Brain Advance Access published online on March 24, 2008
Brain, doi:10.1093/brain/awn061
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Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions
1Department of Pathology, 2Division of Neurology, 3Department of Pathology, University of Ottawa, Canada and 4Department of Psychiatry, University of British Columbia, Vancouver, British Columbia
Correspondence to:
Ian R. A. Mackenzie, Department of Pathology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, British Columbia, V5Z 1M9 Canada E-mail: ian.mackenzie{at}vch.ca
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, 
-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.
Key Words: frontotemporal lobar degeneration; frontotemporal dementia; FTLD-U; ubiquitin; TDP-43
Abbreviations: aFTLD-U, atypical FTLD-U; ALS, amyotrophic lateral sclerosis; BIBD, basophilic inclusion body disease; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; IF, intermediate filament; MAPT, microtubule associated protein tau; MND, motoneuron disease; NCI, neuronal cytoplasmic inclusion; NF, neurofilament; NIFID, neuronal intermediate filament inclusion disease; NII, neuronal intra-nuclear inclusion; PGRN, progranulin; PNFA, primary non-fluent aphasia; PPA, primary progressive aphasia; SD, semantic dementia; TAR, transactive response; VCP, valosin containing protein.
Received December 18, 2007. Revised February 13, 2008. Accepted March 3, 2008.