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

被引:237
作者
Mackenzie, Ian R. A.
Baker, Matt
Pickering-Brown, Stuart
Hsiung, Ging-Yuek R.
Lindholm, Caroline
Dwosh, Emily
Gass, Jennifer
Cannon, Ashley
Rademakers, Rosa
Hutton, Mike
Feldman, Howard H.
机构
[1] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
[2] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada
[3] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada
[4] Vancouver Coastal Hlth, Vancouver, BC, Canada
[5] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA
[6] Univ Manchester, Div Lab & Regenerat Med, Manchester, Lancs, England
基金
英国医学研究理事会;
关键词
frontotemporal dementia; frontotemporal lobar degeneration; ubiquitin; progranulin; neuronal intranuclear inclusions;
D O I
10.1093/brain/awl271
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:3081 / 3090
页数:10
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