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Brain 2006 129(11):3081-3090; doi:10.1093/brain/awl271
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene

Ian R. A. Mackenzie1, Matt Baker4, Stuart Pickering-Brown5, Ging-Yuek R. Hsiung2, Caroline Lindholm2, Emily Dwosh3, Jennifer Gass4, Ashley Cannon4, Rosa Rademakers4, Mike Hutton4 and Howard H. Feldman2

1 Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver Coastal Health Vancouver, BC, Canada 2 Division of Neurology, University of British Columbia and Vancouver Coastal Health Vancouver, BC, Canada 3 Department of Medical Genetics, University of British Columbia and Vancouver Coastal Health Vancouver, BC, Canada 4 Department of Neuroscience, Mayo Clinic College of Medicine Jacksonville, FL, USA 5 Division of Laboratory and Regenerative Medicine, University of Manchester Manchester, UK

Correspondence to: Dr Ian R. A. Mackenzie, Department of Pathology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC, Canada V5Z 1M9 E-mail: ian.mackenzie{at}vch.ca

The most common pathology in frontotemporal dementia (FTD) is tau-negative, ubiquitin-immunoreactive (ub-ir) neuronal inclusions (FTLD-U). Recently, we identified mutations in the progranulin (PGRN) gene as the cause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in 13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistent feature was the presence of ub-ir lentiform neuronal intranuclear inclusions (NII) in the neocortex and striatum. In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerative changes, ub-ir neurites and well-defined ub-ir neuronal cytoplasmic inclusions (NCI). In the striatum, there were numerous ub-ir neurites. NCI in the hippocampus usually had a granular appearance. In contrast, familial FTLD-U cases without PGRN mutations had no NII, less severe neocortical and striatal pathology and hippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also had NII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NII showed the same pattern of pathology as those with mutations. These findings suggest that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.

Key Words: frontotemporal dementia; frontotemporal lobar degeneration; ubiquitin; progranulin; neuronal intranuclear inclusions

Abbreviations: FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FTLD-U, FTLD with ubiquitin-positive inclusions; MAPT, microtubule-associated protein tau; MND, motor neuron disease; NCI, neuronal cytoplasmic inclusions; NII, neuronal intranuclear inclusions; PGRN, progranulin; ub-ir, ubiquitin-immunoreactive

Received August 24, 2006. Revised August 29, 2006. Accepted August 30, 2006.


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