Decoding neural systems underlying anosognosia for memory loss in aging and Alzheimer's disease

摘要 对认知和行为缺陷的意识障碍，即病感失认症，是脑卒中的常见症状。 阿尔茨海默病（AD）对家庭来说特别令人沮丧，并可能影响早期发现。有一个 不断增长但不完全理解的神经生物学机制的基础崩溃 AD中的记忆自我意识最近的神经影像学发现，包括我们自己的工作，表明， AD的病感失认不仅反映了离散脑区的功能改变， 不同大脑区域之间的功能连接中断，即网络崩溃，特别是在 自我参照处理的大脑网络。这项研究旨在测试我们的核心 病感失认症是自我功能、结构和病理变化的症状， 参照脑网络为了解决这些目标，记忆措施的自我意识将涉及多方面的问题， 示踪剂正电子发射断层扫描（PET），以评估淀粉样蛋白负荷和tau负荷，以及功能 静息磁共振成像（rsfc-MRI）以及弥散加权成像（dMRI），获得 从临床正常到轻度认知障碍和轻度AD的共150名老年受试者中 个体具体来说，在目标1中，我们将评估大脑网络的功能完整性（如使用 rsfc-MRI），并检查记忆自我意识预测的程度 早期AD临床谱的静息状态内在连接强度。我们亦会研究 执行技能是否会影响这种关系以及自我功能的特异性， 与其他大脑网络相比，参考网络对记忆能力的洞察力。在目标2中，我们将使用 dMRI研究白色束的结构完整性，这对自我参照处理至关重要， 研究局部结构和功能连接之间的解耦是否与改变 记忆自我意识最后，在目标3中，我们将研究分子病理学的作用，例如： 淀粉样蛋白（Aβ）沉积（用PiB-PET评估）和tau沉积（用flortaucipir PET评估， FTP-PET或T807）在解耦过程中的作用及其与整个大脑中记忆自我意识改变的关系。 AD的临床谱。该项目可能提供有关导致人口减少的因素的关键信息。 功能状态、残疾发展和丧失独立性。因此，这项研究的结果可能 对患者及其家属具有重要的临床和实践意义，特别是对发展 以及痴呆症管理干预措施的使用。

ABSTRACT Disordered awareness of cognitive and behavioral deficits, i.e. anosognosia, is a common symptom of Alzheimer’s disease (AD) that is particularly frustrating to families, and may impact early detection. There is a growing yet incomplete understanding of the neurobiological mechanisms that underlie the breakdown of memory self-awareness in AD. Recent neuroimaging findings, including our own work, suggest that anosognosia in AD not only reflects functional alteration in discrete brain regions but likely results from functional connectivity disruption between different brain regions, i.e. network breakdown, particularly in the brain networks subserving self-referential processing. The proposed research aims to test our central hypothesis that anosognosia occurs as a symptom of functional, structural and pathological changes in self- referential brain networks. To address these aims, self-awareness of memory measures will be related to multi- tracer Positron Emission Tomography (PET) to assess amyloid burden and tau burden, and functional magnetic resonance imaging during rest (rsfc-MRI) as well as diffusion-weighted imaging (dMRI), obtained from a total of 150 older subjects ranging from clinically normal to mild cognitive impairment and mild AD individuals. Specifically, in Aim 1 we will assess the functional integrity of brain networks (as assessed with rsfc-MRI) recruited during self-referential processing and examine the extent memory self-awareness predicts the resting state intrinsic connectivity strength across the clinical spectrum of early AD. We will also investigate whether executive skills might influence this relationship as well as the specificity of the functioning of the self- referential networks as compared to other brain networks to insight of memory abilities. In Aim 2 we will use dMRI to investigate the structural integrity of white tracts that are critical for self-referential processing and investigate whether decoupling between local structural and functional connectivity is related to altered memory self-awareness. Finally, in Aim 3 we will investigate the role of molecular pathology e.g. fibrillary amyloid (Aβ) deposition (as assessed with PiB-PET) and tau deposition (as assessed with flortaucipir PET, FTP-PET or T807) in the decoupling process and its relation to altered memory self-awareness across the clinical spectrum of AD. This project may provide critical information about factors contributing to decline in functional status, development of disability, and loss of independence. As such, the results from this study may have important clinical and practical implications for patients and their families, particularly for the development and use of dementia management interventions.