title: The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver Coastal Health Vancouver, BC, Canada. ian.mackenzie@vch.ca
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Caroline
authors.initials: C
authors.lastname: Lindholm
authors.forename: Emily
authors.initials: E
authors.lastname: Dwosh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
mesh_terms: D000368:Aged; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D002479:Inclusion Bodies / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D012189:Retrospective Studies; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin