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部分 痴呆症患病率惊人增加的人口。与年轻群体不同，阿尔茨海默病 神经病理学(ADNP)不再是老年人和老年人最主要的退行性神经病理 痴呆症通常是由于多种神经病变引起的。海马区硬化症与小血管 病变(SVL)是导致高龄老人痴呆的重要因素。由于缺乏可靠的生物标志物，HS 在生命中仍未被发现，SVL未被识别。这些限制阻碍了开发 靶向治疗学。该项目的长期目标是改进对这些疾病的活体诊断 使用从尸检脑核磁共振获得的洞察力的重要病理学。与在以下时间获得的磁共振成像进行比较 LIFE，尸检MRI能够获得明显更高质量的扫描，从而实现更好的量化 以及脑组织异常的定位。 这项90+研究是对该大学90岁或以上的参与者进行的纵向观察性研究 加州大学欧文分校，提供了一个独特的机会来研究最古老的尸检脑核磁共振的实用性 年长的。目前正在对捐赠的大脑进行神经病理学评估，并有相当多的 一部分参与者将在有生之年接受过脑部核磁共振检查，以便比较体内和 死后的影像表现和将死后的洞察力转化为活体磁共振成像。我们有 已经开发了序列并开始采集尸检MRI扫描，证明了我们的 接近。我们预计将获得50名参与者的尸检MRI扫描，根据我们目前的数据，这 样本将提供足够数量的病例，其中包含两种感兴趣的病理，即HS和SVLS。 此外，我们的功率计算表明，我们将能够用这个来检验这个提议的假设 样本大小。 在目标1中，我们将检验这一假设，即海马区硬化将与mri可检测的体积相关。 海马区的丢失和信号变化，尸检MRI对检测这些有更高的敏感性 与在生活中获得的MRI进行比较。在目标2中，我们将测试尸检MRI允许的假设 与生活中获得的MRI相比，检测到更多的SVLS。 在完成这项工作并利用从这项研究中获得的见解后，我们将申请R01拨款 前瞻性研究尸检MRI在预测大范围海马区硬化和SVLS中的应用 一群人。从这些研究中获得的见解将被用来预测HS并改进检测 在生命中获得的核磁共振成像中SVLS的比例。这将使随后能够开发出针对 这两种重要的病理因素显著促进了痴呆症的快速发展 到2050年，我们人口的一部分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.