Rush Alzheimer Disease Center, Rush University Medical Center, Suite 1000, 1750 W Harrison Street, Chicago, IL, 60612, USA.
Departments of Pathology (Neuropathology), Rush University Medical Center, Chicago, IL, USA.
Acta Neuropathol Commun. 2018 May 1;6(1):33. doi: 10.1186/s40478-018-0531-3.
TDP-43 pathology was investigated in the anterior temporal pole cortex (ATPC) and orbital frontal cortex (OFC), regions often degenerated in frontotemporal lobar degenerations (FTLD), in aging and Alzheimer's disease (AD). Diagnosis of dementia in the 1160 autopsied participants from 3 studies of community-dwelling elders was based on clinical evaluation and cognitive performance tests which were used to create summary measures of the five cognitive domains. Neuronal and glial TDP-43 cytoplasmic inclusions were quantitated in 8 brain regions by immunohistochemistry, and used in ANOVA and regression analyses. TDP-43 pathology was present in 547 (49.4%) participants in whom ATPC (41.9%) was the most frequently involved neocortical region and in 15.5% of these cases, ATPC was the only neocortical area with TDP-43 pathology suggesting not only that ATPC is involved early by TDP-43 but that ATPC may represent an intermediate stage between mesial temporal lobe involvement by TDP-43 and the last stage with involvement of other neocortical areas. To better study this intermediary neocortical stage, and to integrate with other staging schemes, our previous 3 stage distribution of TDP-43 pathology was revised to a 5 stage distribution scheme with stage 1 showing involvement of the amygdala only; stage 2 showed extension to hippocampus and/or entorhinal cortex; stage 3 showed extension to the ATPC; stage 4 - showed extension to the midtemporal cortex and/or OFC and finally in stage 5, there was extension to the midfrontal cortex. Clinically, cases in stages 2 to 5 had impaired episodic memory, however, stage 3 was distinct from stage 2 since stage 3 cases had significantly increased odds of dementia. The proportion of cases with hippocampal sclerosis increased progressively across the stages with stage 5 showing the largest proportion of hippocampal sclerosis cases. Stage 5 cases differed from other stages by having impairment of semantic memory and perceptual speed, in addition to episodic memory impairment. These data suggest that of the regions studied, TDP-43 pathology in the ATPC is an important early neocortical stage of TDP-43 progression in aging and AD while extension of TDP-43 pathology to the midfrontal cortex is a late stage associated with more severe and global cognitive impairment.
TDP-43 病理学在额颞叶变性（FTLD）中经常退化的额极皮质（ATPC）和眶额皮质（OFC）中进行了研究，在衰老和阿尔茨海默病（AD）中。在 3 项社区居住老年人研究中的 1160 名尸检参与者中，根据临床评估和认知表现测试诊断为痴呆症，这些测试用于创建五个认知领域的综合指标。通过免疫组织化学定量测定了 8 个脑区的神经元和神经胶质 TDP-43 细胞质包含物，并用于方差分析和回归分析。在 547 名参与者（49.4%）中存在 TDP-43 病理学，其中 ATPC（41.9%）是最常涉及的新皮质区域，在这些病例中，有 15.5%的 ATPC 是唯一具有 TDP-43 病理学的新皮质区域，这不仅表明 ATPC 早期受到 TDP-43 的影响，而且 ATPC 可能代表 TDP-43 累及内侧颞叶和最后累及其他新皮质区域之间的中间阶段。为了更好地研究这个中间新皮质阶段，并与其他分期方案整合，我们之前的 TDP-43 病理学 3 期分布被修订为 5 期分布方案，第 1 期仅涉及杏仁核；第 2 期扩展到海马和/或内嗅皮质；第 3 期扩展到 ATPC；第 4 期扩展到中颞叶皮质和/或 OFC；最后，第 5 期扩展到中前额叶皮质。临床上，第 2 至 5 期的病例均存在情节记忆障碍，但第 3 期与第 2 期不同，因为第 3 期病例发生痴呆的几率显著增加。随着第 5 期病例中出现最大比例的海马硬化病例，各期病例中海马硬化的比例逐渐增加。第 5 期病例与其他阶段不同，除了情节记忆障碍外，还存在语义记忆和知觉速度障碍。这些数据表明，在所研究的区域中，ATPC 中的 TDP-43 病理学是衰老和 AD 中 TDP-43 进展的重要早期新皮质阶段，而 TDP-43 病理学扩展到前额叶皮质是与更严重和全面认知障碍相关的晚期阶段。
