Neuroimaging Predictors of Cognitive Decline and Impairment

认知衰退和损伤的神经影像学预测因素

• 批准号: 9549250
• 负责人: Susan Resnick
• 金额: $ 113.25万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9549250
• 关键词: 3-Dimensional; Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid deposition; Annual Reports; Area; Baltimore; Biological Markers; Blood Vessels; Brain; Cerebrovascular Circulation; Cognition; Cognitive; Cognitive aging; Corpus striatum structure; Data; Decision Making; Development; Disease; Early Diagnosis; Elderly; Equilibrium; Evaluation; Feedback; Functional Magnetic Resonance Imaging; Funding; Gait speed; Genetic; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Impaired cognition; Individual; Individual Differences; Inflammatory; Intervention; Investigation; Limb structure; Longitudinal Studies; Lower Extremity; Magnetic Resonance Imaging; Manuscripts; Measurement; Measures; Medial; Memory; Memory Loss; Metabolic; Methodology; Modeling; Motor; Nerve Degeneration; Neurobiology; Neuropsychology; Onset of illness; Paper; Participant; Pathologic; Pattern; Performance; Physical Performance; Pittsburgh Compound-B; Positron-Emission Tomography; Prevention; Process; Publishing; Research; Rest; Risk; Risk Factors; Risk-Taking; Sampling; Scanning; Sex Characteristics; Structure; Task Performances; Testing; Time; Variant; Water; Work; age effect; age related; aged; aging brain; amyloid imaging; amyloid pathology; base; brain behavior; cognitive change; cognitive function; cognitive performance; cost; follow-up; imaging study; improved; in vivo; memory recognition; method development; neural correlate; neuroimaging; neuropathology; operation; pre-clinical; preference; programs; relating to nervous system; resilience; response; reward processing; tau Proteins; theories; tool

Summary of work: As part of our program of research on early markers of Alzheimers disease, we are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early preclinical predictors of cognitive change and impairment, including Alzheimer's disease (AD). We continue longitudinal testing of older participants and evaluation of new participants, including MRI and neuropsychological assessments of participants younger than 55 years old. For a subsample aged 55 and older, we performed PET measurements of cerebral blood flow, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid deposition. Over the last year we expanded our amyloid imaging studies from 50 scans per year to 70 scans per year through AD funding initiatives. In addition, we initiated Tau PET (AV-1451) studies of BLSA participants receiving PET amyloid scans (separate annual report). Our progress includes continued acquisition of new neuroimaging assessments and continued analysis of existing data and methods development. We use neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in cognitive and brain aging, genetic, metabolic, and inflammatory risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes during the preclinical or asymptomatic stage of disease will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of disease is available. We have published a number of papers describing results from the BLSA neuroimaging study: Decision Making and Brain Activation in Older Adults. Frontal, striatal, and medial temporal functions implicated in value-based decision processing of rewards and costs undergo substantial age-related changes. However, age effects on brain function and cognition differ across individuals. How this normative variation relates to older-adult value-based decision making is unclear. We performed a functional magnetic resonance imaging study in 173 human older adults during a lottery choice task in which costly to more desirable stakes were depicted using low to high expected values (EVs) of points (Goh et al., 2016). Across trials that varied in EVs, participants decided to accept or decline the offered stakes to maximize total accumulated points. We found that greater age was associated with less optimal decisions, accepting stakes when losses were likely and declining stakes when gains were likely, and was associated with increased frontal activity for costlier stakes. Risk preferences varied substantially across older adults and neural sensitivity to EVs in the frontal, striatal, and medial temporal areas dissociated risk-aversive from risk-taking individuals. Risk-averters increased neural responses to increasing EVs as stakes became more desirable, whereas risk-takers increased neural responses with decreasing EV as stakes became more costly. Risk preference also modulated striatal responses during feedback with risk-takers showing more positive responses to gains compared with risk-averters. Our findings highlight the frontal, striatal, and medial temporal areas as key neural loci in which individual differences differentially affect value-based decision-making ability in older adults. Through longitudinal follow-ups we will determine whether changes in decision making and their neural correlates predict subsequent cognitive impairment. Brain network changes and memory decline. It has been suggested that age-related changes within the default mode network (DMN) of the brain impact the ability to successfully perform cognitive operations. We investigated this this theory by examining functional covariance within brain networks using regional cerebral blood flow data, measured by 15O-water PET. We assessed data from 99 BLSA participants (mean baseline age 68.6 7.5) over a 7.4 year period (Beason-Held et al., 2017). The sample was divided in tertiles based on longitudinal performance on a verbal recognition memory task administered during scanning, and functional covariance was compared between the upper (improvers) and lower (decliners) tertile groups. The DMN and verbal memory networks (VMN) were then examined during the verbal memory scan condition. For each network, group differences in node-to-network coherence and individual node-to-node covariance relationships were assessed at baseline and in change over time. Compared with improvers, decliners showed differences in node-to-network coherence and in node-to-node relationships in the DMN but not the VMN during verbal memory. These DMN differences reflected greater covariance with better task performance at baseline and both increasing and declining covariance with declining task performance over time for decliners. When examined during the resting state alone, the direction of change in DMN covariance was similar to that seen during task performance, but node-to-node relationships differed from those observed during the task condition. These results suggest that disengagement of DMN components during task performance is not essential for successful cognitive performance as previously proposed. Instead, a proper balance in network processes may be needed to support optimal task performance. Motor Function and Amyloid Burden. With Drs. Stephanie Studenski, Luigi Ferrucci and Teresa Tian, we examined the relation between amyloid burden and longitudinal change in motor function (Tian et al., 2017). We studied 59 cognitively normal participants in the neuroimaging substudy of the BLSA. Participants had baseline PET-PiB scans and repeated measures of lower (usual gait speed, 400-m time, Health ABC Physical Performance Battery (HABCPPB) score, total standing balance time) and upper (mean tapping time) extremity performance during a mean follow-up of 4.7 years. After adjusting for covariates, linear mixed effect models revealed that higher mean cortical A burden was associated with greater declines in gait speed and HABCPPB score and a greater increase in 400-m time. These findings suggest that amyloid burden predicts subsequent decline in lower extremity motor function. Methodological Developments. We have continued to optimize our approach for MRI volumetric analysis. We have used the MUSE analysis pipeline to harmonize MRI volumetric data over more than 20 years, allowing analysis of predictors of neurodegeneration. In addition to these selected highlights, we are completing a manuscript investigating the independent effects of amyloid burden and neurodegeneration on cognitive change in cognitively normal older adults.

工作摘要：作为阿尔茨海默病早期标志物研究计划的一部分，我们正在对巴尔的摩纵向衰老研究 (BLSA) 的参与者进行系列磁共振成像 (MRI)，包括血管变化测量、正电子发射断层扫描 (PET) 和神经心理学评估，以研究记忆变化和认知障碍的神经生物学基础。这些评估使我们能够检查大脑结构和功能的变化，这可能是认知变化和损伤（包括阿尔茨海默病（AD））的早期临床前预测因子。我们继续对老年参与者进行纵向测试并对新参与者进行评估，包括对 55 岁以下参与者进行 MRI 和神经心理学评估。对于 55 岁及以上的子样本，我们对脑血流进行 PET 测量，然后使用 11-C-Pittsburgh 化合物 B (PiB) 进行 PET 扫描以测量体内淀粉样蛋白沉积。 去年，我们通过 AD 资助计划将淀粉样蛋白成像研究从每年 50 次扫描扩大到每年 70 次扫描。此外，我们还对接受 PET 淀粉样蛋白扫描的 BLSA 参与者启动了 Tau PET (AV-1451) 研究（单独的年度报告）。 我们的进展包括持续获取新的神经影像评估以及持续分析现有数据和方法开发。我们使用神经影像工具来研究认知和大脑变化的调节因素，包括认知和大脑衰老的性别差异、遗传、代谢和炎症风险因素，以及性类固醇和其他激素的影响。了解这些大脑行为关联并及早发现疾病临床前或无症状阶段加速的大脑变化对于确定可能从干预措施中受益的个体至关重要（如果有成功的预防或延迟疾病发作的治疗方法）。 我们发表了多篇论文，描述 BLSA 神经影像研究的结果： 老年人的决策和大脑激活。 涉及基于价值的奖励和成本决策处理的额叶、纹状体和内侧时间功能会发生与年龄相关的重大变化。然而，年龄对大脑功能和认知的影响因人而异。这种规范差异与老年人基于价值的决策有何关系尚不清楚。我们在一项彩票选择任务中对 173 名老年人进行了一项功能性磁共振成像研究，其中使用从低到高的分数预期值 (EV) 来描述从昂贵到更理想的赌注（Goh 等人，2016）。在不同电动汽车的试验中，参与者决定接受或拒绝所提供的赌注，以最大化总累积积分。我们发现，年龄越大，决策越不理想，即在可能损失时接受赌注，在可能获利时拒绝赌注，并且与更昂贵的赌注的正面活动增加相关。老年人的风险偏好差异很大，额叶、纹状体和内侧颞区对 EV 的神经敏感性将厌恶风险的个体与冒险个体分开。当赌注变得更加可取时，风险规避者会增加对增加的 EV 的神经反应，而随着赌注变得更加昂贵，冒险者会随着 EV 的减少而增加神经反应。风险偏好也在反馈过程中调节纹状体反应，与风险规避者相比，风险承担者对收益表现出更积极的反应。我们的研究结果强调额叶、纹状体和内侧颞区是关键的神经位点，其中个体差异对老年人基于价值的决策能力产生不同的影响。通过纵向随访，我们将确定决策及其神经相关因素的变化是否可以预测随后的认知障碍。 大脑网络变化和记忆力下降。有人认为，大脑默认模式网络（DMN）内与年龄相关的变化会影响成功执行认知操作的能力。我们通过使用 15O-水 PET 测量的局部脑血流数据检查大脑网络内的功能协方差来研究这一理论。我们评估了 99 名 BLSA 参与者（平均基线年龄 68.6 ± 7.5）7.4 年期间的数据（Beason-Held 等，2017）。根据扫描期间执行的言语识别记忆任务的纵向表现将样本分为三分位数，并比较上三分位数组（改善者）和下三分位数组（下降者）之间的功能协方差。然后在言语记忆扫描条件下检查 DMN 和言语记忆网络 (VMN)。对于每个网络，在基线和随时间变化的情况下评估节点到网络一致性和个体节点到节点协方差关系的组差异。与进步者相比，下降者在言语记忆过程中在 DMN 中的节点到网络一致性和节点到节点关系方面表现出差异，但在 VMN 中则没有差异。这些 DMN 差异反映了基线时更好的协方​​差和更好的协方​​差，以及随着时间的推移，随着时间的推移，下降者的任务表现下降的协方差的增加和下降。当仅在静息状态下进行检查时，DMN 协方差的变化方向与任务执行期间观察到的方向相似，但节点到节点的关系与任务条件下观察到的不同。这些结果表明，在任务执行过程中脱离 DMN 组件对于成功的认知表现并不重要，正如之前提出的那样。相反，可能需要网络进程的适当平衡来支持最佳的任务性能。 运动功能和淀粉样蛋白负担。 与博士。 Stephanie Studenski、Luigi Ferrucci 和 Teresa Tian，我们研究了淀粉样蛋白负荷与运动功能纵向变化之间的关系 (Tian et al., 2017)。 我们在 BLSA 的神经影像子研究中研究了 59 名认知正常的参与者。在平均 4.7 年的随访期间，参与者进行了基线 PET-PiB 扫描，并重复测量下肢（通常步态速度、400 米时间、Health ABC 身体表现电池 (HABCPPB) 评分、总站立平衡时间）和上肢表现（平均拍打时间）。调整协变量后，线性混合效应模型显示，较高的平均皮质 A 负担与步态速度和 HABCPPB 评分的较大下降以及 400 米时间的较大增加相关。这些发现表明淀粉样蛋白负荷预示着下肢运动功能的随后下降。 方法论的发展。 我们继续优化 MRI 体积分析方法。 20 多年来，我们一直使用 MUSE 分析流程来协调 MRI 体积数据，从而可以分析神经退行性疾病的预测因素。 除了这些精选的亮点之外，我们正在完成一份手稿，调查淀粉样蛋白负担和神经变性对认知正常老年人认知变化的独立影响。