Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions (original) (raw)

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1Department of Pathology, 2Division of Neurology, University of British Columbia, Vancouver, 3Department of Pathology, University of Ottawa, Ottawa and 4Department of Psychiatry, University of British Columbia, Vancouver, Canada

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1Department of Pathology, 2Division of Neurology, University of British Columbia, Vancouver, 3Department of Pathology, University of Ottawa, Ottawa and 4Department of Psychiatry, University of British Columbia, Vancouver, Canada

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1Department of Pathology, 2Division of Neurology, University of British Columbia, Vancouver, 3Department of Pathology, University of Ottawa, Ottawa and 4Department of Psychiatry, University of British Columbia, Vancouver, Canada

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1Department of Pathology, 2Division of Neurology, University of British Columbia, Vancouver, 3Department of Pathology, University of Ottawa, Ottawa and 4Department of Psychiatry, University of British Columbia, Vancouver, Canada

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Received:

18 December 2007

Revision received:

13 February 2008

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Ian R. A. Mackenzie, Dean Foti, John Woulfe, Trevor A. Hurwitz, Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions, Brain, Volume 131, Issue 5, May 2008, Pages 1282–1293, https://doi.org/10.1093/brain/awn061
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Abstract

Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.

© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Topic:

• aphasia
• frontotemporal dementia
• cytoplasm
• hippocampus
• neocortex
• neurons
• ubiquitin
• pathology
• national cancer institute
• frontotemporal lobar degeneration
• protein tdp-43
• neuropathology
• mapt gene
• granules
• amyotrophic lateral sclerosis, sporadic

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