Background Post-mortem studies have not identified an association between beta-amyloid or tau and rates of hippocampal atrophy in Alzheimer’s disease. TAR DNA binding protein of 43kDa (TDP-43) is another protein recently linked to Alzheimer’s disease. We aimed to determine whether hippocampal TDP-43 is associated with faster rates of hippocampal atrophy. Methods Two-hundred ninety-eight autopsied cases with Alzheimer’s spectrum disease that had antemortem head MRI scans between 1/1/1999–12/31/2012 recruited into the Mayo Clinic Alzheimer’s Disease Research Center or Patient Registry/Study of Aging were analyzed. TDP-43 immunohistochemistry was performed and cases classified as follows: no TDP-43; TDP-43 restricted to amygdala; and TDP-43 spreading into hippocampus. Eight-hundred sixteen MRI scans, spanning 1.0–11.2 years prior to death, were analyzed. We utilized longitudinal FreeSurfer and tensor-based morphometry with symmetric normalization to calculate hippocampal volume on all serial MRI and performed linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy, and determine the trajectory of TDP-43 associated atrophy. Findings One-hundred forty-one cases showed no TDP-43, 33 had TDP-43 restricted to the amygdala and 124 had TDP-43 in hippocampus. Cases with hippocampal TDP-43 had faster rates of hippocampal atrophy compared to cases with amygdala-only TDP-43 and those without TDP-43 in cases with an intermediate-high likelihood of having Alzheimer’s disease (N=261). Hippocampal TDP-43 was not associated with rate of hippocampal atrophy in cases with low likelihood of having Alzheimer’s disease (N=37). The trajectory analysis suggested that increased rates of TDP-43 associated hippocampal atrophy may be occurring at least 10-years before death. Results were similar for FreeSurfer and tensor-based morphometry. Interpretation In Alzheimer’s disease, TDP-43 should be considered a potential factor related to increased rates of hippocampal atrophy. Given the importance of hippocampal atrophy in Alzheimer’s disease, it is imperative that we develop techniques for detecting TDP-43 pathology in-vivo. Funding National Institute of Aging

中文翻译：

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阿尔茨海默病患者海马萎缩率和死后 TDP-43 的存在：一项纵向回顾性研究

背景 尸检研究尚未确定 β-淀粉样蛋白或 tau 蛋白与阿尔茨海默病海马萎缩率之间存在关联。43kDa 的 TAR DNA 结合蛋白 (TDP-43) 是另一种最近与阿尔茨海默病相关的蛋白质。我们旨在确定海马 TDP-43 是否与更快的海马萎缩率有关。方法 分析了在 Mayo Clinic 阿尔茨海默病研究中心或患者登记处/衰老研究中心招募的 298 例阿尔茨海默病谱系疾病尸体解剖病例，这些病例在 1/1/1999 至 12/31/2012 期间进行了死前头部 MRI 扫描。进行了 TDP-43 免疫组化，病例分类如下：无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43；无 TDP-43。TDP-43 仅限于杏仁核；和 TDP-43 扩散到海马体。816 次 MRI 扫描，跨越死亡前 1.0-11.2 年，进行了分析。我们利用纵向 FreeSurfer 和基于张量的对称归一化形态测量来计算所有系列 MRI 上的海马体积，并执行线性混合效应回归模型来估计 TDP-43 与海马萎缩率之间的关联，并确定 TDP-43 相关的轨迹萎缩。结果 141 例没有 TDP-43，33 例 TDP-43 局限于杏仁核，124 例 TDP-43 位于海马。与只有杏仁核 TDP-43 的病例和没有 TDP-43 的病例相比，海马 TDP-43 病例的海马萎缩率更快，并且患有阿尔茨海默病的中高可能性（N = 261）。在患有阿尔茨海默病的可能性较低的病例 (N=37) 中，海马 TDP-43 与海马萎缩率无关。轨迹分析表明，与 TDP-43 相关的海马萎缩率增加可能发生在死亡前至少 10 年。FreeSurfer 和基于张量的形态测量的结果相似。解释 在阿尔茨海默病中，TDP-43 应被视为与海马萎缩率增加相关的潜在因素。鉴于海马萎缩在阿尔茨海默病中的重要性，我们必须开发用于体内检测 TDP-43 病理的技术。资助国家老龄化研究所 TDP-43 应被视为与海马萎缩率增加相关的潜在因素。鉴于海马萎缩在阿尔茨海默病中的重要性，我们必须开发用于体内检测 TDP-43 病理的技术。资助国家老龄化研究所 TDP-43 应被视为与海马萎缩率增加相关的潜在因素。鉴于海马萎缩在阿尔茨海默病中的重要性，我们必须开发用于体内检测 TDP-43 病理的技术。资助国家老龄化研究所