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

父母补助金的目标是研究认知老化的异质性以及癌症相关性之间的关系。 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是否是由于癌症及其治疗引起的损害的结果， ADRD或对ADRD中涉及的类似系统的损害。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年龄增长的总体假设 60+ CRCD患者的血浆ADRD病理学生物标志物异常比无CRCD的存活者更多 认知异常或同期评估的非癌症对照。原本建议的 母基金中的ADRD生物标志物为Aβ1-42、p-tau和神经丝轻链[NfL]。这些测定 计划在一个合作的联邦实验室，主任已经离开了该机构。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，他加入了印第安纳州大学（MPI Saykin的所在地）， NIA国家阿尔茨海默氏症和相关痴呆症集中储存库（NCRAD）。在这段时间内， 该项目在基于血液的AD生物标志物领域也取得了重大的新突破。 目前，Aβ42和Aβ40（报告为42/40比值）、P-tau和神经丝轻链（NfL）的测量值 在临床试验中用于筛选AD病理学患者并监测药效学反应 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。 在AD的最早阶段淀粉样蛋白病理学。这些突破之所以成为可能，是因为 血浆生物标志物测定的精确度，尽管这也伴随着成本的增加 就一直在申请资助随着该领域的这些快速变化，成本上升， NIA NCRAD实验室的实施，本补充将：1）利用机会移动 生物标志物测试的NCRAD实验室，2）使用补充资金来修改我们的测定，以匹配 该领域最先进的生物标志物（Aβ1-42、Aβ1-40、P-tau 181、NfL和GFAP [新标志物以粗体显示]），以及 3)将可测试的纵向样本数量从两个时间点（n=617个样本）扩展至 基线样本和两个纵向随访时间点（n=817个样本）。应对外地的变化 在我们提交母基金时没有预料到的，这将使我们能够扩大母基金的目标。 以更灵敏的检测方法，以稳健、最新的方式解决新的研究问题，包括使用 在NCRAD实验室中建立了P-tau 181的预定截止值，并比较了癌症幸存者 并控制结果达到NCRAD标准。此外，由于TLC参与者在认知上正常， 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 ADRD生物标志物变化。父母补助金现在是在第3年开始时（5/22-4/23），当时所有测定都是 因此，在NCRAD中使用多重检测试剂盒在一个批次中检测所有可用标本的时机是理想的 确保实验室质量控制。这些结果将为未来的数据共享提供出色的资源。

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.