Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype

Abstract

Background: TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity.

Methods: Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls.

Results: Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity.

Conclusions: The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.

Figure 1

abTDP-43 immunoreactivity in AD was classified into one of three histologic types according to the scheme proposed by Mackenzie et al. with medial temporal cortex (A, B and C) and dentate fascia of the hippocampus (D, E and F). Type 1 had neuronal cytoplasmic inclusions and short neurites in the cortex (A) and granular cytoplasmic inclusions in the dentate fascia (D). Some cases had intranuclear inclusions (inset). Type 2 had neurites but few or no cytoplasmic inclusions in the cortex (B) and characteristic long, tapering neurites (inset); round, Pick body-like inclusions were noted in the dentate fascia (E). Type 3 had cytoplasmic inclusions with few neurites in the cortex (C) and variable dentate fascia inclusions (F).

Figure 2

Results of VBM showing similarity in the patterns of gray matter atrophy in both groups of subjects with and without abTDP-43 immunoreactivity on a 3D render. Panel A shows the patterns of gray matter atrophy in AD subjects without abTDP-43 immunoreactivity compared to controls (corrected for multiple comparisons using the FWE, p<0.05). Panel B shows the patterns of gray matter atrophy in the AD subjects with abTDP-43 immunoreactivity compared to controls (corrected, p<0.05). Panel C shows greater hippocampal loss observed in the abTDP-43 immunoreactive subjects compared to the AD subjects without abTDP-43 immunoreactivity overlaid on a representative slice through the customized template (corrected for multiple comparisons using the FDR, p<0.05).