Deficits in top-down processes during episodic memory in aging and preclinical AD

衰老和临床前 AD 情景记忆过程中自上而下过程的缺陷

• 批准号: 8455762
• 负责人: ELIZABETH MORMINO
• 金额: $ 5.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455762
• 关键词: Aging; Alzheimer' s Disease; Amyloid beta-Protein; Attention; Behavior; Brain; Brain region; Categories; Clinical; Cognitive aging; Cues; Dementia; Deposition; Elderly; Episodic memory; Etiology; Event; Face; Female; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Impaired cognition; Individual; Laboratories; Light; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Names; Nerve Degeneration; Neuronal Dysfunction; Pathology; Pattern; Performance; Phase; Positron-Emission Tomography; Process; Reporting; Research; Staging; Stream; System; Temporal Lobe; Visual; White Matter Disease; age effect; age related; amyloid pathology; beta amyloid pathology; design; directed attention; disease diagnosis; executive function; forgetting; male; memory encoding; neuroimaging; pre-clinical; relating to nervous system; research study; selective attention

DESCRIPTION (provided by applicant): Although episodic memory is traditionally associated with the medial temporal lobe system, it is clear that top-down processes subserved by frontoparietal regions interact with this system to influence what information is encoded. Top-down processes (ie. control processes) originate in "top" regions (ie. frontoparietal) and influence "bottom" sensorimotor regions to complete goal directed behavior. Given that successful encoding depends on directing attention to towards relevant information as well as inhibiting irrelevant information, it is not surprising that subsequent memory contrasts (activatio for subsequently remembered versus forgotten items) reveals FP activation. Although the relevance of top-down processes during episodic memory encoding can be inferred by examining activation related to subsequent memory effects, few studies have implemented a design that varies top-down processes during memory encoding. Furthermore, dysfunction in medial temporal lobe and FP networks is consistently reported in aging, and it is unclear how disruption within these networks influences memory performance in aging. Interestingly, a substantial proportion number of clinically normal elderly individuals have elevated levels of beta-amyloid (A?) plaques, a pathology strongly associated with Alzheimer's disease (AD). Research investigating the relevance of early A? deposition suggests this pathology may be an initiating event that leads to neuronal dysfunction and neurodegeneration, cognitive loss and eventually AD. Within this framework, clinically normal individuals with high levels of A? are thought to represent the earliest signs of Alzheimer's disease ("preclinical AD"), with a delay of approximately 10 years between initial pathological accumulation and the onset of clinical dementia. Thus, an understanding of this preclinical stage is of utmost importance to uncover mechanisms underlying A?-induced neuronal dysfunction before the widespread damage that is typical in AD has occurred. Although research examining preclinical AD has focused on episodic memory decline (since this domain is the first to show decline in AD), it is possible that this pathology has an impact on top-down processes mediated by frontoparietal regions. For instance, A? deposition is highly prevalent throughout frontoparietal regions and decline in executive function is known to occur in close proximity to AD diagnosis. Thus, the overall goal of this proposal is to incorporate components of top-down processes (ie. selective attention and task switching) in an episodic memory design to better understand effects of age and A? on patterns of activation in frontoparietal regions. PUBLIC HEALTH RELEVANCE: Although beta-amyloid pathology is commonly found in clinically normal elderly individuals, the relationship between this pathology and changes that occur during aging remain elusive. This proposal employs a multimodal neuroimaging approach to investigate the impact of amyloid pathology (via PIB-PET imaging) on brain networks subserving episodic memory and executive function (via task-related fMRI), which will shed light on cognitive aging mechanisms as well as our understanding of preclinical Alzheimer's disease.

描述（由申请人提供）：虽然情景记忆传统上与内侧颞叶系统相关，但很明显，额顶叶区域支持的自上而下的过程与该系统相互作用，以影响编码的信息。自上而下的过程（即控制过程）起源于“顶部”区域（即额顶叶）并影响“底部”感觉运动区域以完成目标导向的行为。鉴于成功的编码取决于将注意力集中到相关信息以及抑制不相关信息，因此随后的记忆对比（随后记住的项目与遗忘的项目的激活）揭示 FP 激活也就不足为奇了。尽管可以通过检查与后续记忆效应相关的激活来推断情景记忆编码期间自上而下过程的相关性，但很少有研究实现了在记忆编码期间改变自上而下过程的设计。此外，在衰老过程中，内侧颞叶和 FP 网络的功能障碍一直存在，但目前尚不清楚这些网络的破坏如何影响衰老过程中的记忆表现。有趣的是，相当一部分临床正常的老年人的β-淀粉样蛋白（Aβ）斑块水平升高，这是一种与阿尔茨海默病（AD）密切相关的病理学。研究调查早期 A 的相关性？沉积表明，这种病理学可能是导致神经元功能障碍和神经变性、认知丧失并最终导致 AD 的始发事件。在此框架内，临床正常的个体具有高水平的 A？被认为是阿尔茨海默氏病（“临床前 AD”）的最早迹象，从最初的病理积累到临床痴呆的发作之间大约有 10 年的延迟。因此，在 AD 中典型的广泛损伤发生之前，了解这一临床前阶段对于揭示 Aβ 诱导的神经元功能障碍的潜在机制至关重要。尽管临床前 AD 的研究重点是情景记忆衰退（因为该领域是第一个显示 AD 衰退的领域），但有可能 这种病理学对额顶叶区域介导的自上而下的过程有影响。例如，A?沉积在整个额顶叶区域非常普遍，并且执行功能的下降已知发生在 AD 诊断附近。因此，该提案的总体目标是将自上而下过程的组成部分（即选择性注意和任务切换）纳入情景记忆设计中，以更好地理解年龄和 A？关于额顶叶区域的激活模式。 公众健康相关性：尽管β-淀粉样蛋白病理学常见于临床正常的老年人，但这种病理学与衰老过程中发生的变化之间的关系仍然难以捉摸。该提案采用多模式神经影像方法来研究淀粉样蛋白病理学（通过 PIB-PET 成像）对促进情景记忆和执行功能（通过任务相关功能磁共振成像）的大脑网络的影响，这将揭示认知衰老机制以及我们对临床前阿尔茨海默病的理解。