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J Poirier

Publications and source records attributed to J Poirier.

At least 37 records · Page 2Linked to original sources
PubMed2002

Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action.

Since degenerative alterations associated with cholinergic changes in the brains of demented patients occur in specific regions, optimal efficacy may be achieved by targeting the actions of potent cholinesterase inhibitors in relevant regions. When evaluating the activities of these agents, only cerebrospinal fluid (CSF)-based studies in demented patients provide reliable data. Preclinical or healthy volunteer studies of cholinesterase inhibitory activity using plasma or erythrocytes as an enzyme source are inconclusive due to differences between enzymes, their relative activities, and the profiles of their isoforms from different sources, with additional changes during disease progression. Tacrine and rivastigmine inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the CSF of Alzheimer's disease patients. Both enzymes are involved in the breakdown of acetylcholine (ACh) in the brain and dual inhibition may lead to greater, broader efficacy, as well as a greater potential for disease modification. However, potent and rapid elevation in levels of ACh may also induce more acute tolerability problems, such as nausea and vomiting. Only rivastigmine appears to show brain region-selectivity, particularly for regions involved in attention and behaviour and that are known to degenerate during the progression of various dementia types. This selectivity is due to preferential inhibition of the G1 form of AChE and, probably, also BuChE. Cholinesterase inhibitors that lack preferential selectivity for particular isoforms may provide less targeted actions. This may explain the relatively higher incidences of certain peripheral side effects observed during maintenance treatment with some of these drugs. All cholinesterase inhibitors interact via ACh, additionally available due to enzyme inhibition, with nicotinic and muscarinic receptors (nAChRs and mAChRs). Allosteric modulation of a presynaptic nAChR has been shown in vitro with many of these agents, and it has been proposed, but not demonstrated, that this may result in an increased release and potentiation of ACh in the brain. The clinical relevance of this mechanism is unknown. The rapidly reversible actions of donepezil, tacrine and galantamine may lead to tolerance due to their ability to upregulate target enzyme activities; however upregulation is not seen with the slowly reversible (pseudo-irreversible) inhibitor rivastigmine. Available clinical data support the hypothesis that potent, slowly reversible inhibitors of AChE and BuChE targeted to the G1 isoforms may lead to greater, broader and more sustained benefits. However, further investigation of the cholinesterase inhibitors to elucidate more definitely the clinical consequences of their differing pharmacological properties is required.

Cholinesterase Inhibitors↗
PubMed2001

Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression.

OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.

Adult↗
PubMed2001

Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

Aged↗
PubMed2001

OLIG2 as a specific marker of oligodendroglial tumour cells.

OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.

Astrocytoma↗
PubMed2001

Impact of apoE deficiency on oxidative insults and antioxidant levels in the brain.

Apolipoprotein E (apoE) is a lipid transport molecule, which has been linked to the pathogenesis of Alzheimer's disease. Recently we have demonstrated that the oxidative insults in hippocampus from AD patients were dependent on the apoE genotype. Interestingly, apoE protein concentration in hippocampus follows a genotype-dependent gradient with the lowest level occurring in varepsilon4 allele carrier. We raised the possibility that, in the hippocampus, the apoE level affects the oxidant/antioxidant balance. Here, we have examined in the apoE-deficient mouse the oxidant/antioxidant status in hippocampus and in frontal cortex from APOE-KO and wild-type mice at 3 and 13 months. We provided evidence that, in the hippocampus, the absence of apoE has a clear impact on the oxidant/antioxidant status. Endogenous level of thiobarbituric acid-reactive substances (TBARS) was found to be markedly elevated whereas level of alpha-tocopherol was decreased in APOE-deficient mice at 3 and 13 months. Superoxide dismutase activities were also lower in APOE-deficient mice at 13 months. Taken together, these data indicate that the steady state level of apoE may influence, to a certain extent, the balance between oxidants and antioxidants in hippocampus.

Alzheimer Disease↗
PubMed2001

Apolipoprotein C-I expression in the brain in Alzheimer's disease.

The H2 allele of apolipoprotein (apo) C-I is associated with Alzheimer's disease (AD). However, this association is potentially confounded by the linkage disequilibrium of H2 with the epsilon2 and epsilon4 alleles of apoE and of H1 with the epsilon3 allele. To establish plausibility for a direct role for apoC-I in AD, we compared apoC-I and apoE protein and mRNA levels in postmortem specimens of frontal cortex and hippocampus from AD patients with levels in nondemented controls. In H2-allelic individuals (usually also epsilon4 carriers), apoC-I mRNA levels were strikingly lower with AD (by 65%, P < 0.05), but apoC-I protein levels in AD were significantly higher (by 34%, P < 0.05). The opposite direction of the apoC-I mRNA and apoC-I protein level changes in AD in the epsilon4/H2 genotype may reflect decreased clearance of CNS lipoproteins associated with apoE4. In H1/H1 (usually epsilon3/epsilon3) individuals, both apoC-I protein and mRNA were lower in AD. ApoC-I protein levels in hippocampus were nearly twice those in frontal cortex. Immunohistochemistry of hippocampus revealed colocalization of apoC-I protein with the astrocytic marker GFAP. In addition, cultured human astrocytes expressed the mRNA for apoC-I. This study confirms apoC-I expression in the CNS and identifies astrocytes as the source of apoC-I. In addition, it has revealed differences in apoC-I expression based on site, genotype, and disease status that may reflect a role for apoC-I in the pathogenesis of AD.

Aged↗
PubMed2001

Amyloid beta peptide levels and its effects on hippocampal acetylcholine release in aged, cognitively-impaired and -unimpaired rats.

Excessive extracellular deposition of amyloid beta (Abeta) peptide in neuritic plaques and degeneration of forebrain cholinergic neurones, which innervate the hippocampus and the neocortex, are the invariant characteristic features of Alzheimer's disease (AD). Studies of the pathological changes that characterize AD, together with several other lines of evidence, indicate that Abeta accumulation in vivo may initiate and/or contribute to the process of neurodegeneration observed in the AD brain. However, the underlying mechanisms by which Abeta peptide influences/causes degeneration of the basal forebrain cholinergic neurones in AD brains remain obscure. We reported earlier that nM concentrations of Abeta-related peptides, under acute conditions, can potently inhibit K+-evoked endogenous acetylcholine (ACh) release from the hippocampus and the cortex but not from striatum in young adult rats (J. Neurosci. 16 (1996) 1034). In the present study, to determine whether the effects of Abeta peptides alter with normal aging and/or cognitive state, we have measured Abeta1-40 levels and the effects of exogenous Abeta1-40 on hippocampal ACh release in young adult as well as aged cognitively-unimpaired (AU) and -impaired (AI) rats. Endogenous levels of Abeta(1-40) in the hippocampus are significantly increased in aged rats. Additionally, 10 nM Abeta1-40 potently inhibited endogenous ACh release from the hippocampus of the three groups of rats, but the time-course of the effects clearly indicate that the cholinergic neurones of AI rats are more sensitive to Abeta peptides than either AU or young adult rats. These results, together with earlier reports, suggest that the processing of the precursor protein of Abeta peptide alters with normal aging and the response of the cholinergic neurones to the peptide possibly varies with the cognitive status of the animals.

Acetylcholine↗
PubMed2001

Glioblastomas with an oligodendroglial component: a pathological and molecular study.

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.

Adult↗
PubMed2001

Meta-modelling: the appropriate solution for a family of applications.

The aim of this paper is to present an appropriate framework able to generate models and to implement them, in the objective of computerizing a family of medico-technical reports. The accelerated rate of technical development makes it necessary to design computerized applications independently of data-processing technology. This apparent paradox is a quite real challenge which needs research and development software environments to support frameworks. In this article, we present a meta-model (i.e. a generic structure - supported by the Méta-Gen software tool) ) which is able to generate various models of medico-technical reports. These models in turn are able to generate various types of instances. This meta-model is a "Meta-medical record", it is constituted of basic concepts : " User Semantic Group " to which are attached a set of " sentence-type ", a set of several corpus of variables with a set of graphs ("navigators"). Five models (echocardiography for hospital "A", echocardiography for hospital "B", gastroscopy, fibercoloscopy A.E.P.). were already generated from this "Meta-Medical Record". A beginning of implementation in echocardiography report is presented here. The advantages are a very thorough personalization of the document for the user, and a greater independence of the design diagram from the technological platform.

Echocardiography↗
PubMed2000

Phospholipase A2 activity is decreased selectively in the hippocampus of aged apolipoprotein E deficient mice.

Because apolipoprotein E (ApoE) deficient mice have cognitive deficits (Neurosci. Lett., 199 (1995) 1-4; Neuroscience, 92 (1999) 1273-1286; Brain Res., 752 (1997) 189-196) that may involve decreased phospholipase A(2) (PLA(2)) activity (Neuroscience, 92 (1999) 1273-1286), striatal, hippocampal, and parieto-temporal PLA(2) activity was measured in cytosol from 3 and 20-month-old ApoE deficient and control mice. Samples were homogenized and cytosol prepared by ultracentrifugation. PLA(2) activity in each cytosolic fraction was measured in triplicate using a continuous fluorometric assay (J. Neurosci. Methods (2000) in press). In 3-month-old animals, there was a trend for decreased hippocampal PLA(2) activity between groups. In 20-month-old animals, hippocampal PLA(2) activity was significantly (P=0.0304) decreased nearly 20% in ApoE deficient mice as compared to age-matched control mice. No differences were found in other brain regions, although activity in the striatal samples were nearly 65% less than in the other two regions.

Aging↗
PubMed2000

Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion.

The GAA triplet repeat expansion that causes Friedreich ataxia is found only in individuals of European, North African, Middle Eastern, or Indian origin (Indo-European and Afro-Asiatic speakers). Analysis of normal alleles of the GAA repeat and of closely linked markers suggests that expansions arose through a unique two-step process. A major implication of these findings is that Friedreich ataxia may not exist among sub-Saharan Africans, Amerindians, and people from China, Japan, and Southeast Asia.

Africa, Northern↗
PubMed2000

Oxidative insults are associated with apolipoprotein E genotype in Alzheimer's disease brain.

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with sporadic and familial late-onset Alzheimer's disease (AD). Oxidative stress is believed to play an important role in neuronal dysfunction and cell death in AD. We now provide evidence that in the hippocampus of AD, the level of thiobarbituric acid-reactive substances (TBARS) and the APOE genotype are linked. Within AD cases, the levels of TBARS were found to be higher among epsilon4 carriers while the apoE protein concentrations were lower. The relationship between the levels of TBARS and apoE proteins was corroborated by the results from the APOE-deficient mice, in which the levels of TBARS were higher than those in wild-type mice. Among AD cases, tissues from patients with the epsilon4 allele of APOE displayed lower activities of catalase and glutathione peroxidase and lower concentration of glutathione than tissues from patients homozygous for the epsilon3 allele of APOE. Together these data demonstrate that, in AD, the epsilon4 allele of APOE is associated with higher oxidative insults.

Aged↗