Cognitive Aging, Alzheimers disease, and Cancer-related Cognitive Decline

摘要 随着美国人口老龄化，了解认知老化的异质性越来越重要， 病理状况如阿尔茨海默病（AD）和癌症相关的认知衰退（CRCD）。有 数据表明，CRCD和AD共享重要的认知老化特征。这一次的目标是 数据分析项目是测试患有CRCD的老年乳腺癌幸存者是否具有以下临床病理特征： AD，包括AD病理学生物标志物异常、认知变化、脑成像改变等 风险因素概况。为了实现这一目标，我们将使用现有的去识别数据和库存标本， Thinking and Living with Cancer（TLC）研究小组。TLC包括60岁的女性乳腺癌幸存者， 98岁的老年人在治疗前和每年评估一次，最长持续60个月， 同时评估非癌症对照（n = 700/组）。同意包括未来使用数据， 用于新的研究目的。研究老年乳腺癌幸存者是合乎逻辑的，因为他们已经 面对认知老化，CRCD最常被描述为乳腺癌，幸存者在年龄 在非癌症人群中APOE-104发生AD的范围内，女性的AD发生率高于男性， 35%的TLC幸存者已经有全球认知能力下降，其变化明显大于 非癌症对照。纵向TLC数据包括记忆力、执行力和记忆力的神经心理学测试分数。 功能，语言和视觉空间能力;人口统计学; AD风险因素;和炎症标志物（IL-10）。 6、TNF-α、IL-8、IL-10、IFNg、CRP）。我们通过使用库存样本来测试血浆AD来增加这些数据- 病理学生物标志物（A β 1 - 42、tau、p-tau和神经丝轻链[NFL]）和β 1相关分子 模式（DAMP：A β、S100蛋白和HMBG1）。印第安纳州大学的一部分TLC幸存者 基线和12个月的MRI数据，使用NIA资助的印第安纳州阿尔茨海默病中心（IADC）方案。 我们将对这些幸存者（n = 75）进行24个月的成像，以评估急性后效应。我们将比较 TLC非癌症对照和已发表的AD数据（包括女性特有的数据）的TLC幸存者结果。 目的是检验关于以下方面之间的关联的假设：1）CRCD和临床病理特征， AD，2）CRCD和确定的AD风险因素，以及3）AD相关炎症标志物和AD临床- CRCD的病理特征，并探讨炎症是否介导CRCD风险。这项研究意义重大 因为我们正在研究两个重要的认知老化过程的生物学机制-CRCD和AD。 我们将通过阐明遗传学和炎症过程对NIA的影响来推进NIA研究目标。 认知老化这项研究意义重大，因为认知老化对日常生活有重要的临床影响。 生活我们不知道有任何比较CRCD和AD的研究，也没有一项研究包括确定的 癌症，阿尔茨海默氏症和老年病研究人员的合作，跨越筒仓一起工作。总体而言，这 这项研究将通过确定CRCD和AD之间的潜在双向机制来推动该领域的发展。

ABSTRACT As the US population ages, it is increasingly important to understand heterogeneity in cognitive aging including pathologic conditions like Alzheimer’s disease (AD) and cancer-related cognitive decline (CRCD). There is data to suggest that CRCD and AD share important cognitive aging features. The objective of this secondary data analysis project is to test if older breast cancer survivors with CRCD have clinical-pathological features of AD, including AD-pathology biomarker abnormalities, cognitive changes, brain imaging alterations, and similar risk factor profiles. To accomplish this goal, we will use existing de-identified data and banked specimens from the Thinking and Living with Cancer (TLC) study cohort. TLC includes female breast cancer survivors ages 60- 98 years old assessed pre-treatment and annually for up to 60 months and an equal number of contemporaneously assessed non-cancer controls (n=700/group). Consent included future use of data and specimens for new research purposes. Studying older breast cancer survivors is logical since they are already facing cognitive aging, CRCD has been described most often in breast cancer, the survivors are in the age range where non-cancer populations with APOE-4 develop AD, AD rates are higher in females vs. males, and 35% of TLC survivors already have global cognitive decline based on significantly greater change than the non-cancer controls. Longitudinal TLC data include scores on neuropsychological tests of memory, executive functioning, language, and visuospatial abilities; demographics; AD risk factors; and inflammation markers (IL- 6, TNF-a, IL-8, IL-10, IFNg, CRP). We add to these data by using banked specimens to test plasma AD- pathology biomarkers (Aβ1-42, tau, p-tau, and neurofilament light chain [NFL]) and danger-associated molecular patterns (DAMPs: Aβ, S100 proteins, and HMBG1). A sub-set of TLC survivors at Indiana University has baseline and 12-month MRI data using the NIA-funded Indiana Alzheimer’s Disease Center (IADC) protocol. We will complete 24-month imaging of these survivors (n=75) to assess post-acute effects. We will compare TLC survivor results to TLC non-cancer controls and published AD data, including those specific to women. The aims are to test hypotheses about associations between: 1) CRCD and clinical-pathological features of AD, 2) CRCD and established AD-risk factors, and 3) AD-related inflammatory markers and AD clinical- pathological features in CRCD and explore if inflammation mediates CRCD risk. This research is significant because we are looking at biological mechanisms for two important cognitive aging processes- CRCD and AD. We will advance NIA research goals by elucidating the impact of genetics and inflammatory processes on cognitive aging. This research is significant because cognitive aging has clinically important effects on daily life. We are not aware of any studies comparing CRCD and AD, and none that include an established collaboration of cancer, Alzheimer’s, and geriatrics investigators working together across silos. Overall, this study will move the field forward by determining potential bidirectional mechanisms between CRCD and AD.