The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was recommended at a consensus conference in 1997 to denote a growing number of families recognized, in which frontotemporal dementia (FTD), behavioral disturbances, language abnormalities, and/or parkinsonism are inherited in an autosomal dominant fashion and genetic analysis shows linkage to chromosome 17 (100). The following year, a number of reports were published, describing mutations in the tau gene in some of these families (101-104). It is now common for a "T" to be added to the end of the acronym to distinguish these cases from other chromosome 17-linked FTD in which the tau gene is normal and there is no tau accumulation in the brain (105,106). At the present time, more than 80 FTDP-17T kindreds have been identified, with more than 30 different tau mutations (107). The types of genetic abnormality include missense, deletion, and silent transition mutations in the coding region of the tau gene and intronic mutations near the splice site of the intron following exon 10 (108). Sufficient material is just now becoming available to allow for detailed examination of how different genetic abnormalities correlate with the clinical and pathological phenotypes (108,109).
FTDP-17T shows significant heterogeneity in both the clinical manifestations and the underlying neuropathology (100,108-110). In some families, FTD predominates and parkinsonism is variable, mild, or of late onset, whereas other pedigrees have parkinsonism as the major feature. A limited amount of postmortem information is available on FTDP-17T families. Most cases show frontotemporal atrophy with varying degeneration of subcortical nuclei and tracts (100,110). Loss of pigmentation of the substantia nigra is common. The histopathology of all cases described to date is characterized by the accumulation of abnormal hyperphosphorylated tau in neurons and/or glial cells (108,110). Neuronal changes may include ballooned neurons, pretangles, NFTs, Pick's-like bodies, and/or neuropil threads. A variety of tau-positive inclusions may be seen in both astrocytes and oligodendrocytes. In some cases, the pattern of pathology closely resembles one of the sporadic tauopathies such as AD (111), CBD (112,113), PSP (114), or Pick's disease (115,116), whereas others show some novel combination of findings (117). Although a detailed description of each of the different patterns of pathology in FTDP-17T is not possible in this review, two specific conditions are worth mentioning because of the prominence of parkinsonism and availability of detailed neuropathology.
Parkinsonism is the dominant feature of several families with the N279K mutation in the alternatively spliced exon 10; this includes the American kindred designated as having pallido-ponto-nigral degeneration (PPND), for which there is detailed pathological information (118). Most patients show mild frontotemporal atrophy with grossly obvious degeneration of the globus pallidus and substantia nigra. The histopathologic and immunohistochemical findings include ballooned neocortical neurons and tau-positive subcortical threadlike structures, globose NFTs (corticobasal bodies), and oligoden-droglial inclusions resembling coiled bodies. Astrocytic inclusions are uncommon and tufted astro-cytes and astrocytic plaques are not a feature. Although these findings most closely resemble sporadic CBD, the anatomic distribution is more similar to that seen in PSP.
Parkinsonism is also a major feature in the Irish-American kindred with disinhibition-dementia-parkinsonism-amyotrophy-complex (DDPAC). This was the first family to be linked to chromosome 17 and has subsequently been show to be owing to an intronic mutation of the exon 10 5' slice site (119). There is gross atrophy of temporal lobes, prefrontal cortex, cingulum, basal ganglia, and substantia nigra (120). Affected cortical regions show gliosis, occasional ballooned neurons, and taupositive NFTs and spheroids. The hippocampus is relatively spared. Subcortical regions affected include the amygdala, substantia nigra, globus pallidus, striatum, midbrain tegmentum, and hypothalamus. In these areas, neuronal loss and gliosis are accompanied by small numbers of ballooned neurons, argyrophilic neuronal inclusions, and spheroids. Some neuronal inclusions resembled AD-type NFTs and are immunoreactive for tau whereas other have a more spiculated appearance and are positive for neurofilament and ubiquitin but are tau negative. Argyrophilic, tau-positive tanglelike inclusions are also present in oligodendrocytes in various white matter tracts.
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