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

响应PAS-19-391，该提案将利用现有数据来促进我们对 阿尔茨海默病和相关痴呆症(AD/ADRD)和培养有前途的早期职业生涯 调查员，Tammy Hshieh博士。这项建议将使用从临床富有的队列中提取的数据，成功的 560名非临床痴呆症老年人(70岁以上)的择期手术后衰老(SAGE)研究 术前行大手术，随访6年，反复进行神经心理测试。我们计划 探索PA中的优先领域：促进我们对认知功能如何改变的理解 正常到病理性认知老化，我们在这里广义地定义为包括与AD和ADRD相关的 流程。Sages收集了有关并发疾病、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 认知轨迹的共同因素，以及精神错乱和/或载脂蛋白E-E4状态的调节作用， 这可能是大脑脆弱性的标志。 我们的具体目标是：(1)评估并发医学因素对UP认知轨迹的影响 到6年：我们将首先单独检查因素，然后在假设某些因素将 单独考虑更大的减量，并且更多的因素将导致更陡峭的斜率 随着时间的推移而下降，实现与MCI或AD/ADRD早期相当的下降速度。(二)考察效果 异常基线实验室结果和炎性生物标志物(如C-反应蛋白、白细胞介素6) 认知轨迹：我们假设实验室异常数值和/或生物标记物的数量越多 认知减退率最高，达到与MCI或AD/ADRD早期相当的减退率。(3) 为了阐明精神错乱的发展和/或遗传风险(ApoE-E4状态)是否缓和了这种联系 单个或累积的主要共同因素或异常实验室或生物标志物对认知的影响 弹道。我们的分析将利用一种创新的纵向数据分析方法 预测器，用于为动态指数(一个人内部可以改变的指数)生成加权算法 随着时间的推移)，代表潜在的认知侮辱的累积效应。我们已经证明了 实现我们目标的统计力量。高技能的员工进一步保证了拟议工作的成功 10多年来一直密切合作的跨学科团队，并将指导谢博士。 该项目将帮助确定共同因素或异常实验室-或生物标记物，可能导致 认知能力下降，特别是那些大脑更脆弱的人，如ApoE-E4或 神志不清的发展。了解这些因素将有助于我们确定可能 将正常认知老化转变为病理性认知老化。这样的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.