B Frigard

University of Lille Nord de France, Lille, Nord-Pas-de-Calais, France

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Publications (28)125.17 Total impact

  • [Show abstract] [Hide abstract]
    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.
    Neurobiology of aging 10/2011; 32(10):1839-48. · 5.94 Impact Factor
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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.
    Surgical and Radiologic Anatomy 12/2005; 27(4):265-70. · 1.13 Impact Factor
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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.
    Journal of Neurology Neurosurgery &amp Psychiatry 08/2005; 76(7):928-33. · 4.92 Impact Factor
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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.
    Neuroscience Letters 07/2004; 363(2):139-43. · 2.03 Impact Factor
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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.
    L Encéphale 01/2004; 30(6):570-7. · 0.49 Impact Factor
  • L’Encéphale. 01/2004; 30:570-577.
  • Neurobiology of Aging - NEUROBIOL AGING. 01/2004; 25.
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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.
    Journal of Medical Genetics 07/2003; 40(6):424-30. · 5.70 Impact Factor
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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.
    Journal of Neurology Neurosurgery &amp Psychiatry 08/2002; 73(1):62-4. · 4.92 Impact Factor
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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.
    Journal of Neural Transmission 08/2002; 109(7-8):1023-7. · 3.05 Impact Factor
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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.
    Neurology 07/2002; 59(1):59-66. · 8.25 Impact Factor
  • Les cahiers de l année gérontologique 01/2002; 16:261-272.
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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.
    Neuroscience Letters 11/2000; 293(1):29-32. · 2.03 Impact Factor
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    ABSTRACT: Although the ϵ4 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/CP2/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 = 0.58, 95% 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/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP‐1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSK&bgr;, Fe65 and certain factors involved in the inflammatory response.
    Human Molecular Genetics 10/2000; · 7.69 Impact Factor
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    Nature Genetics 06/1999; 22(1):17-9; author reply 21-2. · 35.21 Impact Factor
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    ABSTRACT: We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer’s disease (AD) from Northern France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically relevant variability in promoter or other regulatory elements of this large gene.
    Human Genetics 05/1999; 104(5):432-434. · 4.63 Impact Factor
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    ABSTRACT: Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.
    Neuroscience Letters 04/1999; 262(2):137-9. · 2.03 Impact Factor
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    ABSTRACT: Recent reports have suggested that variability in the α2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.
    Neuroscience Letters. 01/1999;
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    ABSTRACT: Possession of the apolipoprotein E (APOE) epsilon4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD). Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues. The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon2/epsilon3/epsilon4 polymorphism effect. However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease. In AD subjects heterozygous for the epsilon4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon4 allele were higher than those of the corresponding controls. Consistent with epidemiological data, the relative level of expression of the epsilon4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population. These data indicate that in addition to the qualitative effect of the APOE epsilon2/epsilon3/epsilon4 polymorphisms on the AD occurrence, the quantitative variation of expression of these alleles due to functional APOE promoter mutations, is a key determinant of AD development.
    Human Molecular Genetics 10/1998; · 7.69 Impact Factor
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    ABSTRACT: The epsilon4 allele of the Apolipoprotein E gene (APOE), one of the main allele of APOE polymorphism, is a major risk factor for the development of Alzheimer's disease. However, several data suggest that genetic factors, within the APOE locus, may also modulate the risk associated with this polymorphism. We look for new mutations in the APOE promoter, susceptible to modify the risk associated with the APOE epsilon4 allele. We characterised a G-->T mutation at -186 bp of the APOE gene TATA box, named Th1/E47cs. This new polymorphism is located in a consensus sequence of a potential transcriptional (Th1/E47) factor binding site. We studied the impact of this new polymorphism with those of other markers of the APOE locus in a large case-control study and observed that Th1/E47cs modulated the influence of the APOE epsilon4 allele on the risk of Alzheimer's disease.
    Human Molecular Genetics 03/1998; 7(3):533-40. · 7.69 Impact Factor

Publication Stats

701 Citations
125.17 Total Impact Points

Institutions

  • 2011
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 1998–2002
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 1992–1995
    • Unité Inserm U1077
      Caen, Lower Normandy, France