Functional and pathological correlates of memory self-awareness in aging and AD

描述（由申请人提供）：K01候选人的目标是建立一个关于神经退行性痴呆的独立研究项目，主要重点是通过多模式成像能力的进步来改善公众健康，从而早期诊断阿尔茨海默病（AD）并监测其进展。由于自我评价在很大程度上指导着人类的行为，许多AD患者表现出的不准确判断（即自我意识受损或病感失认）可能产生严重后果，并对患者的诊断、治疗和护理构成重大问题。尽管病感失认症对患者及其护理人员有影响，但我们对其临床和神经学相关性以及预后价值的了解甚少。本文提出的研究旨在研究记忆自我意识的神经基础，以及这些系统的进行性功能障碍，这些功能障碍是AD进展中自我意识丧失的基础。具体来说，我们建议利用多模态成像技术的创新组合来探索记忆自我意识的机制基础。我们的初步数据，使用功能连通性分析（通过静息状态fMRI评估）进一步证明，默认模式网络（DMN）中的两个主要中枢后扣带和内侧前额叶皮层对准确的记忆自我评估至关重要。在这里，我们建议将功能磁共振成像与一项新的功能磁共振成像任务结合起来，该任务调查了对记忆表现进行准确评估的关键神经解剖学，以研究这与记忆自我意识的关系。此外，我们计划使用经颅磁刺激（TMS）来证明DMN与fMRI任务中记忆表现的自我评估有因果关系。老年人的记忆变化是否与阿尔茨海默病的脑病理变化平行尚不确定。候选人的初步工作表明增加了A？健康老年人的沉积（阿尔茨海默病的主要组织病理学发现）改变了记忆自我评价和DMN内功能连通性之间的关系，因此主观记忆抱怨的增加与内侧前额叶皮层和后扣带之间的连通性减少有关。为了进一步研究这一点，我们将使用阿尔茨海默病临床阶段（包括轻度认知障碍和轻度阿尔茨海默病患者）的数据来确定记忆自我意识受损是否与DMN核心区域的功能断开和A -病理增加相一致。此外，通过对老年患者和阿尔茨海默病临床分期的纵向数据，我们将在随访（4年）中调查DMN的病理生理变化是否预示着记忆、自我意识和病感失认的丧失。拟议的研究将利用nia资助的队列（哈佛衰老大脑研究）提供的丰富的多模态数据集，并为候选人提供独特的调查途径。这些发现有望具有重要的临床意义，因为对病感失认症的进一步了解可能会导致减少其对健康影响的干预措施。

DESCRIPTION (provided by applicant): The goal of the K01 candidate is to establish an independent research program on neurodegenerative dementias, with the main focus of improving public health through the advancement of multi-modal imaging capabilities to diagnose Alzheimer's disease (AD) early on and monitor its progression. Because self- appraisals guide much of human behavior, inaccurate judgments shown by many AD patients (i.e., impaired self-awareness or anosognosia) can yield serious consequences, and poses a major problem in the diagnosis, treatment and care of the patient. Despite the impact of anosognosia on patients and their caregivers, our knowledge of its clinical and neurological correlates as well as prognostic value is poorly understood. The research proposed herein specifically aims to investigate the neural underpinnings of memory self-awareness and the progressive dysfunction of these systems that underlie the loss of self-awareness with AD progression. Specifically, we propose to probe the mechanistic underpinnings of self-awareness of memory utilizing an innovative and novel combination of multi-modal imaging techniques. Our preliminary data, using functional connectivity analysis (as assessed with resting state fMRI, fcMRI) provides further proof that the posterior cingulate and medial prefrontal cortex, two major hubs in the default mode network (DMN), are crucial for accurate memory self-appraisal. Here, we propose to combine fcMRI with a novel fMRI task that investigates the critical neuroanatomy subserving accurate assessment of memory performance to study how this relates to memory self-awareness. Additionally, we plan to use transcranial magnetic stimulation (TMS) to demonstrate that the DMN is causally related to self-assessment of memory performance in our fMRI task. Whether perceived changes in memory in older adults parallel changes in brain pathology indicative of AD is uncertain. The candidate's preliminary work suggests that increased A? deposition (a major histopathological finding in AD) in healthy older adults modifies the association between memory self-appraisal and functional connectivity within the DMN, such that increased subjective memory complaints were related to decreased connectivity between the medial prefrontal cortex and posterior cingulate. To investigate this further, we will use data across the clinical stages of AD (including mild cognitive impairment and mild AD patients) to determine whether impaired memory self-awareness coincides with functional disconnection and increased A� pathology in core regions of the DMN. Furthermore, using longitudinal data of older adults and patients across the clinical stages of AD, we will investigat whether pathophysiological changes in the DMN portend loss in memory self- awareness and anosognosia at follow-up (4 years). The proposed research will leverage a rich multi-modality dataset available from a NIA-funded cohort (Harvard Aging Brain Study) and provides a unique avenue of investigation for the candidate. The findings are expected to have important clinical implications, as improved understanding of anosognosia may lead to interventions that would lessen its impact on wellbeing.