US-South American Initiative for Genetic-Neural-Behavioral Interactions in Human Neurodegenerative Research

项目概要/摘要 虽然痴呆症具有全球影响，但应对随之而来的挑战的努力主要来自高- 高收入国家。尽管痴呆症的患病率和发病率似乎稳定或下降， 在这些国家中，南美洲国家的典型情况是一种令人震惊的相反趋势（SAC）。这种情况 由于区域特定的特征，证明更具挑战性。第一，特定的遗传和环境 SAC的背景限制了HIC关键发现的普遍性。此外，更大的遗传多样性 和社会经济地位（SES）的SAC的影响仍然显着不足的研究。值得注意的是， 四个最大的SAC（巴西，阿根廷，哥伦比亚和秘鲁），占该地区人口的75%以上。在 此外，战略咨询委员会还面临着缺乏创新、协调和跨区域研究的问题， 流行的神经退行性疾病：阿尔茨海默病（AD）和额颞叶痴呆（FTD）。是 因此，SAC加入正在进行的国际努力并制定检测的黄金标准方法至关重要 在方法学、遗传学和社会经济异质性背景下的疾病特异性改变。对 在此背景下，我们的长期目标是确定驱动AD和FTD的独特遗传和SES因素 相对于美国而言，在SAC中的介绍。为此，我们将建立一个队列，以测试来自 四个上述SAC，以及美国（总计> 3000名参与者，包括1500名对照，750名AD 750例FTD患者）。我们将联合收割机标准化临床评估与创新的分析 包括多模态机器学习在内的技术来解释这些不同人群的异质性。 通过结合标准化的遗传、神经影像学和行为（SES-认知）测量，我们将测试 基础假设，即SAC中存在AD和FTD的独特风险因素，但不具有显著性 在美国人口中。更具体地说，我们的目标是（a）在不同的SAC中确定AD和FTD的遗传风险 队列;（B）测试在考虑SES如何 影响认知和脑成像特征;以及（c）确定遗传、认知、脑和 社会经济因素之间的SAC与美国患者的歧视。这项工作的积极影响包括： 更好地了解遗传和社会经济因素驱动的神经认知表现， 痴呆症，并确定新的遗传靶点，以降低风险和预防疾病的SAC。我们 大型多模式横断面研究将使研究不足的患者群体的临床评估， 协调现有的数据集，促进新措施和多模态机器的发展 学习协议。更一般地说，通过建立一个合作框架， 区域人口，我们的建议可以巩固一个基于SAC的平台，为未来的转化研究， 考核

PROJECT SUMMARY/ABSTRACT Although dementia has a global impact, efforts to address ensuing challenges have come mostly from high- income countries (HICs). Whereas the prevalence and incidence of dementia appear to be stable or declining in such countries, an alarmingly opposite tendency typifies South American countries (SAC). This scenario proves even more challenging due to region-specific traits. First, the particular genetic and environmental backgrounds of SAC limit the generalizability of key findings from HICs. Moreover, the greater genetic diversity and impact of socioeconomic status (SES) of SAC remain markedly understudied. Of note, this is true of the four largest SAC (Brazil, Argentina, Colombia, and Peru), representing over 75% of the region’s population. In addition, SAC face a dearth of innovative, harmonized, and cross-regional studies on two of their most prevalent neurodegenerative disorders: Alzheimer’s disease (AD) and frontotemporal dementia (FTD). It is thus critical for SAC to join ongoing international efforts and develop a gold-standard approach for detecting disease-specific alterations in a context of methodological, genetic, and socioeconomic heterogeneity. Against this background, our long-term goal is to identify the unique genetic and SES factors that drive AD and FTD presentation in SAC relative to the US. To this end, we will establish a cohort to test large samples from the four abovementioned SAC, as well as the US (totaling > 3000 participants, including 1500 controls, 750 AD patients, and 750 FTD patients). We will combine standardized clinical assessments with innovative analytical techniques including multimodal machine learning to account for heterogeneity in these diverse populations. By combining standardized genetic, neuroimaging, and behavioral (SES-cognitive) measures, we will test the underlying hypothesis that there are unique risk factors for AD and FTD in SAC which do not prove significant in US populations. More particularly, we will aim to (a) establish genetic risk to AD and FTD in diverse SAC cohorts; (b) test whether patients from SAC and the US can be discriminated after accounting for how SES affects cognitive and brain imaging signatures; and (c) determine genetic, cognitive, cerebral, and socioeconomic factors that discriminate among SAC vs. US patients. Positive impacts of this work include a better understanding of the genetic and socioeconomic factors driving neurocognitive manifestations of dementia, and the identification of novel genetic targets for risk reduction and disease prevention in SAC. Our large multimodal, cross-sectional study will enable clinical assessment of understudied patient groups, extend and harmonize existing data sets, and prompt the development of novel measures and multimodal machine learning protocols. More generally, by establishing a collaborative framework which capitalizes on unique regional populations, our proposal can consolidate a SAC-based platform for future translational research and assessment.