Publications (31)159.28 Total impact
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Dataset: Depaz-ALZ.DIS.AS.DIS.2011
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Article: Constant transmission properties of variant creutzfeldt-jakob disease in 5 countries.
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ABSTRACT: Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.Emerging Infectious Diseases 10/2012; 18(10):1574-9. · 6.79 Impact Factor -
Article: Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders.
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ABSTRACT: Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.Human Molecular Genetics 09/2012; · 7.64 Impact Factor -
Article: Iatrogenic Creutzfeldt-Jakob disease, final assessment.
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ABSTRACT: The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (228 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use.Emerging Infectious Diseases 06/2012; 18(6):901-7. · 6.79 Impact Factor -
Article: Rapidly progressive Alzheimer's disease: a multicenter update.
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ABSTRACT: The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ε4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease.Journal of Alzheimer's disease: JAD 03/2012; 30(4):751-6. · 3.74 Impact Factor -
Article: Preclinical sporadic Creutzfeldt-Jakob disease in French blood donors: an epidemiologic model-based study.
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ABSTRACT: A recent case-control study showed that transfusion recipients were at an increased risk of developing sporadic Creutzfeldt-Jakob disease (sCJD), suggesting that blood donors with silent preclinical sCJD could transmit the sCJD agent. We therefore estimated the annual number of French blood donors expected to have preclinical sCJD at the time of donation. We developed a mathematical model to estimate the number of blood donors who would subsequently develop sCJD, under various assumptions about how long their blood might be infective before clinical onset. The model used distributions by age group and sex for sCJD cases, blood donor population, French general population, and mortality in the general population. Using 1999 to 2008 data, modeling showed that, each year, a mean of 1.1 (standard deviation [SD], 0.3) donors were within 1 year of sCJD onset at the time of blood donation, 6.9 (SD, 0.5) donors were within 5 years, 18.0 (SD, 0.6) were within 10 years, and 33.4 (SD, 1.1) were within 15 years. Few donors are expected to be in the late preclinical stage of sCJD at the time of blood donation. This result and that of the worldwide absence of any epidemic increase in sCJD over the years indicate that this risk of transfusion-transmitted sCJD, if any, is likely to be very low.Transfusion 12/2011; 52(6):1290-5. · 3.22 Impact Factor -
Article: Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk.
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ABSTRACT: The aim of our study was to discover genomic variations related to variant Creutzfeldt-Jakob disease (vCJD) susceptibility. A genome-wide association analysis with most vCJD samples available in the world was performed. A series of 93 vCJD UK patients and 1504 UK controls were included in the discovery stage. Our best findings were replicated in an independent population of 22 UK and 20 French vCJD cases. Post hoc analysis to assess our main results included 5711 French controls, 445 Dutch controls, and 446 sporadic Creutzfeldt-Jakob disease (CJD) cases. We found 2 genome wide significant variants tagging PRNP: rs6107516 (p = 2.6 × 10(-18)) and rs2065706 (p = 8.8 × 10(-14)). Two other single nucleotide polymorphisms (SNPs) (rs4921542 and rs7565981) were successfully replicated in independent samples and reached genome-wide significance after pooling discovery and replication populations. Rs4921542 (p = 1.6 × 10(-8)) is an intronic variant in the myotubularin related protein 7 gene (MTMR7), which is specifically expressed in the central nervous system (CNS) and dephosphorylates phosphatidylinositol 3-phosphate and inositol 1,3-bisphosphate. Rs7565981 (p = 4.2 × 10(-8)) is in an intergenic region upstream of the neuronal PAS (per-ARNT-sim) domain-containing protein 2 gene (NPAS2), a regulatory gene belonging to a family of transcription factors that has been implicated in memory, seasonal affective disorder, and the molecular clock in the mammalian forebrain. A proxy of rs7565981 (rs17024792; r(2) = 1.0) has been found to regulate the phospholipase C-delta-3 gene (PLCD3) in trans. This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate. Our study reveals 2 new genome-wide significant markers for vCJD outside PRNP and provides evidence supporting a role of the phosphatidylinositol pathway in vCJD susceptibility.Neurobiology of aging 11/2011; 33(7):1487.e21-8. · 5.94 Impact Factor -
Article: Can mortality data provide reliable indicators for Creutzfeldt-Jakob disease surveillance? A study in France from 2000 to 2008.
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ABSTRACT: Surveillance of Creutzfeldt-Jakob disease (CJD) is still an important issue because of the variant CJD epidemic, which is in decline and also because of the emergence of novel forms of animal transmissible spongiform encephalopathy with zoonotic potential and the risk of nosocomial and blood transfusion-related transmission. Active surveillance has been implemented in most European countries and requires important human resources and funding. Here, we studied whether national mortality and morbidity statistics can be used as reliable indicators. CJD data collected by the French national CJD surveillance centre were compared with data registered in the national mortality statistics. From 2000 to 2008, the two sources reported fairly similar numbers of CJD deaths. However, analysis of individual data showed important between-sources disagreement. Nearly 24% of CJD reported by the mortality register were false-positive diagnoses and 21.6% of the CJD cases diagnosed by the surveillance centre were not registered as CJD in the national mortality statistics. One out of 22 variant CJD cases was not reported as having any type of CJD in the mortality statistics. These findings raise doubt about the possibility of a reliable CJD surveillance only based on mortality data.Neuroepidemiology 11/2011; 37(3-4):188-92. · 2.31 Impact Factor -
Article: Long-standing prion dementia manifesting as posterior cortical atrophy.
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ABSTRACT: Prion diseases commonly manifest with the phenotype of subacute myoclonic encephalopathy. However, genetic forms of prion disease may have prolonged evolution mimicking neurodegenerative disease. We present the clinical and neuropathological features of a family with an early and long-standing dementia manifesting with posterior cortical atrophy and related to a 120 bp insertional mutation of the prion protein gene. Two cases exhibited mixed prion and Aβ pathology. The differential diagnosis with Alzheimer disease is discussed.Alzheimer disease and associated disorders 09/2011; 26(3):289-92. · 2.88 Impact Factor -
Article: Biochemical and strain properties of CJD prions: complexity versus simplicity.
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ABSTRACT: Prions, the agents responsible for transmissible spongiform encephalopathies, are infectious proteins consisting primarily of scrapie prion protein (PrP(Sc)), a misfolded, β-sheet enriched and aggregated form of the host-encoded cellular prion protein (PrP(C)). Their propagation is based on an autocatalytic PrP conversion process. Despite the lack of a nucleic acid genome, different prion strains have been isolated from animal diseases. Increasing evidence supports the view that strain-specific properties may be enciphered within conformational variations of PrP(Sc). In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent form of prion diseases and has demonstrated a wide phenotypic and molecular spectrum. In contrast, variant Creutzfeldt-Jakob disease (vCJD), which results from oral exposure to the agent of bovine spongiform encephalopathy, is a highly stereotyped disease, that, until now, has only occurred in patients who are methionine homozygous at codon 129 of the PrP gene. Recent research has provided consistent evidence of strain diversity in sCJD and also, unexpectedly enough, in vCJD. Here, we discuss the puzzling biochemical/pathological diversity of human prion disorders and the relationship of that diversity to the biological properties of the agent as demonstrated by strain typing in experimental models.Journal of Neurochemistry 07/2011; 119(2):251-61. · 4.06 Impact Factor -
Article: Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes.
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ABSTRACT: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease-related prion protein (PrP(Sc) ) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP(Sc) deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt-Jakob disease (sCJD; n=100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP(Sc) molecular types. The numerical density of neurones was estimated with a computer-assisted image analysis system and the accumulation of PrP(Sc) deposits was scored. The scores of PrP(Sc) immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts - the higher the score the higher the neuronal loss - in all sCJD subtypes. Large 5- to 50-µm-wide deposits (focal type) were found in sCJD-MV2 and sCJD-VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5- to 50-µm-wide deposits observed in sCJD-MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD-VV2 subtype. These results support a putative pathogenic role for small PrP(Sc) deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP(Sc) type-2 large deposits is consistent with a possible 'protective' role of aggregated deposits in both sCJD-MV2 and sCJD-VV2 subtypes.Neuropathology and Applied Neurobiology 03/2011; 37(5):500-12. · 3.80 Impact Factor -
Article: Iatrogenic Creutzfeldt-Jakob disease in Australia: time to amend infection control measures for pituitary hormone recipients?
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ABSTRACT: From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt-Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk.The Medical journal of Australia 09/2010; 193(6):366-9. · 2.81 Impact Factor -
Article: Loss of cerebellar granule neurons is associated with punctate but not with large focal deposits of prion protein in Creutzfeldt-Jakob disease.
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ABSTRACT: Whether aggregates of prion protein (PrP) reflect neurotoxicity or are neuroprotective in prion diseases is unclear. To address this question, we performed a clinicopathologic study of cerebellar granular neurons in 100 patients affected with sporadic Creutzfeldt-Jakob disease (CJD). There was significant loss of these neurons in the subset of cases with Val/Val genotype at PRNP Codon 129 and Molecular Isotype 2 of abnormal PrP (sporadic CJD-VV2) (n=32) compared with both the other CJD subtypes and to controls. Pathological PrP deposits of the punctate-type (synaptic-type) in this subgroup correlated with neuronal loss and proliferation of astrocytes and microglia. By contrast, the numbers of large deposits (5- to 50-microm-diameter) and numbers of amyloid plaques did not correlate with neuronal loss. These findings are consistent with the view that large aggregates may protect neurons by sequestering neurotoxic PrP oligomers, whereas punctate deposits may indicate the location of neuronal death processes in CJD.Journal of Neuropathology and Experimental Neurology 09/2009; 68(8):892-901. · 4.26 Impact Factor -
Article: Variant Creutzfeldt-Jakob disease in France and the United Kingdom: Evidence for the same agent strain.
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ABSTRACT: Variant Creutzfeldt-Jakob disease (vCJD) was first reported in the United Kingdom in 1996. Since then, the majority of cases have been observed in the United Kingdom where there was a major epidemic of bovine spongiform encephalopathy. France was the second country affected. To address the hypothesis of the involvement of a common strain of agent, we have compared clinical, neuropathological, and biochemical data on vCJD patients from both countries. In France and the United Kingdom, epidemiological and clinical data were obtained from analysis of medical records and direct interview of the family of the patients using the same standardized questionnaire in both countries. When brain material was available, we performed with similar methods a comparative study of brain lesions and PrP(res) glycoform ratios in both vCJD populations. Clinical data, genetic background, neuropathological finding, and biochemical findings in the 185 patients observed in France (n = 23) and the United Kingdom (n = 162) were similar except for age at death. Currently, blood transfusion is a risk factor identified only in the United Kingdom. The close similarity between the cases of vCJD in France and the United Kingdom supports the hypothesis that a common strain of infectious agent is involved in both countries. The 5-year delay in the peak that we observed in France compared with the United Kingdom fits well with the increase in the importation of beef products to France from the United Kingdom between 1985 and 1995.Annals of Neurology 04/2009; 65(3):249-56. · 11.09 Impact Factor -
Article: [Creutzfeldt-Jakob disease in patients before and after 80 years of age].
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ABSTRACT: The frequency of sporadic CJD is maximum in the 70 to 79 years age group and decreases later. Clinical signs of CJD after the age of 80 do not differ from those before 80 excepted for myoclonia and cerebellar symptoms that are less frequently observed. The results of surrogate markers, neuropathological and biochemical examinations are comparable before or after 80 years old. This last result suggests that the causal event of the disease, potentially the conversion of PrP(c) into PrP(sc), is not qualitatively regulated by brain aging.Psychologie & neuropsychiatrie du vieillissement 10/2008; 6(3):219-24. · 0.45 Impact Factor -
Article: In vivo detection of thalamic gliosis: a pathoradiologic demonstration in familial fatal insomnia.
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ABSTRACT: Increasing evidence supports the usefulness of brain magnetic resonance imaging (MRI) for the diagnosis of human prion diseases. From the neuroradiological point of view, fatal familial insomnia is probably the most challenging to diagnose because brain lesions are mostly confined to the thalamus. To determine whether multisequence MRI of the brain can show thalamic alterations and establish pathoradiologic correlations in a patient with familial fatal insomnia. Radioclinical prospective study. We describe a patient with fatal familial insomnia and normal MRI images. Because the MRI study was performed only 4 days before the patient's death, we were able to compare radiological data with the lesions observed at the neuropathologic level. A 55-year-old man with familial fatal insomnia. Magnetic resonance spectroscopy combined with the measurement of apparent diffusion coefficient of water in different brain areas. The neuroradiological study showed, in the thalamus but not in the other brain regions studied, an increase of apparent diffusion coefficient of water and a metabolic pattern indicating gliosis. These alterations closely correlated with neuropathologic data showing an almost pure gliosis that was restricted to the thalami. Considering fatal familial insomnia as a model of thalamic-restricted gliosis, this case demonstrates that multisequences of magnetic resonance can detect prion-induced gliosis in vivo, as confirmed by a neuropathologic examination performed only a few days after radiological examination.Archives of neurology 05/2008; 65(4):545-9. · 6.31 Impact Factor -
Article: Regulating factors of PrP glycosylation in Creutzfeldt-Jakob disease--implications for the dissemination and the diagnosis of human prion strains.
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ABSTRACT: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD.PLoS ONE 02/2008; 3(7):e2786. · 4.09 Impact Factor -
Article: Erratum.
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ABSTRACT: [This corrects the article on p. e2786 in vol. 3, PMID: 18665216.].PLoS ONE 02/2008; 3(9). · 4.09 Impact Factor -
Article: V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation.
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ABSTRACT: A valine to isoleucine mutation at residue 180 was identified in a French patient with Creutzfeldt-Jakob disease (CJD). The mutation is located in the close vicinity of one of the two N-glycosylation sites of the cellular prion protein (PrP(C)). Western blot analysis revealed accumulation in the brain of the pathogenic proteinase K-resistant PrP (PrP(Sc)) isoform with the notable absence of the diglycosylated band. The mutant protein expressed in CHO cells was correctly glycosylated, suggesting that the atypical glycosylation pattern of PrP(Sc) was not due to the mutation at position 180. These results suggest that the diglycosylated form of the mutant PrP(180I) prevents its conversion into the pathogenic mutant form PrP(Sc180I), supporting a central role of N-linked glycan chains in the PrP conversion process.Neuroscience Letters 12/2006; 408(3):165-9. · 2.11 Impact Factor -
Article: Iatrogenic Creutzfeldt-Jakob disease: the waning of an era.
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ABSTRACT: The outbreaks of iatrogenic Creutzfeldt-Jakob disease (CJD) from cadaveric human growth hormone and dura mater are winding down and, like the only other environmentally acquired form of CJD (variant CJD due to infection with the agent of bovine spongiform encephalopathy), iatrogenic disease seems to have reached its high water mark during the 1990s. The total number of cases has reached 405, and the diminishing number of new cases is due to extremely long incubation periods from infections acquired before 1985 (up to 23 years for dura mater and 36 years for growth hormone). Although no cases associated with surgical or other invasive procedures have been identified during the past several decades, the recent discovery of three transfusion-associated variant CJD infections has provoked new concerns about the possibility of further secondary transmissions from operative procedures as well as blood and tissue donations. Therefore, at least in those countries in which variant CJD has occurred, precautionary measures must continue for the indefinite future.Neurology 09/2006; 67(3):389-93. · 8.31 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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Université Paris Descartes
Paris, Ile-de-France, France
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2011
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Institut de veille sanitaire
Charenton-le-Pont, Ile-de-France, France -
Hôpital La Pitié Salpêtrière – Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix"
Paris, Ile-de-France, France
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2008–2011
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Assistance Publique – Hôpitaux de Paris
- Département de Neurologie
Paris, Ile-de-France, France -
INSERM, GIP CYCERON
Caen, Basse-Normandie, France
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2008–2009
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Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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2006
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Instituto de Salud Carlos III
Madrid, Madrid, Spain
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2005–2006
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Harvard University
Boston, MA, USA
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2002
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London School of Hygiene and Tropical Medicine
- Department of Infectious Disease Epidemiology
London, ENG, United Kingdom
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