Establishing cellular-validated standards for parcellating hippocampal subfields in aging and Alzheimer's disease

衰老和阿尔茨海默病(AD)对海马区的影响不同。一个健壮的， 需要可靠的成像工具来评估海马区和区分早期AD 来自正常的老化。尽管最近的神经成像研究已经统一了对 整个海马体成功，多个小组进一步分割海马体 进入子领域，出现了高度可变的结果。关于萎缩的报道相互矛盾 随着年龄的增长而发生的变化--阿尔茨海默氏症。海马体中含有选择性 脆弱的细胞群体。识别所有皮质下锥体细胞轮廓，CA1， CA2和CA3对于开发严格的、细胞验证的海马区定义是必不可少的 并将其作为可靠的生物标志物是确定AD的关键一步 脆弱性。组织学需要准确地区分亚场。我们的总体目标是 根据细胞而不是层次或显微解剖来描述海马区的特征 功能。这项提议的目标是建立12个经过组织学验证的海马体 基于新的单元格标准(大小、模式、方向性度量)的子域，并应用此 神经成像映射到活体人群。这一区域综合地图将建立新的 代表亚群最多的海马区的细胞读数 在AD中易受攻击。该项目将结合高分辨率的体外核磁共振成像，一种临床前脑组织 收藏和我们的神经解剖学专业知识。AIM 1将建立一种新的神经成像工具 在Freesurfer中对12个海马亚区进行分割。AIM 2将验证海马区 尼氏染色的亚区组织学对应于相同的病例并建立 每个分区的新解剖和细胞框架：锥体细胞直径 细胞方向性测量的锥体神经元模式和我们的三个“c” 计算建筑边界的协议。目标3将应用海马子场 分割工具用于3T活体MRI数据，包括哈佛大学脑老化研究，人类 Connectome项目，阿尔茨海默病神经成像计划和验证 已建立的生物标志物。我们需要区域整合的子场地图来消除老化的歧义 早期预测AD的特异度、敏感度和可靠性。工作地点-- 微尺度-将产生经过充分验证的标准，将有助于解开细胞和 未来AD导致的健康老龄化中的网络漏洞功能、纵向或 治疗性研究。

Aging and Alzheimer’s Disease (AD) differentially affect the hippocampal subfields. A robust, reliable imaging tool is needed to evaluate the hippocampal subfields and distinguish early AD from normal aging. Though recent neuroimaging studies have harmonized the labeling of the whole hippocampus with success, multiple groups have parcellated the hippocampus further into subfields and highly variable results emerged. Conflicting reports exist about atrophy changes along the aging-Alzheimer’s continuum. The hippocampus contains selective vulnerable cell populations. Identifying pyramidal cell profiles for all subicular cortices, CA1, CA2, and CA3 is essential to develop rigorous, cell-validated definitions for the hippocampal subregions and to corroborate these as reliable biomarkers is a critical step to determine AD vulnerability. Histology is required to differentiate subfields accurately. Our overall goal is to characterize the hippocampus subregions based on cells, not layers or microanatomical features. The objective of this proposal is to create twelve histologically-validated hippocampal subfields based on novel, cellular criteria (size, pattern, directionality measures) and apply this neuroimaging map to in vivo populations. This regionally integrated map will establish new cellular readouts for the hippocampal formation that represent the subpopulations most vulnerable in AD. The project will combine high-resolution ex vivo MRI, a preclinical brain tissue collection, and our neuroanatomical expertise. Aim 1 will establish a novel neuroimaging tool that segments twelve hippocampal subfields in FreeSurfer. Aim 2 will validate hippocampal subregions histologically with Nissl staining corresponding to the same cases and establish novel anatomical and cellular frameworks for each subregion: pyramidal cell diameter measures, pyramidal neuronal pattern profiles from cell directionality measures and our triple “c” protocol to compute architectonic boundaries. Aim 3 will apply the hippocampus subfield segmentation tool to 3 T in vivo MRI data including the Harvard Aging Brain Study, the Human Connectome Project, Alzheimer’s disease Neuroimaging Initiative and validate against established biomarkers. Our regionally integrated subfield map is needed to disambiguate aging from AD in terms of specificity, sensitivity and reliability in early prediction of AD. The work – at the microscale – will generate well-validated standards that will help to disentangle cellular and network vulnerabilities in healthy aging from AD in future in vivo functional, longitudinal, or therapeutic studies.