Motor neuron disease (MND) can be associated with frontotemporal dementia (FTD) and circumscribed lobar atrophy of frontal and temporal lobes. Neuropathological correlations were sought in postmortem studies from a woman with these associated conditions. Cerebral blood flow imaging and autopsy showed cortical abnormalities in the frontal and temporal lobes, but typical argyrophilic Pick's bodies were absent and ubiquitin-positive neuronal cytoplasmic inclusions were rare. However, hematoxylin and eosin staining revealed eosinophilic, granular, central cytoplasmic 'clearing' in most neurons of the substantia nigra and in cervical anterior horn cells. Electron microscopy showed that these neurons contained a central cytoplasmic zone cleared of neuromelanin and normal cytoplasmic organelles containing small mitochondria with matrix inclusions and randomly oriented filamentous material. A mitochondrial dysfunction or defective transport of mitochondria into axonal processes needs to be studied as a potential cause for the coassociation of MND and FTD.