Post-mortem MRI for improving the diagnosis of Alzheimer’s mimics in the oldest old

年龄最大的老年人，即90岁或以上的人，是世界上增长最快的老年人群体。 老年痴呆症的患病率急剧上升。与年轻群体不同，老年痴呆症 神经病理学（ADNP）不再是最古老的老年人中最主要的退行性神经病理学， 痴呆症通常是由于多种神经病变的存在。海马硬化（HS）和小血管 病变（SVL）是导致老年痴呆的重要因素。由于缺乏可靠的生物标志物，HS 仍然未被检测到，SVL在生命期间被低估。这些限制阻碍了发展中国家的努力。 靶向特异性治疗。该项目的长期目标是改善这些疾病的体内诊断。 重要的病理学研究。与2011年12月至2012年12月期间 死后MRI能够获得更高质量的扫描，从而实现更好的量化 和脑组织异常的定位。 90+研究，一项对大学90岁或以上参与者的纵向观察研究 加州欧文的一项研究提供了一个独特的机会，可以在最古老的 老了目前正在对捐赠的大脑进行神经病理学评估， 一部分参与者将在生命期间接受脑MRI，以允许在体内和 死后成像结果和翻译的见解获得死后在体内MRI。我们有 已经开发了序列，并开始获取死后MRI扫描，证明我们的可行性， approach.我们预计将获得50名参与者的死后MRI扫描，根据我们目前的数据， 样本将提供足够数量的包含两种感兴趣病理（即HS和SVL）的病例。 此外，我们的功率计算表明，我们将能够用这个来测试这个提议的假设。 样本量 在目标1中，我们将检验海马硬化与MRI可检测体积相关的假设 死亡后的MRI对检测这些变化具有更高的灵敏度。 与在生命中获得的MRI相比。在目标2中，我们将检验死后MRI允许以下假设： 与在生命期间获得的MRI相比，检测到更高数量的SVL。 在这项工作完成后，并利用从这项研究中获得的见解，我们将申请R01赠款 前瞻性研究死后MRI在预测海马硬化和SVL中的实用性， 队列。从这些研究中获得的见解将用于预测HS并改善检测 的SVL在生命期间获得的MRI中。这将随后能够开发针对 这两种重要的病理，显着有助于发展痴呆症，在增长最快的 到2050年，这部分人口将占所有痴呆症患者的一半。

The oldest old, people aged 90 years or older, are the fastest growing segment of the worldwide population with a staggering increase in the prevalence of dementia. Unlike younger groups, Alzheimer’s disease neuropathology (ADNP) is no longer the most dominant degenerative neuropathology in the oldest old and dementia is often due to the presence of multiple neuropathologies. Hippocampal sclerosis (HS) and small vessel lesions (SVL) are important contributors to dementia in the oldest old. Due to lack of reliable biomarkers, HS remains undetected and SVLs are under-recognized during life. These limitations hamper efforts in developing target-specific therapeutics. The long-term goal of this project is to improve the in vivo diagnosis of these important pathologies using insights gained from postmortem brain MRI. Compared with MRIs acquired during life, postmortem MRI has the ability to acquire significantly higher quality scans allowing for better quantification and localization of abnormalities of brain tissue. The 90+ Study, a longitudinal observational study of participants aged 90 years or older at the University of California, Irvine, provides a unique opportunity to examine the utility of postmortem brain MRI in the oldest old. Neuropathological assessments are currently being conducted on the donated brains and a considerable subset of participants will have undergone brain MRI during life allowing for comparisons between in vivo and postmortem imaging findings and translation of the insights gained from postmortem to in vivo MRIs. We have already developed the sequences and started acquisition of postmortem MRI scans proving the feasibility of our approach. We anticipate acquiring postmortem MRI scans for 50 participants and based on our current data, this sample will provide sufficient number of cases harboring the two pathologies of interest i.e. HS and SVLs. Moreover, our power calculations indicate that we will be able to test the hypotheses of this proposal with this sample size. In aim 1, we will test the hypothesis that hippocampal sclerosis will be associated with MRI detectable volume loss and signal change in the hippocampus and that postmortem MRI has a higher sensitivity to detect these compared with MRI acquired during life. In aim 2, we will test the hypothesis that postmortem MRI allows for detection of higher numbers of SVLs when compared with MRI acquired during life. At completion of this work and utilizing the insights gained from this study, we will apply for an R01 grant to prospectively study the utility of post-mortem MRI in prediction of hippocampal sclerosis and SVLs in a large cohort. The insights gained from these studies will be used to enable prediction of HS and improve the detection of SVLs in MRIs acquired during life. This will subsequently enable development of targeted therapies against these two important pathologies that significantly contribute to development of dementia in fastest growing segment of our population that will represent half of all of those suffering from dementia by 2050.