Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer’s disease and can be mistaken for AD. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick’s disease and FTD with motor neuron disease (MND), all characterized by distinct histological features, a common clinical frontal presentation and various neurological associated symptoms. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, the temporal and frontal cortex was associated mainly with the MND-type. Such inclusions were also observed in a few sporadic cases of FTD with or without parkinsonism (FTDP) in the absence of MND. The aetiology of FTD is still unknown, but positive family history was reported in about 50-60% of the cases. A subset of FTD families, called FTD with parkinsonism or FTDP were linked to chromosome 3 or 17. The latter were called FTDP-17 and several mutations in the tau gene were implicated. We present clinical, neuropathological and immunohistochemical data, as well as genetical analysis about a Swiss FTD family with FTDP-like features but without MND. In the brain of diseased members, spongiosis and mild gliosis were observed in the grey matter. Ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus, in the absence of tau positive signals, except for one case. Analysis of brain tau and neurofilaments indicated that all three members of the family expressed comparable levels of total tau protein (detected with polyclonal and monoclonal antibodies) to that of AD and control cases, suggesting that modifications of tau protein are not at the origin of FTD in this family. However, Alzheimer-like tau phosphorylation was demonstrated in one family member, neuropathologically diagnosed as mixed AD and vascular dementia, but with uncertain concomitant FTD. Genetic analysis was performed and no novel or known mutations were detected, neither near or within the microtubule binding sites within exons 9-13, nor in the exon 10 splice site of the tau gene. Further linkage analysis disclosed association with locus 17q21-22 and the centromeric region of chromosome 3, but 3 patients shared a common haplotype on chromosome 9q21-22. Altogether, these data emphasize the clinico-pathological and genetic heterogeneity of familial FTD.
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