Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke family 1684

Frontotemporal dementia with parkinsonism (FTDP-17) is an autosomal dominan t disorder that presents clinically with dementia, extrapyramidal signs, an d behavioral disturbances in mid-life and progresses to death within 5 to 1 0 years. Pathologically, the disorder is characterized by variable neuronal loss and gliosis in the frontal and temporal lobes, limbic structures, and the midbrain. Autopsied individuals from some kindreds display abundant ne urofibrillary change while others, including a single affected individual f rom Duke Family 1684, lack distinctive histological features and exhibit on ly mild neuronal loss and gliosis in limbic structures and subcortical nucl ei when examined by routine silver stain. Recently, mutations in the microt ubule associated protein tau have been shown to segregate with the disease in this family and in many other affected kindreds. In order to examine the distribution of tau deposits, we performed tau immunohistochemistry, immun oblotting, and immunoelectron microscopy of tau-containing filaments. Immun ohistochemistry revealed numerous tau deposits within glial cells and withi n neurons. Twisted ribbon-like filaments observed by immunoelectron microsc opy were immuno-decorated with tau AT8 antibody. Sarkosyl-insoluble tau ext racted from the hippocampus and cortex migrated as 2 major bands at 64 and 68 kilodaltons and a minor band at 72 kilodaltons, which after alkaline pho sphatase treatment appeared to contain mainly tau isoforms with 4 repeats. Furthermore, the ratio of soluble tau with 4 to 3 microtubule-binding repea ts was increased. The role of tau mutations in this disorder is discussed i n this paper.