Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations.

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.

Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations.

BACKGROUND: Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families. OBJECTIVE: To determine whether there is a difference in the patterns of atrophy in FTLD-U cases with and without PGRN mutations. DESIGN: Case-control study. SETTING: Brain bank of a tertiary care medical center. Patients Eight subjects who had screened positive for PGRN mutations (PGRN-positive) and who underwent volumetric magnetic resonance imaging were identified. Subjects were then matched by clinical diagnosis to a group of 8 subjects with a pathological diagnosis of FTLD-U who had screened negative for PGRN mutations (PGRN-negative). All subjects were then age-matched and sex-matched to a control subject. MAIN OUTCOME MEASURES: Voxel-based morphometry was used to assess the patterns of gray matter atrophy in the PGRN-positive group compared with the PGRN-negative group and compared with controls. RESULTS: The PGRN-positive group showed a widespread and severe pattern of gray matter loss predominantly affecting the frontal, temporal, and parietal lobes. The PGRN-negative group showed a less severe pattern of gray matter loss restricted mainly to the temporal and frontal lobes. On direct comparison, the PGRN-positive group showed greater gray matter loss in the frontal and parietal lobes compared with the PGRN-negative group. CONCLUSION: Findings from this study suggest that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.