Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions

Objective: To describe the clinical features, neuropathology, and genetic s tudies in a family with autosomal dominant frontotemporal dementia (FTD). B ackground: Clinical Pick's disease, or FTD with parkinsonism, has been desc ribed in several families linked to chromosome 17 (FTDP-17). Most of these have shown tau protein mutations. The clinical and pathologic variations in these families resemble the spectrum of sporadic FTD or "Pick complex." Me thods: Clinical and behavioral analysis of the affected members with extens ive histochemical and neuropathologic description of thr ee cases, genetic analysis of three clinically affected members and seven at risk members to assess linkage to chromosome 17, and sequencing of the tau gene in two pati ents were performed. Results: The clinical pattern shows a highly stereotyp ic disinhibition dementia with late extrapyramidal features, progressive mu tism, and terminal dysphagia in three generations of affected individuals. Neuropathology showed frontotemporal atrophy, and microscopically tau- and synuclein-negative and ubiquitin-positive neuronal inclusions, in the backg round of superficial cortical spongiosis, neuronal loss, and gliosis. Tau e xpression was restricted to oligodendroglia, All exons and surrounding intr ons of the tau gene were sequenced, and no mutation or disease-related poly morphisms were detected in either of two affected pedigree members. Conclus ion: This family with autosomal dominant frontotemporal dementia (FTD) show s no tau expression in neurons. The ubiquitin-positive, tau-negative inclus ions have been described before in FTD with and without motor neuron diseas e, but not in a familial form. The clinical and some pathologic features ar e similar to those of several of the families included in descriptions of F TD with parkinsonism linked to chromosome 17, but the linkage to tau has be en excluded. The defect in this family, however, could be functionally rela ted to tau mutations.