TY - JOUR
T1 - The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene
AU - Mackenzie, Ian R.A.
AU - Baker, Matt
AU - Pickering-Brown, Stuart
AU - Hsiung, Ging Yuek R.
AU - Lindholm, Caroline
AU - Dwosh, Emily
AU - Gass, Jennifer
AU - Cannon, Ashley
AU - Rademakers, Rosa
AU - Hutton, Mike
AU - Feldman, Howard H.
N1 - Funding Information:
Immunohistochemistry was performed by Julie Chow (Department of Pathology, University of British Columbia) and the technical staff in the immunohistochemistry laboratory at Vancouver General Hospital. Tissue samples were generously provided by Dr Chris Dunham, Dr Arthur Clark and Dr Bernadette Curry (Foothills Hospital, Calgary, Canada), Dr John Woulfe (Ottawa Civic Hospital, Ottawa, Canada), Dr John Rossiter (Queen’s University, Kingston, Canada) and Dr Catherine Joachim (The Radcliffe Infirmary, Oxford, UK). I.R.A.M., G.R.H., C.L., E.D. and H.H.F. supported by the Canadian Institutes of Health Research (grant 74580). M.B., J.G., A.C. and M.H. were supported by the National Institute of Health (grants P01 AG017216, R01 AG026251), the Mayo Clinic ADRC (P50 AG16574) and the Mayo Clinic Research Foundation. S.P.B. was supported by the UK Medical Research Council Motor Neuron Disease Association. R.R. supported by the Fund for Scientific Research, Flanders.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
KW - Frontotemporal dementia
KW - Frontotemporal lobar degeneration
KW - Neuronal intranuclear inclusions
KW - Progranulin
KW - Ubiquitin
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U2 - 10.1093/brain/awl271
DO - 10.1093/brain/awl271
M3 - Article
C2 - 17071926
AN - SCOPUS:33750590113
SN - 0006-8950
VL - 129
SP - 3081
EP - 3090
JO - Brain
JF - Brain
IS - 11
ER -