Chromosome 3 linked frontotemporal dementia (FTD-3).

BACKGROUND: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. METHODS: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. RESULTS: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H2 15 O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. CONCLUSIONS: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Molecular genetic characterisation of frontotemporal dementia on chromosome 3.

We have previously localized a locus causing familial nonspecific dementia to the centromeric region of chromosome 3 in a pedigree from the Jutland area of Denmark. This pedigree shows anticipation. Here we present further analysis of these anticipation data which are suggestive of trinucleotide repeat expansion involvement. We also outline our strategies to clone the mutant gene via its putative associated trinucleotide repeat sequence.

Reconstruction of radionuclide releases from the Hanford Site, 1944-1972.

Historic releases of key radionuclides were estimated as a first step in determining the radiation doses that resulted from Hanford Site operations. The Hanford Site was built in southcentral Washington State during World War II to provide plutonium for the U.S. nuclear weapons program. As part of the Hanford Environmental Dose Reconstruction (HEDR) Project, releases to the Columbia River of 24Na, 32P, 46Sc, 51Cr, 56Mn, 65Zn, 72Ga, 76As, 90Y, 131I, 239Np, and nonvolatile gross beta activity from operation of eight Hanford single-pass production reactors were estimated. Releases of 90Sr, 103Ru, 106Ru, 131I, 144Ce, and 239Pu to the atmosphere from operation of chemical separation facilities were also estimated. These radionuclides and the atmospheric and Columbia River pathways were selected for study because scoping studies showed them to be the largest contributors to dose from Hanford operations. The highest doses resulted from releases to the atmosphere of 131I from chemical separations plants in the pre-1950 period. Prior to 1950, the technology for limiting iodine releases had not been developed. Hence, a very detailed reconstruction of the hourly 131I release history was achieved for 1944-1949 using Monte Carlo methods. Atmospheric releases of the other radionuclides were estimated on a monthly basis for 1944-1972 using deterministic calculations. Monthly releases to the Columbia River for 1944-1971 were based on Monte Carlo methods.

Familial non-specific dementia maps to chromosome 3.

A significant minority of degenerative dementias lack distinctive inclusion bodies, plagues or tangles on pathological examination. Half of these cases have a positive family history of dementia. We have studied the largest published family with such a dementia and mapped the disease locus to a 12 cM region of chromosome 3 spanning the centromere. Haplotype analysis demonstrates a common region shared between all affected individuals between the markers D3S1284 and D3S1603. Like a number of other late onset neurodegenerative diseases, the disease presents at an earlier age when paternally inherited.

Exclusion mapping in familial non-specific dementia.

We present genetic linkage data in a large family in which non-specific dementia is inherited as an autosomal dominant trait. We have analyzed 45 highly polymorphic microsatellite sequences and excluded a quarter of the genome as the site of the pathogenic mutation in this family.

Genetic characterization of a familial non-specific dementia originating in Jutland, Denmark.

Dementias with non-specific pathological changes are a relatively common but under diagnosed form of presenile dementia. A high proportion of reported cases are familial. We report on molecular genetic findings in the largest known pedigree with this syndrome. We have excluded the mutations known to cause familial prion disease, APP-linked familial Alzheimer's disease and candidate regions for Huntington's disease, other forms of Alzheimer's disease and motor neuron disease. We have demonstrated that familial non-specific dementia is a novel genetic dementia.

Genetic characterization of a novel familial dementia.

Clinical and neuropathologic findings from a Danish family in which a dementing illness is segregating as an apparent autosomal dominant disorder were previously described (Gydesen et al. 1987). We present here genetic findings from this family in which linkage analysis has excluded Huntington's disease and chromosome 21-encoded Alzheimer's disease. None of the known prion mutations has been detected in affected individuals from this family. However, linkage analysis with the prion gene has been uninformative. This family probably represents a novel genetic dementia.

Psychotropic medication in the elderly. A survey of prescribing and clinical outcome.

Due to the increasing elderly population, an increased number of elderly patients requires treatment for mental and behavioural disorders. There are relatively few clinical studies of the prescribing of psychotropic drugs in patients over 65 years of age. A prospective study was undertaken at three centres caring for the elderly, encompassing patients from general nursing homes and a psychiatric department. Entry of patients into the survey was determined by the clinical decision to prescribe psychotropic medication and an age of 65 years or older. Included in the study were 160 patients. The main reasons for initiating psychotropic medication were indicated, and anamnestic data were collected. Initial and continuing dosages of psychotropic medication were recorded. The clinical condition was assessed at the start of treatment and after four and eight weeks, utilising the Clinical Global Impressions (CGI) scale. The patient's daily activity using an abbreviated Stockton Geriatric Rating Scale (SGRS) was assessed. Side effects were recorded using the UKU Scale. Clinical improvement was seen in about half of the patients with the best effect in patients with mainly psychotic symptoms. Patients with chronic dementia-related problems responded less well. Side effects were few and generally mild. This situation may relate to cautious introduction of the medication and adoption of low-dose regimens. All centres avoided, if possible, psychotropic polypharmacy.

Neuropsychiatric studies in a family with presenile dementia different from Alzheimer and Pick disease.

We have studied a family in which 14 persons among 73 are or have been suffering from presenile dementia. Post mortem examination showed atrophy but no sign of any known demential syndrome. Cerebral blood flow measured in the late stage of disease was low, but with no characteristic pattern in flow distribution. In one patient in the initial stage of disease, the cerebral blood flow was unexpectedly increased. The patients with presenile dementia in this family did not reveal pathological signs of any known demential syndrome and showed CBF-changes not earlier reported. Moreover, contrary to widely held views we have evidence that dementia may be connected to a high blood flow at least in the initial state. An increased blood flow was also seen in seven of ten well functioning first degree relatives, in some cases along with cerebral atrophy and/or psychological tests with signs of dementia. Are these people going to develop manifest dementia later in life?