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: 10715609
• 负责人: Jeanne Mandelblatt
• 金额: $ 31.37万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715609
• 关键词: Acceleration; Address; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-42; Assessment tool; Astrocytes; Basic Science; Biological Assay; Biological Markers; Breast Cancer survivor; Cancer Control; Cancer Survivor; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive aging; Collaborations; Data; Dementia; Diagnostic; Disease; Ensure; Environmental Risk Factor; Etiology; Funding; Future; Genetic; Glial Fibrillary Acidic Protein; Goals; Heterogeneity; Home; Impaired cognition; Indiana; Individual; Institution; Laboratories; Left; Light; Longevity; Malignant Neoplasms; Measures; Monitor; Morbidity - disease rate; Older Population; Participant; Pathologic; Pathology; Pharmacodynamics; Plasma; Population; Prevention; Quality Control; Quality of life; Reporting; Research; Research Personnel; Risk Factors; Sampling; Social isolation; Specific qualifier value; Specimen; Survivors; System; Testing; Time; Universities; Validation; aging brain; amyloid pathology; blood-based biomarker; cancer-related cognitive impairment; cognitive testing; cost; data de-identification; data sharing networks; disorder risk; follow-up; genome wide association study; health disparity; improved; insight; mortality; multiplex assay; neurofilament; neuroprotection; novel; novel marker; novel therapeutics; parent grant; patient screening; predictive marker; repository; response; risk prediction; screening; tau-1; therapeutic target

The goal of the parent grant is to study heterogeneity in cognitive aging and relationships between cancer-related cognitive decline (CRCD) and Alzheimer’s disease related dementias (ADRD). The broad research question is whether CRCD is the result of damage due to the cancer and its therapies that accelerate an underlying early ADRD or damage to similar systems as are involved in ADRD. To address this question we are testing ADRD plasma biomarkers and using the results to test the overarching hypothesis that breast cancer survivors ages 60+ with CRCD will have more plasma ADRD-pathology biomarker abnormalities than survivors with no cognitive abnormalities or contemporaneously assessed non-cancer controls. The originally proposed ADRD biomarkers in the parent grant were Aβ1-42, p-tau and neurofilament light chain [NfL]. These assays were planned in a collaborating federal laboratory where the director has left the institution. In the interim, Dr. Jeff Dage, a leading expert in plasma ADRD biomarkers, joined Indiana University (home of MPI Saykin) and the NIA National Centralized Repository for Alzheimer’s and Related Dementias (NCRAD). During the timeframe of this project there have also been significant new breakthroughs in the field of blood-based biomarkers for AD. Measures of Aβ42 and Aβ40 (reported as the 42/40 ratio), P-tau and neurofilament light chain (NfL) are now being used in clinical trials to screen for patients with AD pathology and monitor pharmacodynamic responses to new drugs. Additionally, a marker of reactive astrocytes, GFAP, has been shown to be elevated in response to amyloid pathology in the earliest stages of AD. These breakthroughs have been possible due to advances in the precision of the plasma biomarker assays, although this has also been accompanied by increased costs since the time of parent grant submission. With these rapid changes in the field, cost escalations and the implementation of the NIA NCRAD laboratory, this supplement will: 1) take advantage of the opportunity to move biomarker testing to the NCRAD laboratory, 2) use the supplemental funds to modify our assays to match the most advanced biomarkers in the field (Aβ1-42, Aβ1-40, P-tau181, NfL, and GFAP [new markers bolded]), and 3) expand the number of longitudinal samples that can be tested from two time points (n=617 samples) to a baseline sample and two longitudinal follow-up time points (n=817 samples). Responding to changes in the field that were not anticipated at the time of our parent grant submission will allow us to expand the parent grant aims to address new research questions in a robust, up-to-date manner with more sensitive assays, including use of prespecified cutoffs being established for P-tau181 in the NCRAD lab and comparison of the cancer survivor and control results to NCRAD standards. Additionally, because TLC participants were cognitively normal at baseline, adding testing of more longitudinal specimens will allow us to better understand the time course of any ADRD biomarker changes. The parent grant is now at the start of Year 3 (5/22-4/23), when all assays were planned, so the timing is ideal to use multiplex assays in the NCRAD to test all available specimens in one batch to ensure laboratory quality control. These results will provide an outstanding future resource for data sharing.

家长资助的目标是研究认知衰老的异质性以及癌症相关疾病之间的关系 认知能力下降（CRCD）和阿尔茨海默病相关痴呆（ADRD）。广泛的研究问题是 CRCD 是否是癌症及其加速潜在早期癌症治疗的损害的结果 ADRD 或 ADRD 中涉及的类似系统的损坏。为了解决这个问题，我们正在测试 ADRD 血浆生物标志物，并使用结果来检验乳腺癌幸存者会衰老的总体假设 60 岁以上患有 CRCD 的人比没有患 CRCD 的幸存者有更多的血浆 ADRD 病理学生物标志物异常 认知异常或同时评估的非癌症对照。最初提议的 母基金中的 ADRD 生物标志物是 Aβ1-42、p-tau 和神经丝轻链 [NfL]。这些测定是 计划在主任已离开该机构的合作联邦实验室进行。在此期间，杰夫博士 Dage 是血浆 ADRD 生物标志物方面的领先专家，加入印第安纳大学（MPI Saykin 的所在地）和 NIA 国家阿尔茨海默病和相关痴呆症中央存储库 (NCRAD)。在时间范围内 该项目在AD血液生物标志物领域也取得了重大新突破。 Aβ42 和 Aβ40（报告为 42/40 比率）、P-tau 和神经丝轻链 (NfL) 的测量值现已 用于临床试验，筛选患有 AD 病理的患者并监测药效反应 到新药。此外，反应性星形胶质细胞的标志物 GFAP 已被证明在反应中升高 AD 早期阶段的淀粉样蛋白病理学。这些突破之所以成为可能，是因为技术的进步 血浆生物标志物检测的精确度，尽管这也伴随着成本的增加 自提交家长补助金之时起。随着该领域的快速变化，成本不断上升， 实施NIA NCRAD实验室，本补充将：1）利用搬迁的机会 向 NCRAD 实验室进行生物标志物测试，2) 使用补充资金修改我们的检测方法以匹配 该领域最先进的生物标志物（Aβ1-42、Aβ1-40、P-tau181、NfL 和 GFAP [新标志物加粗]），以及 3）将可测试的纵向样本数从两个时间点（n=617个样本）扩大到 基线样本和两个纵向随访时间点（n=817 个样本）。应对领域变化 在我们提交家长补助金时没有预料到的这一点将使我们能够扩大家长补助金的目标 通过更灵敏的检测以稳健、最新的方式解决新的研究问题，包括使用 NCRAD 实验室正在为 P-tau181 建立预先设定的临界值，并比较癌症幸存者 并将结果控制至 NCRAD 标准。此外，由于 TLC 参与者的认知能力正常 基线，增加更多纵向样本的测试将使我们能够更好地了解任何事件的时间进程 ADRD 生物标志物发生变化。家长资助现在是在第 3 年开始时 (5/22-4/23)，当时所有检测均已完成 已计划，因此现在是在 NCRAD 中使用多重检测来测试一批中所有可用样本的理想时机 以确保实验室质量控制。这些结果将为数据共享提供出色的未来资源。

项目成果

Cancer-related accelerated ageing and biobehavioural modifiers: a framework for research and clinical care.

• DOI: 10.1038/s41571-021-00580-3
• 发表时间: 2022-03
• 期刊: NATURE REVIEWS CLINICAL ONCOLOGY
• 影响因子: 78.8
• 作者: Carroll, Judith E.;Bower, Julienne E.;Ganz, Patricia A.
• 通讯作者: Ganz, Patricia A.

Daily functioning in glioma survivors: associations with cognitive function, psychological factors and quality of life.

• DOI: 10.2217/cns-2022-0002
• 发表时间: 2022-06-01
• 期刊: CNS oncology

Validating the PROMIS cognitive function short form in cancer survivors.

验证癌症幸存者的 PROMIS 认知功能简表。

• DOI: 10.1007/s10549-023-06968-2
• 发表时间: 2023
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Henneghan,AshleyM;VanDyk,Kathleen;Zhou,Xingtao;Moore,RaeanneC;Root,JamesC;Ahles,TimA;Nakamura,ZevM;Mandeblatt,Jeanne;Ganz,PatriciaA
• 通讯作者: Ganz,PatriciaA

Editorial: How Will Aducanumab Approval Impact AD Research?

• DOI: 10.14283/jpad.2021.46
• 发表时间: 2021
• 期刊: The journal of prevention of Alzheimer's disease
• 作者: Weiner MW;Aisen PS;Beckett LA;Green RC;Jagust W;Morris JC;Okonkwo O;Perrin RJ;Petersen RC;Rivera Mindt M;Saykin AJ;Shaw LM;Toga AW;Trojanowski JQ
• 通讯作者: Trojanowski JQ

Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE.

• DOI: 10.1016/j.nbd.2022.105915
• 发表时间: 2022-12
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Ng, Christi Anne S.;Biran, Lucas P.;Galvano, Elena;Mandelblatt, Jeanne;Vicini, Stefano;Rebeck, G. William
• 通讯作者: Rebeck, G. William