Abstract
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.
Highlights
The transactive response DNA-binding protein 43 (TDP43) was first localized in brains of cases with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) [1, 20]
Our results show that the anterior temporal pole cortex (ATPC), but not the orbital frontal cortex (OFC), appears to be a prominent and early neocortical site of involvement in TDP-43 pathology associated with aging and Alzheimer’s disease (AD) and that this stage is related to dementia
TDP-43 in ATPC and OFC In the TDP-43 positive cases, the most frequent neocortical area showing TDP-43 inclusions was the ATPC (41.9%) followed by the midtemporal cortex, the OFC and inclusions were least common in the midfrontal cortex (Table 1)
Summary
The transactive response DNA-binding protein 43 (TDP43) was first localized in brains of cases with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) [1, 20]. Subsequent studies localized this protein in Alzheimer’s disease (AD) [8, 24] and other neurodegenerative diseases such as age-related hippocampal sclerosis [14, 18], Lewy body (LB) diseases [11, 16] and. In stage 1, TDP-43 was localized to the amygdala, in stage 2 there was extension of TDP-43 pathology to the hippocampus and/or entorhinal cortex while in stage 3 there was further extension to neocortical areas such as the midtemporal or midfrontal cortices
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