Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

Abstract

Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.

Keywords: Argyrophilic grain disease; Corticobasal degeneration; Corticobasal syndrome; MAPT; Progressive supranuclear palsy; TDP-43.

Figure 1:

Representative images of immunohistochemistry for phospho-TDP43. Neuronal cytoplasmic inclusions (NCIs), dystrophic neurites, and glial cytoplasmic inclusions in the mesopontine tegmentum (a) and midbrain tectum (b). Double-labeling immunohistochemistry (brown: phospho-TDP43, blue: CP13) shows that neurons express both tau and TDP-43 proteins (c). Spheroid in the substantia nigra (d) and perivascular inclusion in the pontine tegmentum (e). Astrocytic plaque-like lesions in the superior frontal gyrus (f). Neuronal intranuclear inclusion in the cingulate gyrus (g). NCIs with short dystrophic neurites in the superior frontal gyrus (h) Double-labeling immunohistochemistry (brown: phospho-TDP43, blue: CP13) shows TDP-43 inclusion in a balloon neuron (i), astrocytic plaques (j), and coiled body (k). Double-labeling immunofluorescence (green: phospho-TDP43, red: CP13) shows neuronal intranuclear inclusion in a pretangle (l-n), and a subset of astrocytic plaque expresses both proteins (o-q). Bars: 50 µm in a, b, f, and h; 25 µm in c-e, g, i-k; 10 µm in l-q.

Figure 2:

Heatmap and hierarchical clustering based on TDP-43 pathology in 84 TDP-43 positive CBD cases. Three distinct clusters are identified by hierarchical clustering. The heat map reflects the severity of TDP-43 pathology, and a color scale is given at the top left. Missing data are shown in gray. Patients are represented with columns, and study ID of each patient is provided.

Figure 3:

Tau burden in the pontine base, inferior olivary nucleus, and cerebellar white matter are compared between TDP-negative, TDP-limited, and TDP-severe CBD patients. Overall p values are shown. Asterisks indicate significant levels (ANOVA on ranks, followed by Steel-Dwass post hoc test;** p <0.01, *** p <0.001).