TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features.
TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features.
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DOI：
10.1002/ana.24493
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发表时间：
2015-11
影响因子：
11.2
通讯作者：
Dickson DW
中科院分区：
文献类型：
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作者：
Josephs KA;Whitwell JL;Tosakulwong N;Weigand SD;Murray ME;Liesinger AM;Petrucelli L;Senjem ML;Ivnik RJ;Parisi JE;Petersen RC;Dickson DW
确定阿尔茨海默病（AD）中TDP-43沉积的频率是否在病理定义的AD亚型（海马保留[HpSp];典型和边缘）之间存在差异，并进一步检查TDP-43、病理亚型和AD临床特征之间的关系。我们确定了所有经病理证实的AD（NIA-Reagan中-高概率，Braak IV-VI期）病例，这些病例与认知状态无关（n=188）。在海马和三个新皮质区域中使用硫黄-S显微镜进行神经缠结计数，并且所有病例均被分型为：HpSp AD病理学（n=19）;典型AD病理学（n=136）;边缘AD病理学（n=33）。在多个脑区域中进行TDP-43免疫反应性以评估TDP-43和TDP-43分期的存在。所有病例在临床上被细分为遗忘型AD痴呆与非典型AD痴呆。使用线性和惩罚逻辑回归进行统计分析，以评估与病理亚型的关联，以及TDP-43的作用，解释病理亚型和TDP-43之间可能的相互作用。TDP-43沉积在典型AD病理学（59%）和边缘AD病理学（67%）中很常见，但在HpSp AD病理学（21%）中不常见（p=0.003）。观察到的TDP-43与更严重的记忆丧失、命名和功能下降以及最接近死亡的海马体积较小的相关性在AD病理亚型中没有差异。临床表现与病理亚型相关（p=0.01），但与TDP-43无关（p=0.69）。尽管AD中TDP-43沉积的频率因病理亚型而异，但观察到的TDP-43对临床/MRI特征的影响在病理亚型中是一致的。AD的临床表现由病理亚型而不是TDP-43驱动。
To determine whether the frequency of TDP-43 deposition in Alzheimer’s disease (AD) differs across pathologically defined AD subtypes (Hippocampal sparing [HpSp]; Typical and Limbic), and to further examine the relationship between TDP-43, pathological subtype, and clinical features in AD. We identified all cases with pathologically-confirmed AD (NIA-Reagan intermediate-high probability, Braak stage IV–VI) independent of cognitive status (n=188). Neurofibrillary tangle counts were performed using thioflavin-S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD Pathology (n=19); Typical AD Pathology (n=136); Limbic AD Pathology (n=33). TDP-43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP-43 and TDP-43 stage. All cases were clinically sub-classified at presentation as Amnestic AD Dementia versus Atypical AD Dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP-43, accounting for possible interactions between pathological subtype and TDP-43. TDP-43 deposition was frequent in Typical (59%) and Limbic AD pathologies (67%), but not HpSp AD Pathology (21%) (p=0.003). The observed associations of TDP-43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p=0.01), but not TDP-43 (p=0.69). Although the frequency of TDP-43 deposition in AD varies by pathological subtype, the observed effects of TDP-43 on clinical/MRI features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP-43.