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Updated TDP-43 in Alzheimer’s disease staging scheme

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Abstract

In this study, we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer’s disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100 % of the cases (versus 94 % in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.

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Acknowledgments

We wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey Castanedes for pathological support. The work was supported by grants from the National Institutes of Health [R01 AG037491-06 (KAJ) and P50-AG016574 (RCP)].

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Authors and Affiliations

  1. Department of Neurology, Division of Behavioral Neurology, Mayo Clinic, Rochester, 55905, MN, USA

    Keith A. Josephs & Ronald C. Petersen

  2. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic, Rochester, 55905, MN, USA

    Nirubol Tosakulwong & Stephen D. Weigand

  3. Department of Radiology, Mayo Clinic, Rochester, 55905, MN, USA

    Jennifer L. Whitwell

  4. Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA

    Joseph E. Parisi

  5. Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, FL, USA

    Melissa E. Murray, Leonard Petrucelli, Amanda M. Liesinger & Dennis W. Dickson

  6. Department of Neurology, Division of Movement Disorders, Mayo Clinic, Rochester, MN, 55905, USA

    Keith A. Josephs

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  1. Keith A. Josephs
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Correspondence to Keith A. Josephs.

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Josephs, K.A., Murray, M.E., Whitwell, J.L. et al. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 131, 571–585 (2016). https://doi.org/10.1007/s00401-016-1537-1

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  • DOI: https://doi.org/10.1007/s00401-016-1537-1

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