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Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions

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Abstract

Frontotemporal lobar degeneration (FTLD) can be pathologically subdivided into tau-positive and tau-negative types. The most common tau-negative variant is FTLD with ubiquitin-immunoreactive lesions (FTLD-U). Recently, the TAR DNA binding protein 43 (TDP-43) was identified in neuronal inclusions in FTLD-U. After applying TDP-43 immunohistochemistry to a series of 44 cases of FTLD-U with no secondary pathology, three cases (7%) were identified with ubiquitin- and p62-positive neuronal cytoplasmic inclusions (NCI) that were negative for TDP-43. All the three cases had marked brain atrophy with striking atrophy of the striatum. Cases 1 and 2 presented at ages 43 and 38, respectively, as behavioral variant frontotemporal dementia (1 with positive family history) and had ubiquitin- and p62-positive NCI in frontotemporal neocortex and dentate granule cells of the hippocampus. Case 3 presented with the corticobasal syndrome. Unlike the other two cases, ubiquitin- and p62-positive NCI were also visible on hematoxylin and eosin stain. There were no neuronal intranuclear inclusions. Electron microscopic examination of the NCI in cases 2 and 3 revealed granulofilamentous inclusions. These cases confirm the existence of TDP-43-negative FTLD-U and extend the clinical and pathological spectrum of this disorder. The findings raise the possibly of an as yet identified protein that may play a pathogenic role in tau-negative FTLD.

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Authors and Affiliations

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

    Keith A. Josephs

  2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Wen-Lang Lin, Zeshan Ahmed, David Alexander Stroh & Dennis W. Dickson

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

    Neill R. Graff-Radford

  4. Neuropathology Laboratory, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Dennis W. Dickson

Authors
  1. Keith A. Josephs
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  2. Wen-Lang Lin
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  3. Zeshan Ahmed
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  4. David Alexander Stroh
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  5. Neill R. Graff-Radford
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  6. Dennis W. Dickson
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Corresponding author

Correspondence to Dennis W. Dickson.

Additional information

Supported by NIH grants P50-AG16574, P50-NS40256 and Pacific Alzheimer Research Foundation (PARF) grant C06-01.

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Josephs, K.A., Lin, WL., Ahmed, Z. et al. Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions. Acta Neuropathol 116, 159–167 (2008). https://doi.org/10.1007/s00401-008-0397-8

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  • DOI: https://doi.org/10.1007/s00401-008-0397-8

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