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 A. Josephs; Irene Litvan; Neill Graff-Radford; J. Eric Ahlskog; Ryan J. Uitti; Jay A. van Gerpen; Bradley F. Boeve; Adam Parks; Owen A. Ross; Dennis W. Dickson

doi:10.1007/s00401-018-1878-z

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 A. Josephs, Irene Litvan, Neill 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 journal › Article › peer-review

40 Scopus citations

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 language	English
Pages (from-to)	389-404
Number of pages	16
Journal	Acta Neuropathologica
Volume	136
Issue number	3
DOIs	https://doi.org/10.1007/s00401-018-1878-z
State	Published - Sep 1 2018

Bibliographical note

Funding Information:
Acknowledgements We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine.

Funding Information:
We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine.

Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

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

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10.1007/s00401-018-1878-z

Cite this

Koga, S., Kouri, N., Walton, R. L., Ebbert, M. T. W., Josephs, K. A., Litvan, I., Graff-Radford, N., Ahlskog, J. E., Uitti, R. J., van Gerpen, J. A., Boeve, B. F., Parks, A., Ross, O. A., & Dickson, D. W. (2018). Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype. Acta Neuropathologica, 136(3), 389-404. https://doi.org/10.1007/s00401-018-1878-z

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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 A.} and Irene Litvan and Neill Graff-Radford 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.}",

note = "Funding Information: Acknowledgements We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine. Funding Information: We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine. Publisher Copyright: {\textcopyright} 2018, Springer-Verlag GmbH Germany, part of Springer Nature.",

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Koga, S, Kouri, N, Walton, RL, Ebbert, MTW, Josephs, KA, Litvan, I, Graff-Radford, N, Ahlskog, JE, Uitti, RJ, van Gerpen, JA, Boeve, BF, Parks, A, Ross, OA & Dickson, DW 2018, 'Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype', Acta Neuropathologica, vol. 136, no. 3, pp. 389-404. https://doi.org/10.1007/s00401-018-1878-z

TY - JOUR

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 A.

AU - Litvan, Irene

AU - Graff-Radford, Neill

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.

N1 - Funding Information: Acknowledgements We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine. Funding Information: We would like to thank the patients and their families who donated brains to help further the scientific understanding of neurodegeneration. The authors would also like to acknowledge Linda Rousseau, Virginia Phillips, and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support, Laura J. Lewis-Tuffin (Mayo Clinic, Jacksonville) for confocal microscopy support, and Drs. Zbigniew K. Wszolek (Mayo Clinic, Jacksonville), Daniel A. Drubach, and David S. Knopman (Mayo Clinic, Rochester) for contributing patients. This work is supported by NIH Grant P50 NS072187, a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and CBD Solutions Research Grant. DWD and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine. Publisher Copyright: © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2018/9/1

Y1 - 2018/9/1

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.

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KW - Corticobasal syndrome

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KW - Progressive supranuclear palsy

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

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