Staging TDP-43 pathology in Alzheimer's disease

Abstract

TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

Figure 1. Pathological findings from representative cases for each of the five stages

In stage I, scant-sparse TDP-43 immunoreactive inclusions are observed only in the amygdala. In stage II, inclusions are moderate-frequent in the amygdala and extend into entorhinal cortex, but are not identified in dentate, OTC, temporal or frontal cortices. In stage III, inclusions extend into hippocampus and OTC, but are not identified in temporal or frontal cortices. In stage IV, inclusions extend into the inferior temporal cortex. In stage V, TDP-43 immunoreactivity is widespread and affects the frontal cortex or basal ganglia. Bar = 30 micron. All images are the same magnification. Arrows point to NCI’s.

Figure 2. Line plots show significant differences between TDP-negative cases and all five stages

Data points represent median values for each variable. *p<0.05; **p<0.01; ***p<0.001 Hippocampal and entorhinal MRI volumes are shown as volume/TIV × 100. MMSE = Mini-Mental State Examination, CDR-SB = Clinical Dementia Rating Sum of Boxes; mDRS = memory subscale of the Dementia Rating Scale; BNT = Boston Naming Test.

Figure 3. Neuroimaging and pathological findings in a case with AD and TDP-43 type C pathology

Top panel shows three coronal T1-weighted MRI slices highlighting left anteromedial temporal lobe atrophy. Bottom panel shows TDP-43 immunoreactive inclusions consistent with FTLD type C, including long thick DNs in frontal (a) and insula (b) cortices, and Pick body-like NCIs in the putamen (c) and the hippocampal dentate gyrus (d). Bar = 30 micron