Neural Correlates of Apathy Across the Alzheimer's Disease Continuum

阿尔茨海默病连续体中冷漠的神经相关性

• 批准号: 9896450
• 负责人: GAD ASHER MARSHALL
• 金额: $ 82.76万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896450
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Atrophic; Autopsy; Behavioral; Biological Markers; Brain; Clinical; Clinical Trials; Clinical assessments; Cognition; Cognitive; Cost Analysis; Diffusion Magnetic Resonance Imaging; Dimensions; Distress; Elderly; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Image; Impaired cognition; Impairment; Individual; Inferior; Knowledge; Lateral; Link; Magnetic Resonance Imaging; Measures; Medial; Metabolism; Motivation; Multimodal Imaging; Neurobiology; Neurofibrillary Tangles; Parietal; Participant; Pathologic; Pittsburgh Compound-B; Positive Valence; Positron-Emission Tomography; Prevention strategy; Proxy; Public Health; Research; Rest; Rewards; Severities; Structure; Symptoms; Thalamic structure; Time; Work; amnestic mild cognitive impairment; amyloid pathology; amyloid structure; base; behavioral impairment; brain behavior; clinically relevant; connectome; cost; depressive symptoms; effective intervention; experience; functional disability; in vivo; instrumental activity of daily living; interest; mild cognitive impairment; neural correlate; neurobehavioral; neuromechanism; neuropsychiatric symptom; non-demented; pre-clinical; reward circuitry; tau Proteins; tau mutation; therapy development; treatment response; treatment strategy; white matter; β-amyloid burden

Project Summary Apathy is one of the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD), whose neurobiology across the AD clinical spectrum is poorly understood. Although apathy can be reliably measured by several validated scales and has been associated with clinical progression of AD, there are currently few effective interventions for apathy or biomarkers of treatment response. Recently, the ‘mild behavioral impairment (MBI)’ construct has been proposed to capture emergent, prominent NPS that may be among the earliest presentation of underlying AD pathology in non-demented older adults, preceding or coincident with cognitive impairment. MBI consists of 5 domains including a “decreased motivation, interest, and drive” domain, capturing the reward circuitry and positive valence disturbance of apathy. Despite the clinical relevance of apathy, a major research question is whether the disturbances in brain circuits underlying apathy are shared with or different than those underlying cognitive and functional impairment in AD, and whether these mechanisms vary through the behavioral and cognitive spectrum of AD. In the current project, we will visualize the in vivo regional distribution of tau and amyloid and structural and functional brain circuits (network connectivity and white matter abnormalities) to determine whether altered baseline brain circuits and concurrent AD pathology predict baseline severity and future worsening of apathy across individuals with the “full dimensionality of neurobehavioral functioning” (RFA-MH-19-510): 1) Cognitively normal (CN) older adults, 2) amnestic mild cognitive impairment (MCI), 3) MBI-decreased motivation domain, and 4) mild AD dementia. Attaining a better understanding of these neural mechanisms across early-stage AD is crucial for developing new treatment strategies and biomarkers for clinical trials. Our preliminary work investigating brain-behavior relations of apathy in AD has revealed evidence of early inferior temporal and parietal involvement and later frontal-subcortical circuit alterations. Our experience with flortaucipir positron emission tomography suggests that in preclinical AD, tau has an inferior temporal predilection where it is also associated with depressive symptoms, while in MCI and AD dementia, there is wider spread, including to frontal regions that are associated with apathy. We therefore hypothesize that as AD pathology spreads and fronto-parietal circuits are disrupted, apathy will emerge and worsen. We will assess the relationships among baseline measures of functional and structural brain circuits using Connectome sequences, concomitant in vivo regional tau and amyloid pathology, and baseline and longitudinal apathy over 3 years in 200 participants (50 CN, 50 MCI, 50 MBI-decreased motivation, and 50 mild AD dementia). We will leverage funded R01 AG053184 (PI: Marshall) to cover imaging costs for CN and MCI participants, while the current study will cover imaging costs for MBI-decreased motivation and AD dementia participants, and apathy clinical assessment costs for all participants.

项目摘要 冷漠是阿尔茨海默氏症最早期和临床上最令人痛苦的神经精神症状之一 疾病（AD），其在AD临床谱中的神经生物学知之甚少。虽然冷漠可以 可以通过几种经验证的量表可靠地测量，并且与AD的临床进展相关， 目前很少有针对冷漠或治疗反应的生物标志物的有效干预措施。最近，“温和的 行为损伤（MBI）的结构已被提出来捕捉紧急，突出的障碍，可能是 在非痴呆老年人中最早出现的基础AD病理学中， 与认知障碍同时发生MBI由5个领域组成，包括“动机，兴趣和兴趣下降”。 驱动”域，捕获奖励回路和冷漠的正价干扰。 尽管情感淡漠与临床相关，但一个主要的研究问题是， 冷漠背后的回路与认知和功能障碍背后的回路相同或不同 以及这些机制是否通过AD的行为和认知谱而变化。在当前 项目，我们将可视化tau蛋白和淀粉样蛋白的体内区域分布以及大脑的结构和功能 回路（网络连接和白色物质异常），以确定是否改变基线脑回路 和并发AD病理学预测基线严重程度和未来冷漠的恶化， “神经行为功能的全维度”（RFA-MH-19-510）：1）认知正常（CN）老年人 成年人，2）遗忘型轻度认知障碍（MCI），3）MBI降低的动机域，和4）轻度AD 痴呆更好地理解早期AD的这些神经机制对于 为临床试验开发新的治疗策略和生物标志物。 我们对AD患者冷漠的脑-行为关系的初步研究揭示了早期的证据， 下颞叶和顶叶受累以及随后的额叶-皮质下回路改变。我们的经验与 flortaucipir正电子发射断层扫描表明，在临床前AD中，tau蛋白具有较低的颞叶偏好， 它也与抑郁症状有关，而在MCI和AD痴呆中，有更广泛的传播， 包括与冷漠相关的额叶区域。因此，我们假设AD病理学 如果大脑皮层的扩散和额顶叶回路被破坏，冷漠就会出现并恶化。 我们将评估功能和结构脑回路的基线测量之间的关系， 连接组序列，伴随的体内局部tau和淀粉样蛋白病理学，以及基线和纵向 200名参与者（50名CN，50名MCI，50名MBI-动机降低和50名轻度AD）在3年内的冷漠 痴呆症）。我们将利用已资助的R 01 AG 053184（PI：马歇尔）来支付CN和MCI的成像费用 参与者，而目前的研究将涵盖MBI降低的动机和AD痴呆的成像费用 参与者，以及所有参与者的冷漠临床评估费用。