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.

阿尔茨海默病和神经退行性疾病中的跨诊断记忆、情绪和运动回路 老年痴呆症等临床诊断是基于症状的，但同样诊断的患者 可能有不同的症状，并且在不同的诊断中可能存在类似的症状。这包括记忆， 情绪和运动障碍，每一种都可能导致残疾。了解此症状 异质性和重叠可能会导致临床试验设计的改进，个性化的预后，以及更好的 治疗在这里，我们测试的假设，在阿尔茨海默病的具体症状可以预测的基础上， 将个性化的脑萎缩模式转化为跨诊断的人脑回路。为了验证这个假设，我们 利用三项最新进展。首先，现在有症状和解剖MRI的纵向数据库， 来自数千名阿尔茨海默氏症和其他神经退行性疾病患者的数据。第二， MRI处理使我们能够在单个受试者水平上检测脑萎缩的模式。最后，我们现在有一个 人类大脑的接线图（人类连接体），使我们能够将症状映射到大脑回路， 以前不可能的方式。我们先前已经证明，引起记忆、情绪和 运动症状映射到特定的人脑回路。我们的初步数据显示， 对老年痴呆症的萎缩模式很有效。这些萎缩的回路似乎是脊髓特异性的， transdiagnosis转诊断，and pregnancy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的，并且可以映射到与恢复或保存相关的补偿电路。 功能在这里，我们将测试阿尔茨海默病脑萎缩的位置是否映射到转诊断 记忆（目标1）、情绪（目标2）和运动症状（目标3）的大脑回路。成功完成这些 目的将确定1）神经变性位置的个体差异，如通过 脑萎缩，是负责个体差异的症状，2）是否相似，脑萎缩 在不同的诊断中导致相似的症状，3）脑回路的基线萎缩是否预示着 未来的症状，以及4）相关回路中的脑容量增加是否与保留的 功能这些知识可用于控制临床试验中的症状异质性，预测 个体患者可能出现的症状，并确定对症治疗的治疗靶点 老年痴呆症和其他神经退行性疾病的研究。