Effect of baseline and intercurrent medical factors on 6-year cognitive trajectory: Secondary analysis of the SAGES Study

根据PAS-19-391，本提案将利用现有数据， 阿尔茨海默氏病及相关痴呆症（AD/ADRD）和培养有前途的早期职业生涯 调查员谢泰米医生该提案将使用从临床丰富的队列中获得的数据， 择期手术后的衰老（SAGES），涉及560名未评价临床痴呆的老年人（年龄70岁以上） 在大的选择性手术之前，并通过重复的神经心理学测试随访6年。我们计划 探索PA中的一个优先领域：“为了促进我们对认知功能如何从 正常至病理性认知老化”，我们在此将其广义定义为包括AD相关和ADRD相关 流程. SAGES收集了并发疾病、住院、手术和重大疾病的数据。 治疗（例如，化疗，血液透析）长达6年。我们建议评估这些措施的效果 认知轨迹的并发因素，沿着谵妄和/或ApoE-E4状态的调节作用， 这可能是大脑脆弱性的标志。 本研究的具体目的是：（1）探讨并发医学因素对up认知轨迹的影响 到6年：我们将首先单独检查因素，然后累积假设某些因素将 单独考虑更大的递减，并且更多的因素将导致更陡的斜率 随着时间的推移而下降，达到与MCI或早期AD/ADRD相当的下降率。(2)为了检验 异常基线实验室结果和炎症生物标志物（例如，C-反应蛋白，白细胞介素-6） 认知轨迹：我们假设更多的异常实验室值和/或生物标志物将 认知能力下降率最高，达到与MCI或早期AD/ADRD相当的下降率。（三） 阐明谵妄和/或遗传风险（ApoE-E4状态）的发生是否调节了相关性 主要并发因素或异常的实验室或生物标志物，无论是单一的或累积的，对认知 弹道我们的分析将利用创新的纵向数据分析方法， 预测器，以生成用于动态指数（可以在人体内改变的指数）的加权算法 随着时间的推移），代表潜在认知损害的累积效应。我们已经充分证明了 统计力量来实现我们的目标。成功的拟议工作是进一步确保由一个高度熟练的 他是一个跨学科的团队，他们已经有超过10年的密切合作，并将指导谢博士。 这个项目将有助于确定并发因素或异常的实验室或生物标志物，可能导致 认知能力下降，特别是在那些大脑更脆弱的个体中，如ApoE-E4或 谵妄的发展。了解这些因素将有助于我们确定可能的潜在途径， 将正常认知老化转变为病理性认知老化。这种理解将促进我们的病理生理学 了解，并为未来有针对性的干预战略奠定基础。

Responding to PAS-19-391, this proposal will leverage existing data to advance our understanding of Alzheimer’s disease and related dementias (AD/ADRD) and to nurture the career of a promising early stage investigator, Dr. Tammy Hshieh. This proposal will use data drawn from a clinically rich cohort, the Successful Aging after Elective Surgery (SAGES), involving 560 older adults (age 70+) without clinical dementia evaluated prior to major elective surgery and followed for 6 years with repeated neuropsychological testing. We plan to explore a priority area in the PA: ‘to advance our understanding of how cognitive function may change from normal to pathological cognitive aging’, which we here define broadly as including both AD- and ADRD-related processes. SAGES has collected data on intercurrent illnesses, hospitalizations, surgeries, and major treatments (e.g., chemotherapy, hemodialysis) for up to 6 years. We propose to evaluate the effects of these intercurrent factors on cognitive trajectory, along with the moderating effects of delirium and/or ApoE-E4 status, which may serve as markers of brain vulnerability. Our specific aims are: (1) To evaluate the effect of intercurrent medical factors on cognitive trajectory for up to 6 years: We will examine factors first singly then cumulatively with the hypothesis that certain factors will have greater decrements considered singly and that a higher number of factors will result in a steeper slope of decline over time, achieving rates of decline comparable to MCI or early AD/ADRD. (2) To examine the effect of abnormal baseline laboratory results and inflammatory biomarkers (e.g., C-reactive protein, interleukin-6) on cognitive trajectory: We hypothesize that a higher number of abnormal laboratory values and/or biomarkers will have a highest rate of cognitive decline, achieving rates of decline comparable to MCI or early AD/ADRD. (3) To elucidate whether development of delirium and/or genetic risk (ApoE-E4 status) moderates the association of major intercurrent factors or abnormal laboratory- or bio- markers, either singly or cumulatively, on cognitive trajectory. Our analyses will utilize an innovative longitudinal data analysis approach with time-varying predictors to generate a weighting algorithm for a dynamic index (an index that can change within a person over time), representing the cumulative effect of potential cognitive insults. We have demonstrated adequate statistical power to achieve our aims. Success of the proposed work is further assured by a highly skilled interdisciplinary team who have been close collaborators for over 10 years, and who will mentor Dr. Hshieh. This project will help to identify intercurrent factors or abnormal laboratory- or bio- markers that may lead to cognitive decline, particularly in those individuals with more vulnerable brains, as signaled by ApoE-E4 or by development of delirium. Understanding these factors will help us to identify potential pathways which might transform normal to pathological cognitive aging. Such understanding will advance our pathophysiologic understanding, and lay the groundwork for future targeted intervention strategies.