Familial frontotemporal dementia: a report of three cases of severe cerebral atrophy with rare inclusions that are negative for tau and synuclein, but positive for ubiquitin.

We describe the brain autopsy findings from three of five siblings who suffered dementia with clinical diagnoses including Alzheimer's, Parkinson's, and Pick's disease. Five other living siblings appear unaffected. All of the autopsied brains showed severe atrophy (brain weights 613, 641, and 750 g) of the frontal and temporal lobes, and to a slightly lesser extent of the parietal lobes, while the occipital lobes were relatively preserved. The substantia nigra showed marked neuronal loss with gliosis. No ballooned neurons, neurofibrillary tangles, neuritic plaques, Pick bodies, or Lewy bodies were found in these brains. Immunohistochemistry for tau protein failed to reveal neuronal or glial inclusions, and normal tau protein was found in a separate Western blot study [Adamec et al. (2001) Neurosci Lett 315:21-24]. Rare neurons with ubiquitinated cytoplasmic inclusions were scattered in the neocortex and hippocampus. The overall pathological features were consistent with a severe form of frontotemporal dementia (FTD) with involvement of the substantia nigra. Whether the rare ubiquitinated inclusions are sufficient to classify these cases as FTD with motor neuron disease type inclusions but without motor neuron disease, or FTD dementia lacking distinctive histological features remains unclear. The features of lobar circumscribed atrophy without Pick bodies and without ballooned neurons, however, are consistent with Pick disease group C in the Constantinidis classification [Constantinidis et al. (1974) Eur Neurol 11:208-217].