealth assessments. The results of this study will establish the necessary groundwork for the PI’s development as an independent neuropsychologist-investigator using cutting-edge approaches for early identification of risk and resiliency factors that influence AD symptom development, and ultimately, AD treatment.