Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions

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. Man y cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intra nuclear inclusions in a sub-population of cases of neuropathologically veri fied DMND. Immunohistochemical localization of ubiquitin was performed on s ections of post-mortem. brain from 12 patients with DMND as well as from ca ses with other neurodegenerative diseases including amyotrophic lateral scl erosis, Parkinson's disease, dementia with Lewy bodies, corticobasal degene ration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic incl usions 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 muta tions were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. I n addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symp toms, and a family history of dementia. Intranuclear inclusions were not id entified in the control cases with other neurodegenerative diseases. Ubiqui tinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with s triatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD.