Bernard Frigard

Institut Pasteur de Lille, Lille, Nord-Pas-de-Calais, France

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Publications (30)136.05 Total impact


  • No preview · Article · Jan 2012 · Parkinsonism & Related Disorders
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    ABSTRACT: To gain insight into systemic molecular events associated with an age-related neurodegenerative disorder, we compared gene expression patterns in peripheral blood mononuclear cells (PBMCs) sampled from elderly, healthy controls and from Parkinson's disease (PD) patients carrying the most frequently found mutation of the LRRK2 gene (G2019S). A transcriptomic approach enabled us to detect differentially expressed genes and revealed perturbations of pathways known to be involved in PD-related neurodegeneration: the ubiquitin-proteasome system, the mitochondrial oxidation system, inflammation, axonal guidance, calcium signalling and apoptosis. Moreover, alterations of the MAP kinase pathway, the actin cytoskeleton, the ephrin receptor system and vesicular transport - all recently associated with the LRRK2 G2019S mutation pathogenesis - were noted. Furthermore, we acquired new evidences of dysregulation in leukocyte extravasation signalling and immune system pathways in PD. These data show that the G2019S mutation affects the entire body and highlight some of the molecular events observed in the brain. This PBMC transcriptomic approach could be used to better understand neurodegeneration in PD and decipher new pathogenetic mechanisms, even at early stages of the disease.
    No preview · Article · Oct 2011 · Neurobiology of aging
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    ABSTRACT: With the development of long-term disease modifying trials, changes in ADAS-Cog at 18 months will rise certainly many questions. We decided to look in the Real.fr study at the links between changes in cognition, ADAS-Cog and function. A total of 346 Alzheimer's patients with ADAS-cog at entry and at 18 months, were eligible for this analysis. These patients were on average 77.44 years old and 254 (72.36%) were women. The great majority lived at home and about 93% were treated with a cholinesterase inhibitor at baseline. Thirty three patients (9%) had a gain of more than 2 points at the ADAS-cog at 18 months (Group I, improvement); 130 (38%) were considered as stable, the reference group (Group II) characterized by a stability at the ADAS-cog: decline of 2 points to gain of 2 points, 112 subjects (32%) had a moderate decline between 2 and 7 at the ADAS-cog (Group III) and finally 71 subjects (21%) had a severe impairment more than seven points at the ADAS-cog. A loss of one Basic ADL is certainly highly relevant, and such a change was found at 18 months in more than half of the subjects, which is not surprising for a long-term evolution in mild to moderate AD. An impairment of more than 7 points at the ADAS-cog was found in 21% of the subjects at 18 months and was associated with loss of basic ADL. It will be important to see if these percentages can be decreased by anti-amyloid treatments. The Journal of Nutrition, Health & Aging
    No preview · Article · Jul 2007 · The Journal of Nutrition Health and Aging
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    O Merrot · C Vacher · S Merrot · G Godlewski · B Frigard · P Goudot
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    ABSTRACT: Resorption of alveolar bone is the best recognized feature of mandibular aging in the edentate subject. The other consequences of the loss of teeth in the elderly are less well known. An anthropometric study of the mandible by antero-posterior and lateral radiographs of subjects older than 70 years both dentate and edentate but without any maxillo-mandibular dysmorphosis has been done to demonstrate the differences, which exist between the dentate and edentate mandible. The edentate mandibles showed a diminution in the height of the symphysis and increase in the height of the mandibular incisure. A diminution in the height of the body and an increase in the gonial angle in the significant manner. No significant difference was seen for the height of the ramus and the length of the mandible, the minimum width of the ramus and the bigonial width. The diminution in the height of the mandibular symphysis and of the body is explained by the resorption of the alveoli part of the mandible. The increase in the mandibular angle and the diminution in the height of the mandibular incisure may be explained by disequilibrium between the elevator and depressor muscles of the mandible, as a function of the elevator muscles or by the absence of the molar buttress.
    Full-text · Article · Dec 2005 · Surgical and Radiologic Anatomy
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    ABSTRACT: It has been proposed that, independent of the epsilon4 allele, APOE promoter polymorphisms (-491 A/T and -219 G/T) may be risks factor for Alzheimer's disease by modulating APOE expression. To measure the level of APOE expression in Alzheimer's disease. Brains were obtained at necropsy from 114 patients with early and late onset sporadic Alzheimer's disease in Greater Manchester (UK) during years 1986 to 2001. Total RNA was extracted from 84 brains. Purified lymphocytes were obtained from fresh blood from 16 probable Alzheimer cases from Lille (France). APOE and beta-actin gene expression was determined by reverse transcriptase polymerase chain reaction in brain and lymphocytes. An inverse correlation between APOE expression level and A beta loads was observed. As previously described and extended to 114 cases here, an association between the -219 TT genotype and a higher level of parenchymal A beta deposition was found, irrespective of APOE epsilon4 allele status. This effect was more pronounced in older individuals, whereas higher A beta load appeared more closely related to epsilon4 in the younger age group (cut off point at the median age at death (72.5 years)). The -219 TT genotype was associated with a decrease in APOE expression. There was a 60% decrease in APOE expression in lymphocytes from probable Alzheimer cases v controls (p = 0.01). In the oldest individuals, reduced APOE expression, modulated in part by -219 G/T polymorphism, may influence risk and constitute a determinant A beta load in Alzheimer's disease.
    Full-text · Article · Aug 2005 · Journal of Neurology Neurosurgery & Psychiatry
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    ABSTRACT: The leptin, protein of 146 amino acids, produced gene ob (chromosome 7) acts via the hypothalamus on the control of energy balance. It is implied in the adequacy between the food intake and the energy expenditure, and maintains stable body mass. We studied leptine's diurnal rhythm in old person of more than 75 years in institution, according to its state of nutrition and the undercurrent events likely to modify it. The study subjects were divided in two groups according to BMI < or superior 20 kg/m2. In the group of the patients with BMI higher than 20 kg/m2, there exists a correlation of the variation of the plasma leptin levels according to the BMI. At the subjects having a BMI lower than 20 kg/m2, the plasma leptin level is higher than the awaited value and the Leptin/BMI ratio is increased significantly compared to the subjects having a BMI higher than 20 kg/m2 (p < 0,05). Reduced nutritional status has largely exceeded capacities of adaptation to the nutritional needs and the capacity of response to the stress via the leptin is very disturbed.
    No preview · Article · Jan 2005 · The Journal of Nutrition Health and Aging

  • No preview · Article · Jan 2005 · The Journal of Nutrition Health and Aging
  • C. Antoine · P. Antoine · R. Poinsot · D. Balieu · B. Frigard

    No preview · Article · Dec 2004 · Journal de Thérapie Comportementale et Cognitive
  • Antoine C · Antoine P · Guermonprez P · Frigard B

    No preview · Article · Dec 2004 · L Encéphale
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    C Antoine · P Antoine · P Guermonprez · B Frigard
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    ABSTRACT: This article reviews studies concerning unawareness of deficits in Alzheimer's disease. Unawareness of the deficits associated with dementia has frequently been reported in clinical descriptions of the later stages of the disease. Consistent with the literature, we shall use the expressions impaired awareness, unawareness of deficits, anosognosia, and lack of insight interchangeably. Anosognosia can be defined as an impaired ability to recognize the presence or appreciate the severity of deficits in sensory, perceptual, motor, affective, or cognitive functioning. Unawareness has been operationally defined in a variety of ways. Unawareness can be measured as the discrepancy between the patient's self-report and the report of a natural caregiver or the clinical rating of a health care professional. The reports generally concern with several domains, most often memory domain. Discrepancy between subjective ratings and neuropsychological performance during clinical assessment has also been used to measure anosognosia. Advantages, limits and equivalence of these different methods are discussed. The impact of family burden has to be considered as a systematic methodological bias if the natural caregiver is implicated in the assessment. The psychometric properties of the clinical assessment have also to be discussed. The psychological nature of the discrepancy between patient's self-report and cognitive performances has to be analyzed and the necessity of ecological protocols, longitudinal assessment is discussed. The major results concerning prevalence, nature of anosognosia and the associated disorders are analyzed. In particular, the notion of heterogeneity of anosognosia and the correlates with depression, severity of dementia and executive dysfunction are developed. Prevalence is largely function of methodological choices and conceptual definition of anosognosia. Three major researches are compared and the contrast between their results (prevalence from 23% to 75% in AD) is analyzed. Particularly, the hypotheses about anosognosia play a great role in the findings. At first time of research, anosognosia was considered as a general symptom and so, studies were centered on the unawareness related to only one cognitive function. But the 90's findings suggest that patients with AD have impaired awareness for some types of deficits (affective or cognitive functions) but can more accurately appraise other deficits. Currently anosognosia cannot be considered as a unitary entity. It may be that patients with AD are unaware of some types of deficits, but are aware of others, and that nature and intensity of their anosognosia may change during the course of the dementia. It has been proposed that depression is more common when disease is mild and awareness of deficits is retained, and that depression becomes less common when disease increases and awareness declines. Depression is conceived as a psychological reaction. However, the correlations between anosognosia level and depression scores reveal either weak relationships or no relationships. Alternative hypothesis is that anosognosia is related to overall dementia severity and to memory impairment. However, correlations of unawareness of deficits, i.e. the difference between self-report and relative's -rating, with a measure of dementia and with patient's performance on objective memory tasks did not reveal strong, consistent relationships between degree of anosognosia and severity of dementia or of memory impairment. On the other hand, the best neuropsychological predictors of impaired insight are Trail Making Test or Wisconsin Card Sorting Test, i.e. tests that have been shown to be sensitive to a frontal lobe dysfunction. SPECT measures of regional cerebral blood flow have been used in the study of anosognosia. The main findings are that unawareness in AD is associated with hypoperfusion of the right dorsolateral frontal lobe. Anosognosia may result from the disruption of broader cognitive process that is subsumed by the frontal lobes. The mechanisms of unawareness are not well known and studies are essentially descriptive works and try to give information about pre-valence or clinical associated disorders of anosognosia. Several authors have proposed that unawareness is part of a defensive mechanism that would protect demented patients from depressive feelings. Other authors have proposed that anosognosia may result from dysfunction in specific brain areas. It is suggested that anosognosia in AD may result from greater impairment of a central executive system, which is a metacognitive structure that is involved in planning, cognitive resource allocation, and set shifting. The main problem with those both major hypotheses is their incapacity to explain the heterogeneous impairment of awareness. Other authors speculate that the impaired insight of Alzheimer's disease has several components, psychological and neuropsychological. This view doesn't seem convincing and new components have to be taken in account in order to propose a theoretical framework about anosognosia in AD. Environmental and dispositional components and an interactional view could be interesting. Those possible directions for future research and solutions concerning methodological and conceptual problems are outlined. In particular, a neuro-psycho-social view of unawareness is introduced.
    Full-text · Article · Nov 2004 · L Encéphale
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    ABSTRACT: Alzheimer's disease (AD) is a complex, multifactorial disorder, probably resulting from an interaction between environmental and genetic factors. Increasing evidence points to a link between cholesterol turnover and AD, suggesting that genes implicated in brain cholesterol homeostasis may be potential candidate genes for AD. With this background, we tested the potential association of the CYP46, APOM and APOF genes with the risk of developing AD. CYP46 encodes the enzyme cholesterol 24-hydrolase, which plays a key role in brain cholesterol turnover, and APOF and APOM encode apolipoproteins belonging to the large lipocalin family, which also includes ApoE. In contrast to two previous reports but in accordance with one other, we were unable to detect an association between an intron 2 polymorphism of CYP46 and AD. We also searched for polymorphisms within the APOM and APOF by dHPLC. We were unable to detect any polymorphisms in the coding and exon/intron sequences of the APOF. Finally, we excluded APOM as a genetic determinant of AD in our large French case control population.
    Full-text · Article · Jul 2004 · Neuroscience Letters

  • No preview · Article · Jul 2004 · Neurobiology of Aging
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    ABSTRACT: Although possession of the epsilon 4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12. Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism. Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Abeta(40), Abeta(42), Abeta total, and Tau loads or the level of microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD.
    Full-text · Article · Jul 2003 · Journal of Medical Genetics
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    ABSTRACT: There is evidence that inflammatory processes may contribute to the development of Alzheimer's disease through production of cytokines and free radicals that damage neurones. A recent study has shown that transforming growth factor beta1 (TGF-beta1) signalling in astrocytes promotes Abeta production and could play a critical role in the formation of amyloid plaques in the brain. To explore the impact of the -800 and -509 TGF-beta1 promoter polymorphisms and the +25 polymorphism on the risk of occurrence of Alzheimer's disease in a large population of sporadic cases and controls, and on the amyloid beta (Abeta) load in the brains of Alzheimer patients. The TGF-beta1 genotypes of the three polymorphisms were determined in 678 sporadic Alzheimer's disease patients and 667 controls. They were also characterised, along with Abeta load, in the brains of 81 necropsy confirmed Alzheimer patients. No significant variations in the distribution of the genotypes and haplotypes were observed between Alzheimer patients and controls, or in the amount of Abeta deposition. These results do not suggest an influence of genetic variability at the TGF-beta1 gene locus on the occurrence of Alzheimer's disease.
    Full-text · Article · Aug 2002 · Journal of Neurology Neurosurgery & Psychiatry
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    ABSTRACT: Recently, a polymorphism located in the promoter of the presenilin 1 gene was associated with early-onset Alzheimer disease (EOAD). To determine if this polymorphism is also a risk factor for late-onset Alzheimer's disease (LOAD), we analysed its potential impact in a French population of LOAD patients only. Genotype and allelic distributions of the -48CT polymorphism were similar for controls and AD patients. Our result suggests that this polymorphism may not influence the development of LOAD. Other studies need to be undertaken to confirm this association restricting the impact of this polymorphism to EOAD patients.
    No preview · Article · Aug 2002 · Journal of Neural Transmission
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    ABSTRACT: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.
    Full-text · Article · Jul 2002 · Neurology
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    Full-text · Article · Jan 2002 · Les cahiers de l année gérontologique
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    ABSTRACT: The FE65 protein was previously described interacting with amyloid protein precursor (APP) and mediating its internalization. Hu et al. (Hum. Genet., 103 (1998) 295) recently reported that a deletion polymorphism in intron 13 of the FE65 gene may be protective for sporadic Alzheimer's disease (AD) forms and suggested that this deletion may modify splicing between exon 13 and 14 (the two exons encoding the interaction domain of FE65 with APP). We tested the impact of this polymorphism in 646 controls and 639 sporadic AD cases. We were only able to detect a protective effect of the deletion in the population over 75 years (odds ratio = 0.53, 95% confidence interval (0.35-0.82), P= 0.002). Furthermore, no association of this polymorphism with Abeta40, Abeta42(43) and total Abeta loads were detected in 74 AD brains, although, we could expect that this deletion was associated with modifications of the APP metabolism. In conclusion, the FE65 gene may be a minor genetic determinant only for sporadic late-onset AD forms, although, we cannot conclude that this impact is mediated by a modulation of the APP process and/or Abeta peptide deposition.
    Full-text · Article · Nov 2000 · Neuroscience Letters
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    ABSTRACT: Although the &epsiv;4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer’s disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c&sol;CP2&sol;LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G→A) in the 3′-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR &equals; 0.58, 95&percnt; CI 0.44–0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c&sol;CP2&sol;LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP&dash;1c&sol;CP2&sol;LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c&sol;CP2&sol;LSF interacts with proteins such as GSK&bgr;, Fe65 and certain factors involved in the inflammatory response.
    Full-text · Article · Oct 2000 · Human Molecular Genetics
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    Full-text · Article · Jun 1999 · Nature Genetics

Publication Stats

1k Citations
136.05 Total Impact Points

Institutions

  • 1999-2004
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 1998
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1992-1995
    • Unité Inserm U1077
      Caen, Lower Normandy, France