TDP-43 is a key player in the clinical features associated with Alzheimer's disease

Abstract

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer's disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

Fig. 1

Pathological assessment of TDP-43 immunoreactive inclusions. TDP-43 immunoreactive inclusions identified in the subjects with Alzheimer disease include neuronal cytoplasmic inclusions in the dentate fascia of the hippocampus that were variable in size with some being asterisks-like and small (a), while others were larger, round, and more Pick-body like (b). Dystrophic neurites in the neocortices were predominantly thin and thread-like (c) although in some instances there were large think dystrophic neurites (d). In the CA1 region of the hippocampus, particularly in the cases with widespread TDP-43 immunoreactivity, there were fine neurites (e). Many of these cases with widespread TDP-43 immunoreactivity also had neuronal intranuclear inclusions that were either cat-eye like in appearance (f) or were more rounded (g). TDP-43 immunoreactivity, high power mag × 40. Dentate fascia of the hippocampus (a–b), frontotemporal neocortices (c–d), CA1 region of the hippocampus (e), entorhinal cortex (f) and occipitotemporal cortex (g).

Fig. 2

The range of TDP-43 immunoreactivity observed in the amygdala. Cases without TDP-43 immunoreactivity in the amygdala (a) were classified as TDP-negative while cases showing any amount of TDP-43 immunoreactivity (b–d) were classified as TDP-positive. Amygdala TDP-43 immunoreactivity varied and included cases with scant (b), moderate (c) and severe (c) immunoreactivity. TDP-43 immunoreactivity at mag × 20.

Fig. 3

Histograms showing the prevalence of TDP-43 by region (top) and quantitative TDP-43 burden in the dentate gyrus (bottom). Only TDP-positive subjects are shown for both histograms. Therefore, as would be expected based on our inclusion criteria, 100% of the subjects had amygdala involvement (top). Involvement in other 13 regions was variable with the frontal lobe and basal ganglia being involved in the least number of subjects. In the bottom histogram, TDP-43 burden was highly skewed to the right. As reported, there was a strong correlation between TDP-43 burden in the dentate gyrus and number of regions affected.

Fig. 4

TDP-43 burden assessment. TDP-43 immunoreactive inclusions in the dentate fascia were assessed quantitatively in order to determine TDP-43 burden. High resolution images created with the Aperio slide scanner were utilized to detect abnormal TDP-43 using a custom-designed color deconvolution algorithm. Top panel shows TDP-43 immunoreactive inclusions while bottom panel shows the results of the color deconvolution algorithm in which abnormal TDP-43 is depicted in red.

Fig. 5

Estimates and 95% CIs for the mean difference for each term in the primary model along with the estimates and 95% CIs for the hippocampal sclerosis and TDP terms from the mediation model. P values for the primary models summarize a test of an additive effect of TDP after accounting for Braak stage, age, CERAD, APOE ε4, infarctions, and Lewy bodies (Padd) and a test of an interaction between TDP and Braak stage versus the additive model (Pint). The P values for the mediation model additionally account for HpScl. The cognitive impairment outcome was modeled with logistic regression and the estimates were transformed to the percentage scale with age set to the mean (85). All other outcomes were modeled using linear regression.

Fig. 6

Estimates and 95% CIs for the mean volume difference for each term in the primary model along with the estimates and 95% CIs for the hippocampal sclerosis and TDP terms from the mediation model. The P values for the primary models summarize the test of an additive effect of TDP after accounting for Braak stage, age, CERAD, APOE ε4, infarctions, and Lewy bodies (Padd) and a test of an interaction between TDP and Braak stage versus the additive model (Pint). The P values for the mediation model additionally account for HpScl. All outcomes were modeled using linear regression.

Fig. 7

Regional patterns of grey matter volume loss in TDP-negative and TDP-positive AD subjects within Braak stages IV, V and VI. The TDP-negative and TDP-positive subjects are compared to pathologically normal controls (corrected using family-wise error at p<0.05) and compared to each other (uncorrected p<0.001). Results are shown on three dimensional renderings of the brain.

Fig. 8

Summaries illustrating the relationship between normal cognition, MMSE and hippocampal volume loss, and Braak stage, and TDP-43 status in AD. In the absence of TDP-43, there is a progressively higher proportion of subjects with cognitive impairment across Braak stages with the steepest changes in proportion occurring between Braak stages V and VI. On the contrary TDP-43 is consistently associated with a high proportion of impaired subjects regardless of Braak stage. Similar trends are seen with MMSE and hippocampal volume. While we illustrate this phenomenon using cognition, MMSE and hippocampus, similar trends were observed for other clinical and imaging outcome variables.