Brain Advance Access originally published online on March 24, 2008
Brain 2008 131(5):1282-1293; doi:10.1093/brain/awn061
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions
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
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.