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

父母资助的目标是研究认知老化的异质性以及癌症相关疾病之间的关系。 认知功能减退(CRCD)和阿尔茨海默病相关痴呆(ADRD)。广泛的研究问题是 慢性阻塞性肺疾病是否是癌症损害的结果及其治疗加速了潜在的早期 ADRD或损坏与ADRD中涉及的类似系统。为了解决这个问题，我们正在测试ADRD 血浆生物标记物，并利用结果来检验乳腺癌幸存者年龄增长的主要假设 60例CRCD患者的血浆ADRD-病理生物标记物异常比无CRCD的患者更多 认知异常或同时评估非癌症对照。原建议的 亲本捐赠中的ADRD生物标志物是Aβ1-42、p-tau和神经丝轻链。这些化验是 计划在主任离开该机构的一个合作的联邦实验室进行。在此期间，杰夫博士 达奇是血浆ADRD生物标记物的领先专家，他加入了印第安纳大学(MPI Saykin的故乡)和 NIA阿尔茨海默氏症及相关痴呆国家中央资料库(NCRAD)。在时间范围内 该项目在AD的血液生物标志物领域也有了重大的新突破。 Aβ42和Aβ40(报告为42/40比率)、P-tau和神经丝轻链的测量现在是 用于临床试验筛选AD病理患者并监测药效学反应 为新药干杯。此外，反应性星形胶质细胞的标记物GFAP已被证明在反应中升高。 到阿尔茨海默病早期的淀粉样病理学。这些突破之所以成为可能，是因为 血浆生物标志物分析的精确度，尽管这也伴随着成本的增加 从父母提交助学金的时候起。随着这些领域的快速变化，成本上升和 执行NIA NCRAD实验室，这一补充将：1)利用机会搬家 生物标记物检测到NCRAD实验室，2)使用补充资金修改我们的分析以匹配 该领域最先进的生物标记物(Aβ1-42、Aβ1-40、P-tau181、NFL和GFAP[新标记加粗])，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)扩大到一个 基线样本和两个纵向随访时间点(n=817个样本)。应对现场的变化 在我们提交母基金时没有预料到的，将使我们能够扩大母基金的目标 通过更灵敏的分析以强大、最新的方式解决新的研究问题，包括使用 在NCRAD实验室建立的P-tau181的预先指定的界值和癌症幸存者的比较 并控制结果符合NCRAD标准。此外，由于TLC参与者在以下时间的认知正常 基线，增加对更多纵向样本的测试将使我们能够更好地了解任何 ADRD生物标志物改变。家长资助现在是在第3年开始(5/22-4/23)，当时所有的化验都是 计划好了，所以现在是在NCRAD中使用多重分析来测试一批所有可用样本的理想时机 确保实验室质量控制。这些成果将为数据共享提供一个出色的未来资源。

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.