TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer's disease

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.

Keywords: Alzheimer’s disease; Anterior temporal pole; Dementia; Episodic memory; Hippocampal sclerosis; Orbital frontal cortex; Semantic memory; TDP-43.

Fig. 1

(a-g) The regional distribution of TDP-43 inclusions and percentage of cases showing TDP-43 inclusions in stages 1-5 are shown (a-g). This is a cumulative staging system such that any stage from 2 to 5 is considered to be positive if the previous stages are positive. The Brodmann designation of the cortices is shown in parentheses. AMG = amygdala, EC = entorhinal cortex, CA1 = CA1 sector of the hippocampus, DEN = dentate gyrus, ATPC = anterior temporal pole cortex, MTC = midtemporal cortex, OFC = orbital frontal cortex and MFC = midfrontal cortex

Fig. 2

TDP-43 inclusions in neuronal cytoplasm and neurites in the ATPC are shown (a-d). Representative areas of the ATPC show sparse (a), moderate (b) and frequent (c) intracytoplasmic neuronal TDP-43 inclusions and neurite immunostaining. The areas depicted (a-c) are smaller than the 0.25 mm² counting frame used to quantitate the inclusions. (d) Cytoplasmic TDP-43 in neurons and prominent neurite staining are shown in high magnification. Scale bar = 25 μm (a-c) and 50 μm (d)

Fig. 3

Box plots showing the total number of TDP-43 inclusions per 0.25 mm² area in the eight brain regions by stage. The numbers on the x axis denote the brain regions which are designated as 1: amygdala, 2: entorhinal cortex, 3:CA1 sector of the hippocampus, 4: dentate neurons of the hippocampus, 5: anterior temporal pole cortex, 6: midtemporal cortex, 7: orbital frontal cortex, 8: midfrontal cortex. There is progressive increase of inclusions in the amygdala by stage. Inclusions in all regions including the ATPC are maximal in stage 5