Neuropathologic Features of Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions With Progranulin Gene (PGRN) Mutations

• Published in: Journal of neuropathology and experimental neurology Vol. 66; no. 2; pp. 142 - 151
• Main Authors: Josephs, Keith A, Ahmed, Zeshan, Katsuse, Omi, Parisi, Joseph F, Boeve, Bradley F, Knopman, David S, Petersen, Ronald C, Davies, Peter, Duara, Ranjan, Graff-Radford, Neill R, Uitti, Ryan J, Rademakers, Rosa, Adamson, Jennifer, Baker, Matthew, Hutton, Michael L, Dickson, Dennis W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01-02-2007; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aged; Aged, 80 and over; Atrophy - genetics; Atrophy - metabolism; Atrophy - pathology; Biological and medical sciences; Brain - metabolism; Brain - pathology; Brain - physiopathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - genetics; Dementia - metabolism; Dementia - pathology; Diseases of striated muscles. Neuromuscular diseases; Female; Frontal Lobe - metabolism; Frontal Lobe - pathology; Frontal Lobe - physiopathology; Hippocampus - metabolism; Hippocampus - pathology; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intranuclear Inclusion Bodies - metabolism; Intranuclear Inclusion Bodies - pathology; Male; Medical sciences; Middle Aged; Mutation - genetics; Neurites - metabolism; Neurites - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Retrospective Studies; Ubiquitin - metabolism; Ubiquitin; Nervous system diseases; Inclusion; Progranulin; Frontotemporal lobar degeneration; Cerebral disorder; Gene; TDP-43; Central nervous system disease; Degenerative disease; Degeneration; Mutation; Frontotemporal dementia
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/nen.0b013e31803020cf

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.