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

摘要 认知和行为缺陷的意识障碍，即病感缺失，是 阿尔茨海默病(AD)，尤其令家庭沮丧，并可能影响早期发现。有一个 对神经生物学机制的了解越来越多但不完整，这些机制是导致 阿尔茨海默病的记忆自我意识。最近的神经成像发现，包括我们自己的工作，表明 阿尔茨海默病的感觉失认症不仅反映了离散脑区的功能改变，而且可能是由 不同脑区之间的功能连接中断，即网络崩溃，特别是在 大脑网络从属于自我参照加工。拟议的研究旨在测试我们的中央 认为病感失认症是自我感觉障碍的功能、结构和病理改变的症状。 参考大脑网络。为了达到这些目标，记忆测量的自我意识将与多个 示踪正电子发射断层扫描(PET)评估淀粉样蛋白负荷和tau负荷，以及功能性 获得静息磁共振成像(rsfc-mri)和弥散加权成像(Dmri)。 来自150名老年受试者，从临床正常到轻度认知障碍和轻度阿尔茨海默病 个人。具体地说，在目标1中，我们将评估大脑网络的功能完整性(如通过 Rsfc-MRI)，并检验记忆自我意识预测的程度 早期阿尔茨海默病临床谱系的静息状态内在连接强度。我们还将调查 执行技能是否会影响这种关系，以及自我功能的特殊性 参照网络与其他大脑网络相比，能够洞察记忆能力。在《目标2》中，我们将使用 DMRI检查白束的结构完整性，这对自我参照处理和 调查局部结构和功能连通性之间的脱钩是否与改变 记忆中的自我意识。最后，在目标3中，我们将研究分子病理学的作用，例如纤维 淀粉样蛋白(Aβ)沉积(如用PIB-PET评估)和tau沉积(如用Flortaucipir PET评估， Ftp-PET或T807)在去耦合过程中的作用及其与记忆自我意识改变的关系 阿尔茨海默病的临床谱。该项目可能会提供有关导致 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 对患者及其家属有重要的临床和实际意义，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.