A multiscale investigation of the living human brain

摘要 在过去的十年中，阿尔茨海默病和相关痴呆症的分子研究主要依赖于死后标本，因为活体大脑无法进入。这一框架至少有两个严重的局限性。首先，死亡和濒死过程对人类大脑的分子影响是未知的。这种不确定性笼罩着这个领域，成为几乎所有现代阿尔茨海默病和相关痴呆症的神经生物学研究的潜在混淆因素。第二，脑死后的分析是从深层神经精神评估和神经影像学中提取分子生物学。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大脑结构和功能失调的整体叙述未能出现。这些严重的局限性可以通过对活人大脑进行分子分析的能力来解决。在这里，我们通过活脑项目解决这些严重的局限性，在该项目中，我们对活体和死后人脑组织进行全面的多组分子分析。LBP的主要创新是一种安全的，可扩展的程序，用于对活人的背外侧前额叶皮层（DLPFC）进行采样。我们将在500多个活体和死后人类受试者中分析基因组、转录组（批量和单细胞）、蛋白质组、代谢组和脂质组。对这些数据的分析将确定区分活体和死后状态的分子特征。我们将利用这些见解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症的尸检研究。最后，我们将这些多组学数据集与来自同一个体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）对活体人脑进行的最大规模的分子研究，（2）对活体和死后人脑组织进行的最大规模的分子比较，以及（3）将大脑的多组分子谱与来自同一活体个体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，人类大脑生物学知识和阿尔茨海默病及相关痴呆症的发病机制将取得根本性进展。

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.