A pathological hallmark of motor neuron disease (MND) is the presence of ubiquitinated inclusions in lower motor neurons. Recently, ubiquitin-immunoreactive inclusions have been found in neocortical and hippocampal neurons, indicating that in some cases there may be extensive extra-motor involvement. We have observed that some cases of MND with dementia (MND-D), had ubiquitinated inclusions in the amygdala. In order to study this systematically, we examined 18 cases of 'typical' MND, 4 cases of MND-D and 12 neurologically normal and abnormal controls, using antibodies against ubiquitin and a range of cytoskeletal proteins. In addition to standard neuropathological examination, we examined in detail the anterior thalamus, parahippocampal gyrus, dentate gyrus of the hippocampus, and the amygdala. We found ubiquitin immunoreactive inclusions in the amygdala and parahippocampal gyrus in more than 30% of MND cases, most of whom were not known to have significant cognitive impairment. These inclusions did not react with antibodies against tau or with phosphorylated neurofilaments. They thus differ from the inclusions of Alzheimer's disease, and they do not have the appearance or immunocytochemical features of cortical Lewy bodies. In parallel studies we have found selective cognitive impairments in about 25% of our patients with typical MND, and PET activation studies show impaired activation in the anterior thalamus, parahippocampal gyrus and medial frontal regions. Since the amygdala is an important source of afferents for the limbic system, its involvement may be one of the factors underlying both cognitive changes and PET abnormalities.