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

项目摘要/摘要 尽管痴呆症具有全球性影响，但应对随之而来的挑战的努力主要来自于 收入国家(重债穷国)。而痴呆症的患病率和发病率似乎稳定或下降 在这些国家，南美国家(SAC)表现出惊人的相反趋势。此方案 事实证明，由于地区特有的特点，这一点更具挑战性。第一，特殊的遗传和环境 SAC的背景限制了HICS关键发现的普遍性。此外，遗传多样性越大， 而SAC的社会经济地位(SES)的影响仍明显得不到研究。值得注意的是，这是真实的 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……里面 此外，SAC面临着缺乏创新、协调和跨区域的研究，对他们最 常见的神经退行性疾病：阿尔茨海默病(AD)和额颞痴呆(FTD)。它是 因此，对于SAC来说，加入正在进行的国际努力并开发一种黄金标准方法来检测 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。vbl.反对，反对 在此背景下，我们的长期目标是确定导致AD和FTD的独特遗传和SES因素 在SAC中相对于美国的演示。为此，我们将建立一个队列来测试来自 上述四个SAC以及美国(总计3000名参与者，包括1500名控制组，750名AD 患者和750名FTD患者)。我们将把标准化的临床评估与创新的分析相结合 包括多模式机器学习在内的技术，以解决这些不同种群的异质性。 通过结合标准化的遗传、神经成像和行为(SES-认知)测量，我们将测试 假设SAC中存在AD和FTD的独特风险因素，但事实证明这些因素并不显著 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)测试来自SAC和美国的患者在解释SES后是否会受到歧视 影响认知和脑成像特征；以及(C)决定遗传、认知、大脑和 区分SAC患者和美国患者的社会经济因素。这项工作的积极影响包括 更好地理解遗传和社会经济因素导致的神经认知表现 痴呆症，以及在SAC中确定降低风险和预防疾病的新基因靶点。我们的 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成为可能，扩展 并协调现有数据集，推动新措施和多模式机器的发展 学习协议。更广泛地说，通过建立一个协作框架，利用独特的 我们的建议可以整合一个基于SAC的平台，用于未来的翻译研究和 评估。

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.