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，主要关注通过提高多模态成像能力来早期诊断阿尔茨海默病（AD）并监测其进展，从而改善公共卫生。由于自我评价指导了许多人类行为，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症）会产生严重的后果，并在患者的诊断、治疗和护理中造成重大问题。尽管病感失认症对患者及其照顾者有影响，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。本文提出的研究特别旨在研究记忆自我意识的神经基础以及这些系统的渐进性功能障碍，这些系统是随着AD进展而丧失自我意识的基础。具体来说，我们建议探索的机制基础的自我意识的记忆，利用创新和新颖的组合多模态成像技术。我们的初步数据，使用功能连接分析（与静息状态fMRI，fcMRI评估）提供了进一步的证据，后扣带和内侧前额叶皮层，两个主要枢纽的默认模式网络（DMN），是至关重要的准确的记忆自我评价。在这里，我们建议将联合收割机fcMRI与一种新的fMRI任务相结合，该任务调查了有助于准确评估记忆表现的关键神经解剖学，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与我们的fMRI任务中记忆表现的自我评估存在因果关系。老年人记忆力的变化是否与AD的脑病理学变化平行尚不确定。候选人的初步工作表明，增加A？在健康老年人中，记忆障碍性脑白质沉积（AD中的一个主要组织病理学发现）改变了记忆自我评价与DMN内功能连接之间的关联，使得主观记忆投诉增加与内侧前额叶皮质和后扣带回之间的连接减少有关。为了进一步研究这一点，我们将使用AD临床阶段的数据（包括轻度认知障碍和轻度AD患者）来确定记忆自我意识受损是否与DMN核心区域的功能性断开和A病理学增加相一致。此外，使用老年人和AD临床分期患者的纵向数据，我们将探讨DMN的病理生理学变化是否预示着随访（4年）时记忆丧失、自我意识丧失和疾病感缺失。拟议的研究将利用来自NIA资助的队列（哈佛老龄化大脑研究）的丰富的多模态数据集，并为候选人提供独特的调查途径。这些发现预计将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干预措施，从而减少其对健康的影响。

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.