Transdiagnostic memory, mood and motor circuits in Alzheimer's and neurodegenerative disease

阿尔茨海默病和神经退行性疾病的跨诊断记忆、情绪和运动回路

• 批准号: 10358675
• 负责人: MICHAEL D FOX
• 金额: $ 87.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358675
• 关键词: Age; Aging; Alzheimer' s Disease; Anatomy; Atrophic; Biological Markers; Brain; Clinical; Clinical Trials; Clinical Trials Design; Data; Databases; Development; Diagnosis; Diagnostic; Future; Gender; Genetic; Heterogeneity; Human; Huntington Disease; Individual Differences; Knowledge; Lead; Lesion; Location; Magnetic Resonance Imaging; Major Depressive Disorder; Maps; Measures; Memory; Memory impairment; Mental Depression; Methods; Moods; Motor; Movement; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Patients; Pattern; Prognosis; Source; Symptoms; Testing; Work; aging brain; base; brain volume; burden of illness; cerebral atrophy; clinical Diagnosis; connectome; depressive symptoms; fall risk; falls; improved; individual patient; longitudinal database; mood symptom; motor deficit; motor impairment; motor symptom; neuroimaging; preservation; prognostic; resilience; symptom treatment; therapeutic target

Transdiagnostic memory, mood, and motor circuits in Alzheimer’s and neurodegenerative diseases Clinical diagnoses such as Alzheimer’s disease are based on symptoms, but patients with the same diagnosis can have different symptoms and similar symptoms can be present across diagnoses. This includes memory, mood, and motor impairment, each of which can each be disabling. Understanding this symptom heterogeneity and overlap could lead to improved clinical trial design, personalized prognosis, and better treatment. Here, we test the hypothesis that specific symptoms in Alzheimer’s disease can be predicted based on individualized patterns of brain atrophy to trans-diagnostic human brain circuits. To test this hypothesis, we leverage three recent advances. First, there are now longitudinal databases of symptoms and anatomical MRI data from thousands of patients with Alzheimer’s and other neurodegenerative diseases. Second, advances in MRI processing allow us to detect patterns of brain atrophy at the single-subject level. Finally, we now have a wiring diagram of the human brain (the human connectome) that allows us to map symptoms to brain circuits in ways not previously possible. We have previously shown that focal brain lesions causing memory, mood, and motor symptoms map to specific human brain circuits. Our preliminary data shows that this same approach works well for atrophy patterns in Alzheimer’s disease. These atrophy circuits appear to be symptom-specific, transdiagnostic, and prognostic. Interestingly, regions of increased brain volume (rather than atrophy) are also detected using this method and may map to compensatory circuits associated with resilience or preservation of function. Here, we will test whether locations of brain atrophy in Alzheimer’s diseases map to transdiagnostic brain circuits for memory (Aim 1), mood (Aim 2), and motor symptoms (Aim 3). Successful completion of these aims will determine 1) whether individual differences in the location of neurodegeneration, as measured by brain atrophy, are responsible for individual differences in symptoms, 2) whether similarities in brain atrophy are responsible for similar symptoms across diagnoses, 3) whether baseline atrophy to brain circuits predicts future symptoms, and 4) whether increased brain volume in related circuits is associated with preserved function. This knowledge can be used to control for symptom heterogeneity in clinical trials, predict which symptoms an individual patient is likely to develop, and identify therapeutic targets for symptomatic treatment of Alzheimer’s and other neurodegenerative diseases.

阿尔茨海默氏症和神经退行性疾病中的转诊记忆，情绪和运动回路 诸如阿尔茨海默氏病这样的临床诊断基于症状，但具有相同诊断的患者 可以有不同的症状，并且可以在诊断中存在类似的症状。这包括内存， 心情和运动障碍，每种都可以致残。了解这种症状 异质性和重叠可能会改善临床试验设计，个性化预后，并且更好 治疗。在这里，我们检验了一个假设，即可以预测基于阿尔茨海默氏病的特定症状 关于脑萎缩的个性化模式，对跨诊断的人脑回路。为了检验这一假设，我们 利用最近的三个进步。首先，现在有符号和解剖学MRI的纵向数据库 来自成千上万患有阿尔茨海默氏症和其他神经退行性疾病的患者的数据。第二，进步 MRI处理使我们能够检测单个受试者水平的脑萎缩模式。最后，我们现在有一个 人脑的接线图（人类连接组），使我们能够将符号映射到大脑电路中 以前无法的方式。我们以前已经表明，局灶性大脑病变会导致记忆，情绪和 运动症状映射到特定的人脑电路。我们的初步数据表明这种方法相同 在阿尔茨海默氏病的萎缩模式方面效果很好。这些萎缩回路似乎是特定症状的， 经诊断和预后。有趣的是，大脑体积增加（而不是萎缩）的区域也是 使用这种方法检测到，可能映射到与弹性或保存相关的补偿性电路 功能。在这里，我们将测试阿尔茨海默氏病中脑萎缩的位置是否映射到转诊 记忆的脑电路（AIM 1），情绪（AIM 2）和运动症状（AIM 3）。这些成功完成 目的将确定1）神经退行性位置的个体差异是否由 脑萎缩，导致符号的个体差异，2）脑萎缩的相似性是否相似 在诊断过程中造成类似症状的原因，3）基线萎缩到脑回路是否预测 未来症状，以及4）相关电路中的大脑体积增加是否与保留 功能。这些知识可用于控制临床试验中的症状异质性，预测哪些 症状个体患者可能会发育，并确定症状治疗的治疗靶标 阿尔茨海默氏症和其他神经退行性疾病。