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

Division of Laboratory and Regenerative Medicine,University of Manchester, Manchester, UKCorrespondence to: Dr Ian R. A. Mackenzie, Department of Pathology, Vancouver General Hospital,855 West 12th Avenue, Vancouver, BC, Canada V5Z 1M9E-mail: ian.mackenzie@vch.caThe 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 thecause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistentfeaturewasthepresenceofub-irlentiformneuronalintranuclearinclusions(NII)intheneocortexandstriatum.In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerativechanges, 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 andhippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also hadNII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NIIshowed the same pattern of pathology as those with mutations. These findings suggest that FTD caused byPGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.Keywords: frontotemporal dementia; frontotemporal lobar degeneration; ubiquitin; progranulin;neuronal intranuclear inclusionsAbbreviations: FTD ¼ frontotemporal dementia; FTLD ¼ frontotemporal lobar degeneration; FTLD-U ¼ FTLD withubiquitin-positive inclusions; MAPT ¼ microtubule-associated protein tau; MND ¼ motor neuron disease; NCI ¼ neuronalcytoplasmic inclusions; NII ¼ neuronal intranuclear inclusions; PGRN ¼ progranulin; ub-ir ¼ ubiquitin-immunoreactiveReceived August 24, 2006. Revised August 29, 2006. Accepted August 30, 2006