A multiscale investigation of the living human brain

摘要 在过去的十年里，由于活人无法接触到大脑，对阿尔茨海默病和相关痴呆的分子研究在很大程度上依赖于死后标本。这个框架至少有两个固有的严重限制。首先，死亡和之前的死亡过程对人脑的分子影响尚不清楚。这种不确定性笼罩着该领域，成为几乎所有现代人类阿尔茨海默病和相关痴呆症神经生物学研究的潜在混乱者。其次，对大脑进行尸检可以使分子生物学与深入的神经精神评估和神经成像分离。因此，关于分子生物学如何影响阿尔茨海默病和相关痴呆症中失调的大脑结构和功能的整体叙述未能出现。这些严重的局限性可以通过对活人的大脑进行分子图谱的能力来解决。在这里，我们通过活脑项目来解决这些严重的限制，在该项目中，我们对活体和死后的人脑组织进行全面的多组分子图谱分析。LBP的主要创新是对活人背外侧前额叶皮质(DLPFC)进行安全、可扩展的采样。我们将描述500多名活着和死后的人类受试者的基因组、转录组(散装和单细胞)、蛋白质组、代谢组和脂组。对这些数据的分析将识别区分活着和死后状态的分子特征。我们将利用这些洞察力来确定它们在多大程度上混淆了阿尔茨海默病和相关痴呆的尸检研究。最后，我们将把这些多组学数据集与来自相同个人的神经成像和神经认知评估相结合。据我们所知，拟议的实验和分析将包括(1)对活着的人脑进行最大的分子研究，(2)对活的和死后的人脑组织进行最大的分子比较，以及(3)将大脑的多组分子图谱与来自相同活着的个人的神经成像和深层神经认知表型配对的最大努力。我们预计，通过向科学界免费提供这一丰富的数据集，将在人类大脑生物学以及阿尔茨海默病和相关痴呆的发病机制方面取得根本性进展。

ABSTRACT Molecular investigations of Alzheimer’s disease and related dementias over the past decade have largely relied on postmortem specimens due to the inaccessibility of the brain in living people. At least two serious limitations are inherent to this framework. First, the molecular impact of death and the preceding agonal process on the human brain are unknown. This uncertainty looms over the field as a potential confounder of virtually all modern neurobiological studies of Alzheimer’s disease and related dementias in humans. Second, profiling the brain postmortem decouples molecular biology from deep neuropsychiatric assessment and neuroimaging. As a result, a holistic narrative of how molecular biology influences brain structure and functions dysregulated in Alzheimer’s disease and related dementias has failed to emerge. These serious limitations could be addressed by the ability to molecularly profile the brain in living people. Here, we address these serious limitations through the Living Brain Project, wherein we perform comprehensive multiomic molecular profiling of living and postmortem human brain tissue. The primary innovation of the LBP is a safe, scalable procedure for sampling the dorsolateral prefrontal cortex (DLPFC) in living people. We will profile the genome, transcriptome (bulk and single-cell), proteome, metabolome and lipidome in over 500 living and postmortem human subjects. Analyses of this data will identify molecular signatures differentiating the living and postmortem states. We will harness these insights to determine the extent to which they have confounded postmortem studies of Alzheimer’s disease and related dementias. Finally, we will integrate these multiomics datasets with neuroimaging and neurocognitive assessments from the same individuals. To our knowledge, the proposed experiments and analyses will comprise (1) the largest molecular study of the living human brain, (2) the largest molecular comparison of living and postmortem human brain tissues, and (3) the largest effort pairing multiomic molecular profiles of the brain with neuroimaging and deep neurocognitive phenotyping from the same living individuals. We anticipate fundamental advances in knowledge of human brain biology and the pathogenesis of Alzheimer’s disease and related dementias will be made by making this rich dataset freely available to scientific community.