Frontotemporal lobe dementia FTD

Fronto-temporal dementia is a pleomorphic neuro-degenerative illness which typically begins before the age of 65 years. In a minority of cases, the disease is inherited as an autosomal-dominant trait (Lynch et al., 1994; Wszolek et al., 1992). The disease often begins with personality and behavioral changes including disinhibition manifest by alcoholism, hyper-religiosity, hypersexuality, hyperphagia (elements of the Kluver-Bucy syndrome) and stealing. As the disease progressed in these families, further abnormalities in judgment, language and praxia developed. In addition to these cognitive changes, some patients also developed Parkinsonism and amyotrophy. However, presentations with primary progressive aphasia, Parkinsonism, dystonia and/or oculomotor disturbances are not infrequent. Neuropathologically, the illness is typified by fronto-temporal atrophy with severe neuronal loss, spongiform change in the superficial layers of the neocortex of the temporal lobe and frontal cortex, neuronal loss and gliosis in the substantia nigra and amygdala, and anterior horn cell loss in the spinal cord (Sima et al., 1996). The unifying theme amongst these pedigrees is the predilection for involvement of the frontal and temporal lobes with prominent neuronal loss and gliosis, some spongiform change, and the absence of amyloid or Lewy bodies. In some cases, notably those arising from mutations in the tau gene (see below) the other prominent neuropathological feature is the presence of tau fibrils in neurons and/or glia.

Genetic linkage studies in the subset of FTD cases showing autosomal dominant inheritance revealed that between 10 and 40% of these familial FTD cases showed genetic linkage between a series of DNA markers on chromosome 17 near the tau gene (see below). It was also apparent that a significant proportion of autosomal dominant fronto-temporal dementia pedigrees did not show linkage to this region. Genetic linkage studies in these cases subsequently led to the discovery of an additional genetic locus associated with autosomal dominant fronto-temporal dementia with amyo-trophic lateral sclerosis on chromosome 9q.

The clinical phenotype for the FTDP-17 cases is, as described above, quite pleomorphic. However, one unifying observation has been that there is pathological deposition of hyper-phosphorylated tau either in neurons or in glia. In contrast, in the chromosome 9 variant, the clinical phenotype tends to have more prominent motor signs, and in those individuals who have a fronto-temporal dementia phenotype. In addition, the neuropatho-logical picture is one of fronto-temporal atrophy with gliosis vacuolar changes, but with a relative paucity of amyloid plaques and neurofibrillary tangles.

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