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

认知衰老、阿尔茨海默病和癌症相关的认知能力下降

• 批准号: 10408070
• 负责人: Jeanne Mandelblatt
• 金额: $ 67.21万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408070
• 关键词: Acute; Address; Affect; Aftercare; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Biological; Biological Markers; Biological Specimen Banks; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Breast Cancer survivor; Cancer Etiology; Cancer Survivor; Clinical; Cognition; Cognitive; Cognitive aging; Cohort Studies; Collaborations; Consent; Data; Data Analyses; Dementia; Disease; Education; Eligibility Determination; Episodic memory; Exclusion; Family history of; Female; Female Breast Carcinoma; Frequencies; Funding; Future; Genetic; Genotype; Geriatrics; Geroscience; Goals; Health; Heterogeneity; Hippocampus (Brain); Hormonal; Hormone use; IL8 gene; Image; Impaired cognition; Impairment; Indiana; Individual; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Language; Late Onset Alzheimer Disease; Lead; Life; Light; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Memory; Menopause; Molecular; Morbidity - disease rate; Neuropsychological Tests; Obesity; Older Population; Pathologic; Pathology; Pathway interactions; Pattern; Physical activity; Plasma; Population; Prevention; Process; Prospective cohort; Protocols documentation; Publishing; Quality of life; Race; Reporting; Research; Research Personnel; Risk; Risk Factors; S100 Proteins; Short-Term Memory; Site; Sleep Disorders; Social isolation; Specimen; Survivors; TNF gene; Testing; Thinking; Time; Universities; Visuospatial; Woman; apolipoprotein E-4; base; brain volume; cancer-related cognitive impairment; chemotherapy; clinically significant; cognitive change; comorbidity; conditioned fear; data de-identification; demographics; design; executive function; gray matter; hormone therapy; inflammatory marker; innovation; insight; male; meetings; mortality; neurofilament; non-genetic; novel; risk sharing; secondary analysis; tau Proteins; tau-1

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.

摘要 随着美国人口老龄化，了解认知老龄化的异质性变得越来越重要，包括 阿尔茨海默病(AD)和癌症相关的认知衰退(CRCD)等病理性疾病。的确有 数据表明，CRCD和AD具有重要的认知衰老特征。这个第二阶段的目标是 数据分析项目是为了测试患有CRCD的老年乳腺癌幸存者是否有临床病理特征 AD包括AD-病理生物标记物异常、认知改变、脑成像改变等 风险因素概况。为了实现这一目标，我们将使用现有的未识别数据和来自 思考和生活与癌症(TLC)研究队列。TLC包括60岁的女性乳腺癌幸存者- 98岁的患者在治疗前和每年评估最多60个月和同等数量的 同时评估非癌症对照组(n=700/组)。同意包括未来使用数据和 用于新研究目的的标本。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在乳腺癌中被描述得最多，幸存者都在 携带apoE-4的非癌症人群发生AD的范围，女性的AD发病率高于男性，以及 35%的TLC幸存者已经出现了全球认知能力下降，其原因是 非癌症对照组。纵向TLC数据包括记忆、执行能力等神经心理测试的分数 功能、语言和视觉空间能力；人口统计学；AD危险因素；以及炎症标记物(IL- 6、肿瘤坏死因子α、白介素8、白介素10、干扰素、C反应蛋白)。我们通过使用银行样本来测试血浆AD来增加这些数据- 病理生物标记物(Aβ1-42、tau、p-tau和神经丝轻链)和危险相关分子 模式(DAMPS：Aβ、S100蛋白和HMBG1.印第安纳大学的一组薄层扫描幸存者 使用NIA资助的印第安纳州阿尔茨海默病中心(IADC)方案的基线和12个月MRI数据。 我们将对这些幸存者(n=75)进行为期24个月的成像，以评估急性后的影响。我们会比较一下 TLC幸存者结果与TLC非癌症对照和公布的AD数据，包括那些特定于女性的数据。 其目的是检验以下假设：1)慢性阻塞性肺疾病与临床病理特征之间的关系。 AD，2)慢性阻塞性肺疾病和已建立的AD危险因素，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的风险。这项研究具有重要的意义 因为我们正在研究两个重要的认知衰老过程的生物学机制-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的研究目标 认知老化。这项研究很有意义，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，也没有包括已建立的 癌症、阿尔茨海默氏症和老年病研究人员跨竖井合作。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。