Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions
ABSTRACT Dementia of motor neuron disease type (DMND) is a variety of frontotemporal dementia (FTD) which is pathologically defined by characteristic neuronal ubiquitinated, tau- and synuclein-negative intracytoplasmic inclusions. Many cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intranuclear inclusions in a sub-population of cases of neuropathologically verified DMND. Immunohistochemical localization of ubiquitin was performed on sections of post-mortem brain from 12 patients with DMND as well as from cases with other neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic inclusions in dentate granule cells and cortical neurons. Of these 12 cases of DMND, 3 also showed neuronal ubiquitinated intranuclear inclusions. In 1 of these cases, CAG repeat expansions in the genes known to harbor these mutations were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. In addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symptoms, and a family history of dementia. Intranuclear inclusions were not identified in the control cases with other neurodegenerative diseases. Ubiquitinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with striatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD.
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ABSTRACT: Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). We studied the spatial patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII) in histological sections of the frontal and temporal lobe in eight cases of FTLD-TDP with GRN mutation using morphometric methods and spatial pattern analysis. In neocortical regions, the NCI were clustered and the clusters were regularly distributed parallel to the pia mater; 58% of regions analysed exhibiting this pattern. The NII were present in regularly distributed clusters in 35% of regions but also randomly distributed in many areas. In neocortical regions, the sizes of the regular clusters of NCI and NII were 400-800 μm, approximating to the size of the modular columns of the cortico-cortical projections, in 31% and 36% of regions respectively. The NCI and NII also exhibited regularly spaced clustering in sectors CA1/2 of the hippocampus and in the dentate gyrus. The clusters of NCI and NII were not spatially correlated. The data suggest degeneration of the cortico-cortical and cortico-hippocampal pathways in FTLD-TDP with GRN mutation, the NCI and NII affecting different clusters of neurons.Histology and histopathology 02/2011; 26(2):185-90. · 2.24 Impact Factor
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ABSTRACT: Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a 'continuum' without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the 'stage' of the disease, and (3) within the FTLD-TDP 'continuum' cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.Journal of Neural Transmission 12/2009; 117(2):227-39. DOI:10.1007/s00702-009-0350-6 · 2.87 Impact Factor