Acta Neuropathologica

, Volume 136, Issue 3, pp 389–404 | Cite as

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. DicksonEmail author
Original Paper


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.


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



Alzheimer’s disease


Argyrophilic grain disease


Analysis of variance


Corticobasal degeneration


CBD-olivopontocerebellar atrophy


CBD-Richardson syndrome


Corticobasal syndrome


Dystrophic neurite


Frontotemporal lobar degeneration with TDP-43


Glial cytoplasmic inclusion


Neuronal cytoplasmic inclusion


Neurofibrillary tangle


Progressive supranuclear palsy


Transactive response DNA-binding protein of 43 kDa



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.

Supplementary material

401_2018_1878_MOESM1_ESM.docx (52 kb)
Supplementary material 1 (DOCX 51 kb)
401_2018_1878_MOESM2_ESM.tif (13.4 mb)
Supplementary Figure 1: The thickness of the anterior corpus callosum is measured in a standardized hematoxylin and eosin staining section at the level of the nucleus accumbens. (TIFF 13694 kb)
401_2018_1878_MOESM3_ESM.tif (36.6 mb)
Supplementary Figure 2: (a) The pontine base is annotated for digital quantification of tau immunoreactivity (CP13). (b) The higher magnification image from a box in (a). (c) The custom-designed color deconvolution algorithm to highlight tau deposits (shown in red). Pretangles and threads are observed and quantified. (TIFF 37455 kb)
401_2018_1878_MOESM4_ESM.tif (9.8 mb)
Supplementary Figure 3: Double-labeling immunofluorescence (green: phospho-TDP43, red: CD44) shows TDP-43 inclusions in astrocytic processes (arrows) in the superior frontal gyrus. Bar: 20 µm. (TIFF 10075 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shunsuke Koga
    • 1
  • Naomi Kouri
    • 2
  • Ronald L. Walton
    • 1
  • Mark T. W. Ebbert
    • 1
  • Keith A. Josephs
    • 3
  • Irene Litvan
    • 4
  • Neill Graff-Radford
    • 5
  • J. Eric Ahlskog
    • 3
  • Ryan J. Uitti
    • 5
  • Jay A. van Gerpen
    • 5
  • Bradley F. Boeve
    • 3
  • Adam Parks
    • 6
  • Owen A. Ross
    • 1
  • Dennis W. Dickson
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of PathologyBoston Children’s HospitalBostonUSA
  3. 3.Department of NeurologyMayo ClinicRochesterUSA
  4. 4.Parkinson and Other Movement Disorder Center, Department of NeurosciencesUC San DiegoLa JollaUSA
  5. 5.Department of NeurologyMayo ClinicJacksonvilleUSA
  6. 6.Department of NeuropsychologyUniversity of Kansas Medical CenterKansas CityUSA

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