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Biomedical subjects

C Duyckaerts

Publications and source records attributed to C Duyckaerts.

At least 91 records · Page 5Linked to original sources
PubMed1995

Overexpression of a novel member of the mitochondrial carrier family rescues defects in both DNA and RNA metabolism in yeast mitochondria.

The PIF1 and MRS2 gene products have previously been shown to be essential for mitochondrial DNA maintenance at elevated temperatures and mitochondrial group II intron splicing, respectively, in the yeast Saccharomyces cerevisiae. A multicopy suppressor capable of rescuing the respiratory deficient phenotype associated with null alleles of either gene has been isolated. This suppressor is a nuclear gene that was called RIM2/MRS12. The RIM2/MRS12 gene encodes a predicted protein of 377 amino acids that is essential for mitochondrial DNA metabolism and proper cell growth. Inactivation of this gene causes the total loss of mitochondrial DNA and, compared to wild-type rhoo controls, a slow-growth phenotype on media containing glucose. Analysis of the RIM2/MRS12 protein sequence suggests that RIM2/MRS12 encodes a novel member of the mitochondrial carrier family. In particular, a typical triplicate structure, where each repeat consists of two putative transmembrane segments separated by a hydrophilic loop, can be deduced from amino acid sequence comparisons and the hydropathy profile of RIM2/MRS12. Antibodies directed against the aminoterminus of RIM2/MRS12 detect this protein in mitochondria. The function of the RIM2/MRS12 protein and the substrates it might transport are discussed.

Amino Acid Sequence↗
PubMed1995

An international perspective on the prevalence of the Wernicke-Korsakoff syndrome.

In the Western world previous studies have shown that the majority of cases of the Wernicke-Korsakoff syndrome (WKS), which is caused by thiamine deficiency, occur in alcoholics. However, in France, a country with one of the highest per capita consumptions of alcohol, the prevalence of the WKS was found to be only 0.4% in a small retrospective autopsy study. This figure is compared with data sent to the authors by a number of neuropathologists from the U.S.A., Europe, Scandinavia and Australia. There was no obvious correlation between the prevalence rates of the WKS, which were highest in Australia (2.8%-previously published), and per capita consumption of alcohol. Other issues such as diet, National programs for supplementation of foods with thiamine, and drinking habits are considered. The pathological diagnosis of the WKS can often be made on macroscopic examination of the brain after fixation in formalin. The mammillary bodies are smaller than normal in most cases of chronic WKS. However in this study it was found that the most common causes of small mammillary bodies were Alzheimer's disease and atrophy due to transneuronal degeneration secondary to lesions in the hippocampus.

Alcohol Amnestic Disorder↗
PubMed1995

Massive infarcts involving the territory of the anterior choroidal artery and cardioembolism.

BACKGROUND AND PURPOSE: At neuropathological examination, the territory of the anterior choroidal artery is frequently found to be involved in massive infarcts of the internal carotid artery territory. The aim of our study was to analyze the clinical spectrum, the course, and the mechanism of these massive infarcts compared with the rare infarcts involving only the anterior choroidal artery territory. METHODS: Retrospective clinical examination and pathological study were performed in 35 patients with cerebral infarcts affecting at least the territory of the anterior choroidal artery. RESULTS: In no patient had the involvement of the anterior choroidal territory infarcts been recognized clinically, nor had the triad of clinical signs (hemiplegia, hemianesthesia, and hemianopsia) classically seen in infarcts restricted to this territory been found alone. Impairment of consciousness, cognitive disorders, or oculomotor palsies had been found in addition to one or more signs of the triad. This was probably related to the involvement of other territories (94%), especially the middle cerebral artery territory (68%) and the posterior cerebral artery territory (20%). The concomitant involvement of several territories was due most frequently to an occlusion of the internal carotid artery, which was found at autopsy in 74% of the patients. These occlusions were often associated with cardioembolism (54%). In contrast, artery-to-artery embolism (17%) and small-artery disease (6%) were seldom found. Only two cases of infarcts restricted to the anterior choroidal artery territory were observed. CONCLUSIONS: The involvement of the territory of the anterior choroidal artery in massive infarcts was due mainly to a cardioembolic occlusion of the internal carotid artery.

Aged↗
PubMed1995

[HIV and dementia: neuropathology].

Cognitive disorders associated with HIV infection may be due to focal lesions (lymphoma, toxoplasmosis, progressive multifocal leukoencephalitis, etc.), metabolic encephalopathy (e.g. hepatic insufficiency) or psychiatric disorders (depression). In the absence of such causes a "cognitive and motor syndrome associated with HIV infection" has been defined on clinical criteria (Working group of the American Academy of Neurology, 1991). This syndrome is not consistently associated with any specific lesion. Neither the multifocal encephalitis of HIV or CMV infection nor the diffuse leukoencephalopathy associated with HIV are the only causes. The existence of a neocortical neuronal loss has been suggested by several retrospective studies, but our prospective study has not shown cortical or subcortical atrophy. Measurement of neuronal density in Brodmann's areas 4,9 and 40 has not revealed a significant loss either global, by layer, or by column. The only constant lesion was gliosis of the cortex and white matter. Neuronal loss, therefore, is not indispensable to the occurrence of cognitive disorders in AIDS. The mechanism of dementia might be: dysfunction of cortical neurons (dendritic abnormalities, virus/neurotransmitter competition); subcortical dysfunction, as suggested by the high density of microglial nodules in that region; white matter lesions which could be due to abnormalities in the blood-brain barrier. The expression of cell adhesion molecules (VCAM-1, VLA-4, ICAM-1 and LFA-1) by endothelial cerebral cells is not significantly different in AIDS patients, demented or not, and in patients with multiple sclerosis. In contrast, the expression of VCAM-1 by astrocytes is significantly increased in demented AIDS patients compared with non demented ones.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Dementia Complex↗
PubMed1995

[Fatal familial insomnia and prion diseases].

Fatal familial insomnia has recently enlarged the group of prion diseases. The disease starts between 35 and 60 years of age, is inherited as an autosomic dominant trait, and leads to death within 7 to 32 months. Clinical symptoms and signs include insomnia dysautonomia, cognitive and motor alteration. The discrete topography of the lesions in fatal familial insomnia underlines the role of the thalamus in the regulation of the sleep-wake cycle. Atrophy, neuronal loss and gliosis are prominent in the anterior and dorsomedial nuclei of the thalamus. Spongiosis, which is usually found in prion diseases, is absent in fatal familial insomnia. An abnormal prion protein (PrPsc) is detected in the brain. There is a mutation at codon 178 of the gene encoding this protein. Fatal insomnia is distinct from Creutzfeldt-Jakob disease on clinical, histopathologic and molecular grounds. It provides new information about genetics of prion diseases which share the characteristics of being altogether inherited and, in most cases, transmissible. The recent finding of abnormal PrP in diffuse subcortical gliosis suggests that other degenerative disorders could actually be prion diseases.

Adult↗
PubMed1995

Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.

The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.

Adolescent↗
PubMed1995

[Gliomatous meningitis of hemispheric tumors. Study of 22 cases in adults].

Twenty-two patients suffering from diffuse leptomeningeal gliomatosis (LG) were identified at the Salpêtrière Hospital between January 1989 and January 1994: 20 patients had a known primary supratentorial glioma when LG was diagnosed (8 glioblastomas, 5 anaplastic astrocytomas, 3 anaplasic oligodendrogliomas, 2 astrocytomas and 2 oligodendrogliomas); 2 patients had primary LG. The delay between the discovery of the primary tumour and the development of LG was 5 +/- 4 months in glioblastomas and 22 +/- 16 months for others gliomas. In 1/2 primary LG, autopsy demonstrated an hippocampic astrocytoma which was undetected pre-mortem even on MRI; in the second patient with primary LG no autopsy was obtained and the diagnosis was based on meningeal biopsy. An epidemiological study was made by comparing 13 LG with 275 supratentorial gliomas without LG who were seen during the same period. The incidence of symptomatic LG was 4.7% and was more frequent in anaplasic astrocytomas (6.5%) and anaplasic olidendrogliomas (11.4%) than in glioblastomas (3%) but the difference was not statistically significant. The age at diagnosis of LG was 56 +/- 11 years in glioblastomas and 41 +/- 7 in others gliomas, related to tumour histology. Among the 22 studied cases, only 27% had a meningeal syndrome; multifocal neurological involvement was present in 74% of patients combining at various degree signs of cerebral, cranial nerves and roots or spinal cord dysfunction. Contrast enhancing lesions in the meninges or ventricules on CT/MRI were found in 82% of cases and 45% had an hydrocephalus. In the CSF 94% of patients had a protein level over 1 milligram and 47% of them had a low glucose level < 2.7 mmol/l; malignant cells were found in 47% of cases. Among 11 patients who received radiotherapy and/or chemotherapy, 3 improved and 2 were stable and their survival ranged from 6 to 34+ months. Criteria allowing diagnosis of LG are defined and the therapeutic option are reviewed.

Adult↗
PubMed1995

[Neuropathology of non conventional infectious agents or prions].

The neuropathological diagnosis of infections by non conventional agents relies on four lesions: astrocytic gliosis (cell hypertrophy and proliferation) usually contrasting with absent mononuclear cell infiltrates (lymphocytes, monocytes-macrophages, and/or microglia) revealed by conventional techniques, and neuronal loss in the most affected areas are little specific findings. Amyloid plaques that are inconstantly found, and spongiosis of gray matter, a characteristic and very frequent finding, are most specific. PrP immunohistochemistry brings additional data. The main diagnostic difficulties are emphasized, and guidelines for Pathological studies are recalled.

Animals↗
PubMed1994

Monoamine vesicular uptake sites in patients with Parkinson's disease and Alzheimer's disease, as measured by tritiated dihydrotetrabenazine autoradiography.

The monoaminergic innervation of the caudate nucleus, putamen and ventral striatum was investigated post mortem, in patients with Parkinson's and Alzheimer's disease as compared to control subjects, by autoradiographic detection of tritiated dihydrotetrabenazine (3H-TBZOH), a specific high affinity ligand of the vesicular monoamine transporter. The binding of 3H-TBZOH was specific and saturable (Kd 5.3 nM). In control striatum, the pattern of distribution of 3H-TBZOH binding was heterogeneous, with higher binding levels in the 'matrix' than in the 'striosome' compartment. Changes in ligand binding levels were observed in the pathological brains compared to controls. In Parkinson's disease (PD), characterized by a severe damage of mesostriatal dopaminergic neurons, the density of 3H-TBZOH binding was reduced. A severe decrease in 3H-TBZOH binding was observed in all parts of the striatum (caudate nucleus: -80%, putamen: -86%, ventral striatum: -94%) in PD brains. The data corroborate the deficiency in striatal dopaminergic transmission and suggest that in PD brains dopaminergic terminals have disappeared and/or no longer contain synaptic vesicles. In Alzheimer's disease (AD), 3H-TBZOH binding was significantly reduced by 57% in the ventral striatum and not in the caudate nucleus and putamen. The specific decrease of monoaminergic transporter levels in the ventral striatum confirm that this nucleus is a target area in AD.

Aged↗
PubMed1994

Apolipoprotein E allele epsilon 4 is linked to increased deposition of the amyloid beta-peptide (A-beta) in cases with or without Alzheimer's disease.

To assess the significance of the association between apolipoprotein E (APOE) epsilon 4 allele and amyloid beta-peptide (A-beta) deposits in the brain, we performed APOE-genotyping and measured the density of A-beta deposits, neuritic plaques and neurofibrillary tangles in 27 cases from the Charles Foix clinico-pathological prospective study. We found an increased density of A-beta deposits in the three cases with the epsilon 3/epsilon 4 genotype as compared-with epsilon 3/epsilon 3 subjects. Surprisingly, one of the epsilon 3/epsilon 4 genotypes was a 88-year-old woman, with normal intellectual functions and very low densities of neuritic plaques and neurofibrillary tangles but very high densities of preamyloid diffuse deposits of A-beta. This observation contrasted with the expected association between Alzheimer's disease and APOE epsilon 4 allele.

Aged↗
PubMed1994

[Alzheimer disease. Role of beta A4 peptide and cerebral amyloid substance].

Deposition of large quantities of amyloid substance in the walls of the cerebral vessels and in the core of the senile plaques is characteristic of Alzheimer's disease. beta A4 peptide, the main component of the amyloid substance, is a product of a larger amyloid precursor protein which has the structure of a transmembrane receptor and is widely distributed throughout the body. The pathway leading to beta A4 is not yet fully established but could involve lysosomal degradation. It has been suggested that the beta A4 peptide is of neuronal or vascular origin. The beta A4 peptide is found in diffuse deposits in the cortex and cerebellum as well as in the basal ganglia before the classic senile plaques appear, mainly in layer III of the cerebral cortex. These diffuse deposits are devoid of degenerating neurites (i.e. containing abnormally phosphorylated tau protein). The classical senile plaques contain numerous degenerating neurites linking them to the connective network of the cortex. The intellectual deficit is correlated significantly to the density of the classical senile plaques but not to the density of the diffuse deposits. Although a mutation of the gene coding for the beta A4 peptide appears to be sufficient to induce (or accelerate) Alzheimer's disease, this is undoubtedly an exceptional mechanism. Certain mutations involving the beta A4 precursor protein gene increase in vitro the production of beta A4. The molecular and morphological steps leading, from the accumulation of the peptide (which in itself has no clinical expression) to the neurofibrillary pathology of the senile plaques and of the neurones (which are strongly correlated with clinical dementia), remain hypothetical.

Aged↗
PubMed1994

Effect of aspartate and glutamate on the oxoglutarate carrier investigated in rat heart mitochondria and inverted submitochondrial vesicles.

Interaction of glutamate and aspartate with the oxoglutarate carrier was investigated in rat heart mitochondria or inverted submitochondrial particles. With mitochondria, glutamate and aspartate had no effect on the initial rate of oxoglutarate or malate uptake. With inverted submitochondrial vesicles, binding experiments indicated that aspartate bound to the oxoglutarate carrier on its matricial face and increased the affinity of the substrate binding site for malate but did not change the affinity for oxoglutarate. Glutamate had no effect on both substrate bindings. The dissociation constants of the binary substrate-carrier complexes on the matricial side were determined (1.28 +/- 0.15 mM for oxoglutarate and 2.22 +/- 0.26 mM for malate). These values, compared with those obtained previously on the cytosolic side of intact mitochondria, confirmed the asymmetry of the carrier in the native membrane (higher affinities on the cytosolic face). It is concluded that (1) aspartate and glutamate are not cytosolic effectors of the oxoglutarate carrier, (2) matricial aspartate is a positive effector of the binding of malate on the matricial side of the oxoglutarate carrier, and (3) such a characteristic may play a role in the regulation of the oxoglutarate carrier. Thus, it may be emphasized that (1) this observation is the first clear evidence of a well-defined 'sophisticated regulation' (allosteric) of a mitochondrial metabolite carrier, and (2) this regulation of the oxoglutarate carrier may have important consequences on the efficiency of reducing equivalent import in the matrix space by the malate-aspartate shuttle.

Animals↗
PubMed1994

Cortical tangles in progressive supranuclear palsy.

Ten cases of PSP were examined for the presence of neocortical and hippocampal lesions. Samples from 10 cortical areas were stained by Bodian's method and by tau, ubiquitin and beta A4 immunocytochemistry. For the sake of comparison, 5 Alzheimer's cases were studied with the same techniques. Neocortical tangles, star-like tufts of fibers, and neuropil threads were seen in all the cases of PSP. They were stained by Bodian's technique and labelled by an anti-tau, but not by a polyclonal anti-ubiquitin antibody. Senile plaques (Bodian's technique), diffuse or focal amyloid deposits (beta-A4 immunohistochemistry) were rare or absent. The density of tangles was the highest in area 4 and the lowest in area 17. In area 4, the tangles were mainly located in layers V-VI. By contrast, the Alzheimer's tangles had a bimodal distribution (layers III and V-VI). These results favor the specificity of cortical alterations in PSP.

Aged↗
PubMed1994

Evaluation of neuronal numerical density by Dirichlet tessellation.

The technique that we describe aims at evaluating the numerical density of cells in highly heterogeneous regions, e.g., nuclei, layers or columns of neurones. Rather than counting the number of neuronal sections ('profiles') in a reference frame, we evaluated the 'free area' which lies around each profile. The X and Y coordinates of the neuronal profiles within a microscopical section were measured by 2 linear transducers fastened to the moving stage of the microscope. These coordinates were used by a computer programme that we developed to calculate the 'free area' around each neuronal profile. These areas are polygons that cover the plane of the section without interstice or overlap, i.e., realize a tessellation of the section plane ('Dirichlet tessellation'). Each polygon contains one neuronal profile and the area of the section closest to that profile than to any other. When that area is large, the density is low. An individual value of cellular density = 1/(area of Dirichlet polygon) could thus be assigned to each neuronal profile. Coloured density maps were obtained by attributing a colour to each polygon according to its area. Those maps were useful to demonstrate the presence of neuronal clusters (columns, layers, nuclei, etc.). A confidence interval (CI) of mean polygon areas (standard deviation (SD) of polygon areas/square root of n, n being the number of cells) could be calculated and used to determine the CI of the density of neuronal profiles. This value helped to predict the number of profiles which had to be counted in a particular area to obtain a given precision. The coefficient of variation (CV) of the polygon areas is a dimensionless value, which is not affected by atrophy, shrinkage or stretching of the section, but is sensitive to restricted cell loss. When profiles are regularly spaced, the CV is low; it is high when they are clustered. With computer simulation (Monte-Carlo testing) we established that the CVs ranged from 33% to 64% (P < 0.05) when the profiles were randomly distributed according to a Poisson point process. A value lower than 33% suggested a regular distribution, and a value higher than 64% a clustered distribution. Automatic isolation of cell clusters was made possible with Dirichlet tessellation; a cluster was defined as a group of contiguous cells, exhibiting similar numerical density, i.e., whose polygons had similar surface area.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Count↗
PubMed1994

Iatrogenic Creutzfeldt-Jakob disease in three growth hormone recipients: a neuropathological study.

Since 1985, several cases of Creutzfeldt-Jakob disease, occurring after a treatment by human cadaveric hormone have been reported. Three new iatrogenic cases observed in French patients (two children and one young adult) are described here. Neuropathological study displayed the classical aspects of previously reported sporadic cases of Creutzfeldt-Jakob disease in adults, including severe cortical spongiform change with numerous vacuoles within neuronal dendrites, diffuse astrogliosis and neuronal loss. In addition, the iatrogenic cases described here included two more unusual points: (i) they were homozygotic for the PrP gene on codon 129 and therefore a genetic predisposition could be suspected; (ii) numerous kuru plaques were scattered in the cerebral cortex, the subcortical white matter and in the cerebellar cortex. They were decorated with a PrP monoclonal antibody, but not with a beta A4 antibody. This last point underlines the similarities between iatrogenic Creutzfeldt-Jakob disease and kuru.

Adult↗