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

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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.

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Abbreviations

AD:

Alzheimer’s disease

AGD:

Argyrophilic grain disease

ANOVA:

Analysis of variance

CBD:

Corticobasal degeneration

CBD-OPCA:

CBD-olivopontocerebellar atrophy

CBD-RS:

CBD-Richardson syndrome

CBS:

Corticobasal syndrome

DN:

Dystrophic neurite

FTLD-TDP:

Frontotemporal lobar degeneration with TDP-43

GCI:

Glial cytoplasmic inclusion

NCI:

Neuronal cytoplasmic inclusion

NFT:

Neurofibrillary tangle

PSP:

Progressive supranuclear palsy

TDP-43:

Transactive response DNA-binding protein of 43 kDa

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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.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Shunsuke Koga, Ronald L. Walton, Mark T. W. Ebbert, Owen A. Ross & Dennis W. Dickson

  2. Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

    Naomi Kouri

  3. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Keith A. Josephs, J. Eric Ahlskog & Bradley F. Boeve

  4. Parkinson and Other Movement Disorder Center, Department of Neurosciences, UC San Diego, La Jolla, CA, USA

    Irene Litvan

  5. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Neill Graff-Radford, Ryan J. Uitti & Jay A. van Gerpen

  6. Department of Neuropsychology, University of Kansas Medical Center, Kansas City, KS, USA

    Adam Parks

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  1. Shunsuke Koga
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  12. Adam Parks
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Corresponding author

Correspondence to Dennis W. Dickson.

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Supplementary material 1 (DOCX 51 kb)

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)

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)

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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Koga, S., Kouri, N., Walton, R.L. et al. Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype. Acta Neuropathol 136, 389–404 (2018). https://doi.org/10.1007/s00401-018-1878-z

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  • DOI: https://doi.org/10.1007/s00401-018-1878-z

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