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、情绪和运动神经回路 阿尔茨海默病等临床诊断是基于症状的，但具有相同诊断的患者 可能有不同的症状，而在诊断过程中可能会出现类似的症状。这包括内存， 情绪和运动障碍，它们中的每一个都可以使人失去能力。了解此症状 异质性和重叠性可能导致改进临床试验设计、个性化预后和更好的 治疗。在这里，我们测试了这样一个假设，即阿尔茨海默病的特定症状可以根据 从脑萎缩的个体化模式到跨诊断的人脑回路。为了检验这一假设，我们 充分利用最近的三项进展。首先，现在有了关于症状和解剖核磁共振的纵向数据库 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，科技进步 核磁共振成像处理使我们能够在单一受试者水平上检测大脑萎缩的模式。最后，我们现在有了一个 人类大脑(人类连接体)的接线图，使我们能够将症状与大脑回路相对应 以前不可能实现的方法。我们之前已经证明，局灶性脑损伤会导致记忆、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，同样的方法 对阿尔茨海默病的萎缩模式很有效。这些萎缩回路似乎是特定于症状的， 跨诊断性和预见性。有趣的是，大脑体积增加(而不是萎缩)的区域也 并且可以映射到与恢复能力或保存 功能。在这里，我们将测试阿尔茨海默氏病的脑萎缩部位是否映射到跨诊断 负责记忆(目标1)、情绪(目标2)和运动症状(目标3)的大脑回路。成功完成这些任务 AIMS将决定1)神经变性位置的个体差异，如通过 脑萎缩，是导致个体症状差异的原因，2)脑萎缩是否有相似性 在诊断过程中导致相似的症状，3)大脑回路的基线萎缩是否预示着 未来的症状，以及4)相关回路中脑容量的增加是否与保存 功能。这种知识可以用来控制临床试验中的症状异质性，预测 个别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。

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.