title: Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations.
abstract: Frontotemporal lobar degeneration is heterogeneous; cases with tau- and synuclein-negative, ubiquitin-positive neuronal inclusions are the most common, and some have mutations in the gene for progranulin (PGRN). The purpose of this study was to determine whether there were distinctive clinical and neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with PGRN mutations. A retrospective review of medical records and semiquantitative neuropathologic analysis was performed on 18 PGRN(+) and 24 PGRN(-) cases. Clinically, PGRN(+) cases had more frequent language impairment and parkinsonism. Pathologically, PGRN(+) cases had smaller brains, more marked global atrophy, and more frontal atrophy. There was no difference in the frequency of hippocampal sclerosis. The pathology of PGRN(+) cases was relatively homogeneous, whereas PGRN(-) cases were more heterogenous. PGRN(+) cases had greater density of cortical ubiquitin-immunoreactive lesions, especially dystrophic neurites in layer II. Intranuclear inclusions were present in all PGRN(+) and 42% of PGRN(-) cases. The results suggest that frontotemporal lobar degeneration with ubiquitin-positive inclusions due to PGRN mutations has several characteristic features, including ubiquitin-immunoreactive neuritic pathology in superficial cortical layers and neuronal intranuclear inclusions. On the other hand, there is no histopathologic feature or combination of features that is pathognomonic. Neuronal intranuclear inclusions are virtually always present, but they can be detected in PGRN(-) cases.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Zeshan
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Omi
authors.initials: O
authors.lastname: Katsuse
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Parisi
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Ranjan
authors.initials: R
authors.lastname: Duara
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Matthew
authors.initials: M
authors.lastname: Baker
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / 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