Neural Correlates of Apathy Across the Alzheimer's Disease Continuum

项目摘要 冷漠是阿尔茨海默病患者最早也是临床上最痛苦的神经精神症状之一 阿尔茨海默病(AD)，其整个AD临床谱的神经生物学知之甚少。尽管冷漠可以 通过几个经过验证的量表进行可靠的测量，并与AD的临床进展相关，在那里 目前几乎没有有效的干预措施来治疗冷漠或治疗反应的生物标志物。最近，《温和派》 行为障碍(MBI)的构造已经被提出用来捕捉可能是 在非痴呆的老年人中，潜在的AD病理最早的表现之一，之前或 与认知障碍相吻合。MBI由5个领域组成，包括“动机、兴趣降低和 驱动“域，捕捉奖励回路和冷漠的正价扰动。 尽管冷漠与临床相关，但一个主要的研究问题是，大脑中的障碍 导致冷漠的神经回路与认知和功能障碍的神经回路相同或不同 在AD中，以及这些机制是否在AD的行为和认知光谱中变化。在当前 项目中，我们将可视化活体内tau和淀粉样蛋白的区域分布以及大脑的结构和功能 脑回路(网络连通性和脑白质异常)以确定基线脑回路是否改变 并发的AD病理可以预测患有以下疾病的个体的基线严重程度和未来的冷漠程度恶化 《神经行为功能的全维度》(RFA-MH-19-510)：1)认知正常(CN)老年人 成人，2)遗忘性轻度认知障碍(MCI)，3)MBI动机领域降低，4)轻度AD 痴呆症。在早期AD中更好地理解这些神经机制对于 为临床试验开发新的治疗策略和生物标记物。 我们对阿尔茨海默病患者冷漠的大脑-行为关系的初步研究揭示了早期证据 下颞叶和顶叶受累，后来额叶-皮质下环路改变。我们的经验是 Flortaucipir正电子发射断层扫描显示，在临床前AD中，tau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，它的传播范围更广， 包括与冷漠相关的额叶区域。因此，我们假设作为AD病理 传播和额顶环路被扰乱，冷漠将会出现并恶化。 我们将评估大脑功能和结构回路的基线测量之间的关系 连接体序列，伴随的活体局部tau和淀粉样蛋白病理，以及基线和纵向 200名参与者的冷漠超过3年(50名CN，50名MCI，50名MBI-动机降低，50名轻度AD 痴呆症)。我们将利用资助的R01 AG053184(PI：马歇尔)来支付CN和MCI的成像成本 参与者，而目前的研究将涵盖MBI-动机降低和AD痴呆的成像成本 参与者，以及所有参与者的冷漠临床评估费用。

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.