Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.

IF 5.8 1区 医学 Q1 PSYCHIATRY
Junhao Wen, Zhijian Yang, Ilya M Nasrallah, Yuhan Cui, Guray Erus, Dhivya Srinivasan, Ahmed Abdulkadir, Elizabeth Mamourian, Gyujoon Hwang, Ashish Singh, Mark Bergman, Jingxuan Bao, Erdem Varol, Zhen Zhou, Aleix Boquet-Pujadas, Jiong Chen, Arthur W Toga, Andrew J Saykin, Timothy J Hohman, Paul M Thompson, Sylvia Villeneuve, Randy Gollub, Aristeidis Sotiras, Katharina Wittfeld, Hans J Grabe, Duygu Tosun, Murat Bilgel, Yang An, Daniel S Marcus, Pamela LaMontagne, Tammie L Benzinger, Susan R Heckbert, Thomas R Austin, Lenore J Launer, Mark Espeland, Colin L Masters, Paul Maruff, Jurgen Fripp, Sterling C Johnson, John C Morris, Marilyn S Albert, R Nick Bryan, Susan M Resnick, Luigi Ferrucci, Yong Fan, Mohamad Habes, David Wolk, Li Shen, Haochang Shou, Christos Davatzikos
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引用次数: 0

Abstract

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

阿尔茨海默病连续体中两个神经解剖学 AI 维度的遗传和临床相关性。
阿尔茨海默病(AD)与不同的萎缩模式有关。我们采用了一种名为 "超现实表征学习(Surreal-GAN)"的半监督表征学习技术,通过这种技术,我们确定了有症状的轻度认知障碍(MCI)和阿氏痴呆症患者脑萎缩的两个潜在维度表征:"弥漫-阿氏痴呆症"(R1)维度显示广泛的脑萎缩,而 "MTL-阿氏痴呆症"(R2)维度显示局灶性内侧颞叶(MTL)萎缩。重要的是,只有 R2 与 MCI 和 AD 患者基线时广为人知的散发性 AD 遗传风险因素(如 APOE ε4)相关。然后,我们将训练有素的模型应用于普通人群和两组无症状的认知障碍人群中,独立地检测了这两个维度在早期阶段的存在。在普通人群中,全基因组关联研究发现 77 个与 APOE 无关的基因与 R1 和 R2 有不同的关联。功能分析显示,这些基因在大脑(R1 和 R2)以外的器官(包括心脏(R1)和脑垂体、肌肉和肾脏(R2))的差异表达基因集中的代表性过高。这些基因富集在与树突状细胞(R2)、巨噬细胞功能(R1)和癌症(R1 和 R2)有关的生物通路中。其中几个基因是癌症(R1)、炎症(R1)、心血管疾病(R1)和神经系统疾病(R2)的 "可药用基因"。纵向进展显示,APOE ε4、淀粉样蛋白和 tau 在早期无症状阶段与 R2 相关,但这种纵向关联只出现在 R1 的晚期无症状阶段。我们的研究结果加深了我们对脑外多发性注意力缺失症发病机制的理解。在早期无症状阶段,这两个维度与不同的病理机制有关,包括心血管疾病、炎症和激素功能障碍,这些都是由不同于APOE的基因驱动的,它们可能共同促成了AD的早期发病机制。所有结果均可在 https://labs-laboratory.com/medicine/ 网站上公开获取。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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