ASSOCIATION BETWEEN APOE AND AGE OF ONSET IN ALZHEIMER?S DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。背景：载脂蛋白E （ApoE）基因型是阿尔茨海默病发病年龄的重要危险因素和调节因子；最近的研究表明ApoE-e4等位基因与晚发性阿尔茨海默病（LOAD）之间存在关联；对ApoE-e4等位基因在早发性（EOAD）中的可能作用知之甚少；在这里，我们的目的是研究ApoE-e4等位基因与皮质萎缩和海马体积在EOAD和LOAD患者的关联，使用皮质模式匹配（CPM）算法和海马径向映射（HRM）。方法：将临床严重程度相似的EOAD和LOAD患者的高分辨率3D MR图像与年龄和性别匹配的对照组进行比较。CPM用于识别病例与对照组中皮层灰质密度不同的区域，HRM用于评估海马体积差异。采用12参数线性变换将MR图像归一化为定制模板，提取两个半球的三维皮质表面；在每个半球的外侧和内侧表面手动勾勒出29个沟，并绘制额外的3D线来划定半球间的脑回界限。创建一个特定于人群的模板，平均受试者之间的跟踪沟，并将沟用作标记，将每个受试者的解剖扭曲到模板上。原始MR图像被分割成灰质、白质和脑脊液，并将皮质模式匹配获得的扭曲场应用于GM图像，从而允许在数千个同源皮质位置测量GM。计算每个组的平均灰质比例，并计算显示灰质密度与组之间相关性的统计显著性图（apoE4携带者的EOAD与LOAD，非携带者的EOAD与LOAD，携带者与非携带者）。将原始MRI与立体定向空间匹配后，在35个冠状面切片上手工描摹海马本体和下托轮廓，分离海马结构；内侧曲线将被自动定义为每个图像切片中由海马边界质心描摹出的三维曲线。通过自动测量从表面点到为个体海马表面模型定义的内侧曲线的径向三维距离，来评估每个边界点上每个海马的径向大小。较短的径向距离将被用作萎缩的指标；将生成统计图，显示局部组海马径向距离的差异。预期的结果。ApoE可能与EOAD患者更大的皮质萎缩有关，与LOAD患者更大的海马萎缩有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset in Alzheimer's disease; recent studies showed an association between ApoE-e4 allele and late onset Alzheimer disease (LOAD); less is known about possible ApoE-e4 allele effects in early-onset (EOAD); here we aim to investigate the association of ApoE-e4 allele on cortical atrophy and hippocampal volumes in EOAD and LOAD patients, using cortical pattern matching (CPM) algorithms and hippocampal radial mapping (HRM). Methods: High-resolution 3D MR images of EOAD and LOAD patients of similar clinical severity will be compared to those of age- and sex-matched controls. CPM is used to identify regions where the cortical gray matter density differs in cases vs controls, and HRM to assess hippocampal volumes difference. MR images are normalized to a customized template using a 12 parameter linear transformation and 3D cortical surfaces of both hemispheres are extracted; 29 sulci are manually outlined on the lateral and medial surface of each hemisphere, and additional 3D lines are drawn to delimit interhemispheric gyral limits. A population specific templates is created averaging the traced sulci among subjects, and the sulci are used as landmarks to warp each subject's anatomy to the template. Original MR images are segmented into gray matter, white matter, and CSF, and the warping fields obtained with cortical pattern matching is applied to the GM images, thus allowing measurement of GM at thousands of homologous cortical locations. The mean gray matter proportion is computed for each group, and statistical significance maps showing correlation between gray matter density and group (EOAD vs LOAD in apoE4 carriers, EOAD vs LOAD in noncarriers, carriers vs non-carriers) will be computed. The hippocampal formation will be isolated by manually tracing on 35 coronal slices the outlines of the hippocampus proper and subiculum after registration of original MRI to stereotactic space; a medial curve will be automatically defined as the 3D curve traced out by the centroid of the hippocampal boundary in each image slice. The radial size of each hippocampus at each boundary point will be assessed by automatically measuring the radial 3D distance from the surface points to the medial curve defined for individual¿s hippocampal surface model. Shorter radial distances will be used as an index of atrophy; statistical maps will be generated indicating local group differences in radial hippocampal distance. Expected results. ApoE could be associated with greater cortical atrophy in EOAD patients, and with greater hippocampal atrophy in LOAD.