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C Bouras

Publications and source records attributed to C Bouras.

At least 19 recordsLinked to original sources
PubMed2003

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease.

OBJECTIVE: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. BACKGROUND: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. METHODS: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. RESULTS: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. CONCLUSIONS: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

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PubMed2003

Stereologic analysis of neurofibrillary tangle formation in prefrontal cortex area 9 in aging and Alzheimer's disease.

Alzheimer's disease (AD) is characterized neuropathologically by several features including extensive neuronal death in the cerebral cortex. In fact, while neuropathological changes restricted to the hippocampal formation are a consistent reflection of age-related memory impairment, overt dementia is present only in cases with neocortical involvement. Several quantitative studies have reported a substantial loss of neurons from these regions and a parallel increase in the number of neurofibrillary tangles (NFT). However, accurate quantitative data on the dynamics of NFT formation are lacking. In the present study, we performed a stereologic analysis of the proportions of intracellular and extracellular (ghost) NFT, and unaffected neurons in the deep part of layer III (layer IIIc) and the superficial part of layer V (layer Va) of Brodmann's prefrontal cortex area 9. Elderly cognitively unimpaired cases were compared with cases with different degrees of cognitive dysfunction. The data revealed differential rates of formation of intracellular and extracellular NFT between the two layers, and confirmed the presence of a severe disease-associated, but not age-related, neuronal loss. It was also shown that a susbtantial number of pyramidal cells may persist either unaffected or in a transitional stage of NFT formation in both neocortical layers. These results suggest that a considerable number of neurons containing an intracellular NFT exists in the neocortex until late in the course of AD. Whereas it is not possible to assess whether such transitional neurons are fully functional, these affected neurons might respond positively to therapeutic strategies aimed at protecting the cells that are prone to neurofibrillary degeneration in AD.

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PubMed2002

Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer's disease.

Although the presence of amyloid deposits is required to establish the neuropathologic diagnosis of Alzheimer's disease, from a clinical point of view, a direct contribution of these cerebral lesions to cognitive deficits is still controversial. The development and standardization of quantitative and accurate biochemical and neuropathologic methods may be critical to improve the postmortem diagnosis and clinicopathologic correlations. Here, we used a point counting method, based on the Cavalieri principle, to estimate the volume occupied by amyloid deposits in a discrete region of the prefrontal cortex and in the hippocampal formation, in brains from patients with cognitive status ranging from normal to severely demented. We demonstrate that the assessment of the total volume occupied by the amyloid deposits in the entorhinal cortex and subiculum can be considered an effective predictor of dementia severity. We also reveal the existence of a high degree of regional and interindividual heterogeneity in amyloid distribution and relative volume. Our data suggest that even though a correlation was observed between the stereologic point counting method and a non-stereologic random field thresholding approach, in most cases non-stereologic methods may not provide adequate samples of the tissue and may lead to unreliable estimates of amyloid burden due to the inhomogeneous distribution of amyloid in the cerebral cortex and the large variability among brains.

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PubMed2002

In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations.

This study was conducted to identify enzyme systems eventually catalysing a local cerebral metabolism of citalopram, a widely used antidepressant of the selective serotonin reuptake inhibitor type. The metabolism of citalopram, of its enantiomers and demethylated metabolites was investigated in rat brain microsomes and in rat and human brain mitochondria. No cytochrome P-450 mediated transformation was observed in rat brain. By analysing H2O2 formation, monoamine oxidase A activity in rat brain mitochondria could be measured. In rat whole brain and in human frontal cortex, putamen, cerebellum and white matter of five brains monoamine oxidase activity was determined by the stereoselective measurement of the production of citalopram propionate. All substrates were metabolised by both forms of MAO, except in rat brain, where monoamine oxidase B activity could not be detected. Apparent Km and Vmax of S-citalopram biotransformation in human frontal cortex by monoamine oxidase B were found to be 266 microM and 6.0 pmol min(-1) mg(-1) protein and by monoamine oxidase A 856 microM and 6.4 pmol min(-1) mg(-1) protein, respectively. These Km values are in the same range as those for serotonin and dopamine metabolism by monoamine oxidases. Thus, the biotransformation of citalopram in the rat and human brain occurs mainly through monoamine oxidases and not, as in the liver, through cytochrome P-450.

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PubMed2001

Anatomical distribution of serotonin-containing neurons and axons in the central nervous system of the cat.

By using a monoclonal antibody to serotonin (5-HT), an immunohistochemical study was undertaken to provide a comprehensive description of the 5-HT-containing neurons and of the distribution of their axonal processes in the cat brain and spinal cord. The localization of cell bodies was comparable to that previously reported in studies using formaldehyde-induced fluorescence and other 5-HT antibodies, with a large proportion of labeled neurons in the raphe nuclei and a minor, yet not negligible number, in the ventral, lateral, and dorsal reticular formation. The ascending efferent non-varicose axons were best visualized in sagittal sections and mainly seen taking a rostroventral direction through the tegmentum. The varicose axons could be grossly classified into thin and large fibers, according to the size and shape of the immunoreactive varicosities, which were elongated (up to 2 microm in length and 1 microm in width) or round (2-4 microm in diameter). Varicose axonal arborizations invaded almost every region of the gray matter and avoided large myelinated bundles except in the spinal cord. Variations in the density of the plexuses of immunoreactive fibers generally followed the anatomical divisions and were also observed within nuclei, especially in laminated structures. Only the superior olivary complex could be regarded as devoid of 5-HT-containing axons. A few areas contained extremely rich fiber plexuses. These were the olfactory tubercle, nucleus accumbens, ventral mesencephalon, periventricular gray from the hypothalamus to the pons, facial nucleus, subdivisions of the inferior olive, and the intermediolateral nucleus in the spinal cord. Varicose axons formed tight pericellular arrays in the neocortex, mainly the ectosylvian gyrus, and in the lateral septum and medullar magnocellular nucleus. These data, combined with those of the literature concerning the synaptic versus non-synaptic mode of termination of the 5-HT-immunoreactive varicosities and the high number of distinct receptors, are indicative of the multiple possible actions of serotonin in the central nervous system.

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PubMed2001

Anterior cingulate cortex pathology in schizophrenia and bipolar disorder.

To explore possible morphological abnormalities in the dorsal and subgenual parts of anterior cingulate cortex in mood disorders and schizophrenia, we performed a quantitative postmortem study of 44 schizophrenic patients, 21 patients with sporadic bipolar disorder, 20 patients with sporadic major depression, and 55 age- and sex-matched control cases. All individuals were drug naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Neuron densities and size were estimated on cresyl violet-stained sections using a stereological counting approach. The distribution and density of microtubule-associated (MAP2, MAP1b) and tau proteins were assessed by immunocytochemistry and quantitative immunodot assay. Mean total and laminar cortical thicknesses as well as mean pyramidal neuron size were significantly decreased in the dorsal and subgenual parts of areas 24 (24sg) in schizophrenic cases. Patients with bipolar disorder showed a substantial decrease in laminar thickness and neuron densities in layers III, V, and VI of the subgenual part of area 24, whereas patients with major depression were comparable to controls. Immunodot assay showed a significant decrease of both MAP2 and MAP1b proteins in bipolar patients but not in patients with schizophrenia and major depression. The neuroanatomical and functional significance of these findings are discussed in the light of current hypotheses regarding the role of areas 24 and 24sg in schizophrenia and bipolar disorder.

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PubMed2001

Brain energy metabolism in Alzheimer's disease: 99mTc-HMPAO SPECT imaging during verbal fluency and role of astrocytes in the cellular mechanism of 99mTc-HMPAO retention.

The central hypothesis of the study which has been carried out as part of the NRP38 program, is that perturbations of brain energy metabolism are critically involved in the neurodegeneration occurring in Alzheimer's disease (AD) and that they may correlate with early cognitive dysfunctioning. In the present multidisciplinary study we set out to monitor brain energy metabolism using FDG-PET and HMPAO-SPECT imaging in a cohort of individuals over 65 years of age, drawn from the general population. HMPAO-SPECT imaging, which is a simpler and more widely accessible imaging procedure than FDG-PET, was performed under basal conditions and during the performance of a cognitive task (verbal fluency test). Three groups were studied. Two groups (groups I and II) included individuals age 65 or more, with no cognitive impairment and carrying an APOE4 positive or APOE4 negative phenotype, respectively; a third group (group III) included patients with clinical signs of AD. Each subject entering the study underwent an FDG-PET, an HMPAO-SPECT and an extensive battery of neuropsychological tests which assess various aspects of cognitive functioning, with a strong emphasis on working memory, divided attention and executive functions. A total of 101 participants were submitted to brain imaging and neuropsychological testing. Among these, 60 participants received the same set of imaging and neuropsychological tasks 24-36 months after the first set (phase II). In this article, we present a preliminary analysis performed on ten subjects from groups I and II and nine subjects from group III: activation (verbal fluency task) induced a specific pattern of increase in HMPAO retention (including BA 9/10, BA 18 bilaterally and right BA 17). In contrast to controls, in nine AD subjects no significant differences in HMPAO retention were observed when comparing activation and basal conditions. The cellular and molecular mechanisms that underlie the retention of HMPAO, the tracer used for single photon emission computed tomography (SPECT) imaging, has been studied in vitro in purified preparations of neurons and astrocytes with the aim of investigating the contribution of different cell types to hexamethyl-propyleneamineoxime labeled with technetium-99m (99mTc-HMPAO) retention in vitro. Results show that 99mTc-HMPAO retention predominates in astrocytes over neurons by a factor of approximately 2.5. Diethyl maleate, ethacrynic acid and buthionine sulfoximine, three agents which significantly reduce glutathione levels, also decreased 99mTc-HMPAO retention in both astrocytes and in neurons. Decrease did not always correlate with glutathione levels however, thus suggesting that other factors could be involved. The data presented indicate that astrocytes might constitute a prominent site of 99mTc-HMPAO retention and most likely contribute significantly to the SPECT signal. In addition, they also suggest that specific alterations in glial cell metabolism could explain flow-independent changes in 99mTc-HMPAO retention in the brain as observed by SPECT in certain pathologies (including Alzheimer's disease). In particular, these observations suggest a key role of astrocytes in the signal detected with the imaging procedure, which is altered in the Alzheimer's cohort subjected to the verbal fluency activation task.

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PubMed2001

Clinical validity of A beta-protein deposition staging in brain aging and Alzheimer disease.

Braak's neurofibrillary tangle (NFT) pathology staging system of Alzheimer disease (AD) correlates generally with clinical data. Recently, Braak's group proposed an Abeta-protein staging based on the progression of amyloid deposition in the medial temporal lobe. To examine its clinical validity and evaluate whether it adds predictive power to NFT-based staging, we performed a study comparing both neuropathological classifications with clinical dementia rating scale (CDR) scores in a large autopsy series. The 2 neuropathological staging systems were strongly correlated. Their association with clinical severity was highly significant. However, the strength of the relationship was greater for NFT-based staging. It accounted for 26.5% of the variability in clinical severity, Abeta-protein-based staging for 13.0%, and age for 4.4%. Compared to NFT-based staging, the Abeta-protein-based system was less able to distinguish mild cognitive changes from dementia and showed marked overlap among the various stages of cognitive decline. In a multivariate model, NFT and age together accounted for 27.2% of the clinical variability and the addition of Abeta-protein deposition staging could only explain an extra 2.9%. Our data support the close relationship between NFT progression and amyloid formation within the medial temporal lobe proposed by Braak's group but demonstrate the limited value of Abeta-protein deposition staging in terms of clinicopathological correlations.

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PubMed2000

Intracerebroventricular infusion of leptin decreases serotonin transporter binding sites in the frontal cortex of the rat.

We demonstrate that chronic intracerebroventricular infusion of leptin dramatically decreases the number of [(3)H]paroxetine binding sites in the frontal cortex of the rat brain. In contrast, the density in paroxetine binding sites estimated in the region containing raphe projecting cell bodies (i.e., the dorsal and median raphe nuclei) remains unchanged. Since leptin treatment significantly decreases food intake, [(3)H]paroxetine binding parameters were also estimated in the frontal cortex of pair-fed control rats. No significant difference in [(3)H]paroxetine binding was observed between pair-fed and ad libitum fed control rats. These data indicate that leptin treatment could regionally down-regulate serotonin transporter binding sites in the brain. Although the cellular and molecular mechanisms underlying such an effect of leptin need further investigation, our observations support the notion of a possible interaction between leptin and the serotonergic system of potential interest in the pathophysiology of depression.

Animals↗
PubMed2000

Cytochrome P-450 activities in human and rat brain microsomes.

The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.

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PubMed2000

Search for a mutation in the tau gene in a Swiss family with frontotemporal dementia.

Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau gene located on chromosome 17 has been shown to be implicated in the pathogenesis of several FTD families with parkinsonism, the so called FTDP-17 families. The mutations reported so far are located within exons 9 to 13, a region coding for the microtubule-binding sites. They are causing various cytoskeletal disturbances. We are describing here the main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype. However, if we except two silent polymorphic sites at position 227 and 255 in exon 9, neither a known FTDP-17 mutation nor a novel one was detected in this region of the tau gene. Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family. A mutation in another gene is still possible.

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PubMed2000

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

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PubMed2000

Clinical validity of Braak neuropathological staging in the oldest-old.

Several studies have demonstrated a good correlation between clinical severity and Braak's neuropathological staging in Alzheimer's disease (AD). However, nonagenarians and centenarians display a different pattern of cortical vulnerability to the neurodegenerative process compared to younger elderly, and it is not known whether correlations between clinical severity and neuropathological stages remain valid in this age group. To address this issue we compared Clinical Dementia Rating scale (CDR) scores and Braak stages in 116 patients over 90 years of age with either no cognitive impairment or very mild to severe AD. There is a strong positive correlation between CDR scores and Braak staging (Spearman coefficient = 0.66; P < 0.01). However, neuropathological staging does not distinguish cases with normal cognition (CDR 0) from those with mild cognitive changes (CDR 0.5). Unlike younger cohorts, Braak stages I and II are frequently associated with questionable dementia in this age group. Braak stage III overlaps with all CDR levels and correlates poorly with cognitive function. Braak stages IV or greater are consistently associated with at least mild dementia. Consistent with our previous neuropathological analyses of nonagenarians and centenarians, the present data suggest that the substantial involvement of the hippocampus which characterizes Braak stage IV is a key step in the development of overt clinical signs of dementia in the oldest-old. Moreover, they indicate that Braak staging represents a broad concept of the evolution of neurofibrillary tangles rather than a precise hierarchical model associated with a stepwise deterioration of cognitive abilities near the upper limit of life.

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PubMed2000

Neural substrates of spatial and temporal disorientation in Alzheimer's disease.

To examine the neuroanatomical correlates of spatial and temporal disorientation in Alzheimer's disease (AD), we performed an anterograde clinicopathological study of 29 patients with clinically and neuropathologically confirmed AD. Spatial and temporal disorientation was assessed using the locational orientation subtests of the Mini Mental State Examination and the Benton's test for temporal orientation. Quantitative analysis of neurofibrillary tangles and senile plaques were performed in the CA1 field of the hippocampus, layers II and V of the entorhinal cortex, and layers II-III and V-VI of areas 9, 7, 39, 19, 37, 20 and 23 in the right hemisphere. Forward stepwise logistic regression was used to assess the relationship between lesion densities and the presence of either spatial or temporal disorientation; severity scores and brain weight were included as covariants. A statistically significant relationship was found between neurofibrillary tangle densities in Brodmann's areas 7, 23 and the CA1 field of hippocampus and both spatial and temporal disorientation. Senile plaque counts did not correlate with any of the neuropsychological parameters. Both temporal and spatial disorientation in AD are related to the degeneration of the same pathways linking the hippocampus with the superior parietal and posterior cingulate cortex in the right hemisphere. These observations are discussed with respect to the notion of global corticocortical disconnection in AD.

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PubMed2000

Differential messenger RNA distribution of lactate dehydrogenase LDH-1 and LDH-5 isoforms in the rat brain.

The role of lactate in brain energy metabolism has recently received renewed attention. Although blood-borne monocarboxylates such as lactate poorly cross the blood-brain barrier in the adult brain, lactate produced within the brain parenchyma may be a suitable substrate for brain cells. Lactate dehydrogenase is crucial for both the production and utilization of lactate. In this article, we report the regional distribution of the messenger RNAs for lactate dehydrogenase isoforms 1 and 5 in the adult rat brain using in situ hybridization histochemistry with specific [alpha-(35)S]dATP 3' end-labeled oligoprobes. The autoradiographs revealed that the lactate dehydrogenase-1 messenger RNA is highly expressed in a variety of brain structures, including the main olfactory bulb, the piriform cortex, several thalamic and hypothalamic nuclei, the pontine nuclei, the ventral cochlear nucleus, the trigeminal nerve and the solitary tractus nucleus. In addition, the granular and Purkinje cell layers of the cerebellum showed a strong labeling. The neocortex (e.g., cingular, retrosplenial and frontoparietal cortices) often exhibits a marked laminar pattern of distribution of lactate dehydrogenase-1 messenger RNA (layers II/III, IV and VI being most strongly labeled). In contrast, expression of the lactate dehydrogenase-5 messenger RNA generally seemed more diffusely distributed across the different brain regions. Expression was particularly strong in the hippocampal formation (especially in Ammon's horn and dentate gyrus) and in the cerebral cortex, where no laminar pattern of distribution was observed. Overall, these data are consistent with the emerging idea that lactate is an important energy substrate produced and consumed by brain cells.

Animals↗
PubMed2000

Immediate causes of death of demented and non-demented elderly.

OBJECTIVE: To investigate the immediate causes of death, in autopsied demented and non-demented elderly. DESIGN: Retrospective clinicopathologic correlations. SETTING: Acute and intermediate care geriatric hospital. PARTICIPANTS: 342 hospitalized demented and non-demented elderly (mean age 84.94 +/- 6.9 years) who underwent consecutive postmortem examinations: 120 demented patients with either vascular dementia (VaD, n = 34), mixed dementia (MD, n = 65) or Alzheimer's disease (AD, n=21) neuropathologically confirmed and 222 nondemented elderly. RESULTS: Primary causes of death were similar in both demented and non-demented patients; the commonest were cardiovascular disease and bronchopneumonia. Cardiac causes of death and especially cardiac failure were more frequent in VaD than in AD or MD (respectively P = 0.027 and 0.005). Dementia was an underlying but never a primary cause of death. CONCLUSIONS: Immediate causes of death are similar in elderly demented and non-demented patients.

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PubMed2000

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

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