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

Shunsuke Koga, Naomi Kouri, Ronald L. Walton, Mark T.W. Ebbert, Keith Anthony Josephs, Irene Litvan, Neill R Graff Radford, J. Eric Ahlskog, Ryan J. Uitti, Jay A Van Gerpen, Bradley F Boeve, Adam Parks, Owen A Ross, Dennis W Dickson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jun 20 2018

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Progressive Supranuclear Palsy
Pathology
Subthalamic Nucleus
Mesencephalon
Paralysis
Cluster Analysis
Tegmentum Mesencephali
Tauopathies
Parahippocampal Gyrus
Pons
DNA-Binding Proteins
Prefrontal Cortex
Gene Frequency
Paraffin
Cerebellum
Haplotypes
Autopsy
Immunohistochemistry
Genotype
Brain

Keywords

  • Argyrophilic grain disease
  • Corticobasal degeneration
  • Corticobasal syndrome
  • MAPT
  • Progressive supranuclear palsy
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome : a distinct clinicopathologic subtype. / Koga, Shunsuke; Kouri, Naomi; Walton, Ronald L.; Ebbert, Mark T.W.; Josephs, Keith Anthony; Litvan, Irene; Graff Radford, Neill R; Ahlskog, J. Eric; Uitti, Ryan J.; Van Gerpen, Jay A; Boeve, Bradley F; Parks, Adam; Ross, Owen A; Dickson, Dennis W.

In: Acta Neuropathologica, 20.06.2018, p. 1-16.

Research output: Contribution to journalArticle

Koga, Shunsuke ; Kouri, Naomi ; Walton, Ronald L. ; Ebbert, Mark T.W. ; Josephs, Keith Anthony ; Litvan, Irene ; Graff Radford, Neill R ; Ahlskog, J. Eric ; Uitti, Ryan J. ; Van Gerpen, Jay A ; Boeve, Bradley F ; Parks, Adam ; Ross, Owen A ; Dickson, Dennis W. / Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome : a distinct clinicopathologic subtype. In: Acta Neuropathologica. 2018 ; pp. 1-16.
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title = "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",
author = "Shunsuke Koga and Naomi Kouri and Walton, {Ronald L.} and Ebbert, {Mark T.W.} and Josephs, {Keith Anthony} and Irene Litvan and {Graff Radford}, {Neill R} and Ahlskog, {J. Eric} and Uitti, {Ryan J.} and {Van Gerpen}, {Jay A} and Boeve, {Bradley F} and Adam Parks and Ross, {Owen A} and Dickson, {Dennis W}",
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T1 - Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome

T2 - a distinct clinicopathologic subtype

AU - Koga, Shunsuke

AU - Kouri, Naomi

AU - Walton, Ronald L.

AU - Ebbert, Mark T.W.

AU - Josephs, Keith Anthony

AU - Litvan, Irene

AU - Graff Radford, Neill R

AU - Ahlskog, J. Eric

AU - Uitti, Ryan J.

AU - Van Gerpen, Jay A

AU - Boeve, Bradley F

AU - Parks, Adam

AU - Ross, Owen A

AU - Dickson, Dennis W

PY - 2018/6/20

Y1 - 2018/6/20

N2 - 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.

AB - 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.

KW - Argyrophilic grain disease

KW - Corticobasal degeneration

KW - Corticobasal syndrome

KW - MAPT

KW - Progressive supranuclear palsy

KW - TDP-43

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