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.

Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy

“…Concomitant proteinopathies affect neuropathological and clinical manifestations of any neurodegenerative disorder. It was recently shown that 45% of CBD cases have concomitant TDP‐43 pathology and, when located in the midbrain tegmentum, can lead to VSGP and a PSP‐RS‐like phenotype . Concomitant proteinopathies are also well recognized in all forms of parkinsonism .…”

“…It was recently shown that 45% of CBD cases have concomitant TDP-43 pathology and, when located in the midbrain tegmentum, can lead to VSGP and a PSP-RS-like phenotype. 48 Concomitant proteinopathies are also well recognized in all forms of parkinsonism. 49 The burden and characteristics of copathology may depend on age and APOE ε4 and may be independently influenced by the presence of tau versus α-synuclein.…”

Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates

“…No difference was found in the presence of hippocampal sclerosis (RP-CBD: 1 in 6 (17%), ES-CBD: 10 in 110 (9%); χ 2 test: p = 0.46), argyrophilic grain disease Secondary pathologies may influence the phenotypic presentation and disease course of neurodegenerative tauopathies [29,32,34,43,60,67]. Therefore, it is noteworthy that concomitant pathologies were not contributary to the rapid progression in RP-CBD (Table 3).…”

“…The neuropathological characteristics of autopsy-confirmed CBD cases with a rapidly progressive course (RP-CBD) are not known and whether RP-CBD cases are neuropathologically distinct like other reported CBD variants warrants investigation [32][33][34]41]. In this study, we have investigated these research questions by quantitatively analysing the neuropathological characteristics in six RP-CBD cases and comparing them with other CBD groups.…”

Autopsy findings in the early stage of amyotrophic lateral sclerosis with “dropped head” syndrome

“…TDP‐43 is the diagnostic hallmark of ALS and FTLD; however, recent reports also revealed that TDP‐43 positive structures also appear with aging or neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, argyrophilic grain disease, corticobasal degeneration and progressive supranuclear palsy . These reports suggest TDP‐43 deposition will start from the amygdala and entorhinal cortex.…”