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的跨诊断记忆、情绪和运动回路 阿尔茨海默病等临床诊断基于症状，但具有相同诊断的患者 可能有不同的症状，并且在不同的诊断中可能会出现类似的症状，包括记忆力、 情绪和运动障碍，每一种都可能导致无法理解这种症状。 异质性和重叠可以改善临床试验设计、个性化预后和更好的结果 在这里，我们测试了可以根据阿尔茨海默病的具体症状进行预测的假设。 为了检验这一假设，我们研究了脑萎缩的个体化模式和跨诊断人类大脑回路。 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病和其他神经退行性疾病患者的数据。 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，我们现在有了一个。 人脑（人类连接组）的接线图使我们能够将症状映射到大脑回路 我们之前已经证明局灶性脑损伤会导致记忆、情绪和行为。 我们的初步数据表明，运动症状映射到特定的人类大脑回路。 对阿尔茨海默病的萎缩模式很有效，这些萎缩回路似乎具有症状特异性， 跨诊断和预后的暗示，脑容量增加（而不是萎缩）的区域也是如此。 使用这种方法检测到，并可能映射到与弹性或保存相关的补偿电路 在这里，我们将测试阿尔茨海默病中脑萎缩的位置是否与跨诊断相关。 记忆（目标 1）、情绪（目标 2）和运动症状（目标 3）的大脑回路。 目标将决定 1) 个体神经退行性变的位置是否存在差异，如通过测量 脑萎缩，造成症状的个体差异，2）脑萎缩是否有相似之处 导致不同诊断中的类似症状，3) 脑回路基线萎缩是否可以预测 未来的症状，以及 4）相关回路中脑容量的增加是否与保留的 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。 个体患者可能出现的症状，并确定对症治疗的治疗目标 阿尔茨海默氏症和其他神经退行性疾病。