Susanne Gydesen

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

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; H215O-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.

Frontotemporal dementia linked to chromosome 3

A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.

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 Alzheimers disease and candidate regions for Huntingtons disease, other forms of Alzheimers disease and motor neuron disease. We have demonstrated that familial non-specific dementia is a novel genetic dementia.

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.

Author and Subject Index

Mononuclear cells are activated during hemodialysis. In this study, we provide evidence that in vitro culture of mononuclear cells with Cuprophan, a nonbiocompatible hemodialysis membrane, increases the levels of protein phosphorylation in these cells as well as the expression of surface activation molecules. By contrast, culturing of mononuclear cells with AN69, a more biocompatible membrane, did not increase protein phosphorylation levels or expression of surface activation molecules in these cells. In addition, Cuprophan, but not the AN69 membrane, increased the percentage of mononuclear cell death by apoptosis. Inhibition of G-protein-mediated signal transduction decreased the apoptosis of cells cultured with the Cuprophan membrane. The GTP-binding protein involved in Cuprophan-induced apoptosis was sensitive to the ADP-ribosylating pertussis toxin (PTX). The inhibition of GTP-binding protein decreased apoptosis in the early stage of the activation-induced apoptosis, suggesting that G-proteins are implicated in the transmission of apoptosis-inducing signal(s) but do not interfere with the effector signals that mediate the late stages of apoptotic catabolism. Finally, PTX was capable of inhibiting apoptosis without affecting expression of activation molecules; thus, the inhibition of apoptosis by Cuprophan was not due to quenching of the stimulation signals, because monocytes were still able to be activated by Cuprophan despite the action of PTX. The results obtained in this study suggest that cell activation and apoptosis may be mediated by separate intracellular signals.

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 Huntingtons disease and chromosome 21-encoded Alzheimers 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.

P3-345 Preclinical signs of impairment in persons at high risk of frontotemporal dementia related to chromosome 3 (FTD3): preliminary findings in neuropsychological tests

At risk members of the family and their spouses between 40 and 70 years of age were invited to participate in neuropsychological assessment performed without knowledge of status. 38 family members and 20 spouses participated. Some of the subjects have not yet been haplotyped, and we report preliminary results from comparisons of 20 test measures in 3 well-matched subject groups: 11 high risk subjects, 16 low risk subjects, and 19 spouses. RESULTS