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中最早，最令人痛苦的神经精神症状（NPS）之一 疾病（AD），其在AD临床光谱中的神经生物学知之甚少。虽然冷漠可以 可靠地通过几个经过验证的量表来衡量，并与AD的临床进展有关 目前，很少有有效干预治疗反应的冷漠或生物标志物。最近，“温和” 提出了行为障碍（MBI）的结构来捕获可能是突出的，突出的NP 在非痴呆的老年人中最早的AD病理病理学的介绍中， 与认知障碍一致。 MBI由5个领域组成，包括“动机，利益下降和 Drive”域，捕获了冷漠的奖励电路和积极的价灾难。 尽管冷漠的临床相关性，但一个主要的研究问题是大脑中的灾难是否 与基本的认知和功能障碍的电路共享或不同的电路。 在AD中，这些机制是否通过AD的行为和认知范围而变化。在电流中 项目，我们将可视化tau和淀粉样蛋白以及结构和功能性大脑的体内区域分布 电路（网络连通性和白质异常）以确定基线脑电路是否改变 以及同时的AD病理学预测基线的严重程度和未来对患者的冷漠的担忧 “神经行为功能的完整维度”（RFA-MH-19-510）：1）认知正常（CN）年龄较大 成人，2）敏感轻度认知障碍（MCI），3）MBI降低的动机域，4）轻度AD 失智。在早期广告中更好地了解这些神经元机制对于 为临床试验开发新的治疗策略和生物标志物。 我们调查AD中冷漠的脑行为关系的初步工作揭示了早期的证据 下临时和顶叶的介于下的额叶额叶回路改变。我们的经验 Flortaucipir Positron发射断层扫描表明，在临床前AD中，Tau具有较低的临时预测 它也与抑郁症状相关的地方，而在MCI和AD痴呆症中，散布广泛， 包括与冷漠相关的额叶区域。因此，我们假设这是AD病理学 传播和额叶的额叶电路受到干扰，冷漠会出现，更糟。 我们将使用使用的基线和结构性脑电路的基线测量之间的关系 连接组序列，伴随体内区域tau和淀粉样病理学以及基线和纵向 在200名参与者中有3年以上的冷漠（50 CN，50 MCI，50 MBI动机和50个温和广告 失智）。我们将利用资助的R01 AG053184（PI：MARSHALL）来支付CN和MCI的成像费用 参与者，而当前的研究将涵盖MBI消除动机和AD痴呆的成像成本 参与者和所有参与者的冷漠临床评估费用。