Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrP^{Sc}). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrP^{Sc} seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation

Glycoform-selective prion formation in sporadic and familial forms of prion disease

The four glycoforms of the cellular prion protein (PrP(C)) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrP(Sc)) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrP(Sc) in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJD(V180I)) or from Thr to Ala at residue 183 (fCJD(T183A)). Here we report that fCJD(V180I), but not fCJD(T183A), exhibits a proteinase K (PK)-resistant PrP (PrP(res)) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrP(res) species in both fCJD(V180I) and VPSPr is likewise attributable to the absence of PrP(res) glycosylated at the first N-linked glycosylation site at residue 181, as in fCJD(T183A). In contrast to fCJD(T183A), both VPSPr and fCJD(V180I) exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrP(V180I) with a typical glycoform profile from cultured cells generates detectable PrP(res) that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJD(V180I) share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrP(C) to PrP(Sc) is inhibited, probably by a dominant-negative effect, or by other co-factors

Potential human transmission of amyloid β pathology: surveillance and risks

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. INTERPRETATION: 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

A genome wide association study links glutamate receptor pathway to Sporadic Creutzfeldt-Jakob disease risk.

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 control

De certaines différences entre le français et l'anglais

Kayne Richard S., Haïk Isabelle. De certaines différences entre le français et l'anglais. In: Langages, 14ᵉ année, n°60, 1980. Syntaxe générative et syntaxe comparée, sous la direction de Alain Rouveret. pp. 47-64

La maladie de Parkinson est-elle une maladie à prion ?

National audienceThe accumulation of a specific protein in aggregated form is a common phenomenon in human neurodegenerative diseases. In Parkinson's disease, this protein is α-synuclein which is a neuronal protein of 143 amino acids. With a monomeric conformation in solution, it also has a natural capacity to aggregate into amyloid structures (dimers, oligomers, fibrils and Lewy bodies or neurites). It therefore fulfils the characteristics of a prion protein (different conformations, seeding and spreading). In vitro and in vivo experimental evidence in transgenic and wild animals indicates a prion-like propagation of Parkinson's disease. The sequential and predictive distribution of α-synuclein demonstrated by Braak et al. and its correlation with non-motor signs are consistent with the prion-like progression. Although the triggering factor causing the misfolding and aggregation of the target protein is unknown, Parkinson's disease is a highly relevant model for the study of these mechanisms and also to test specific treatments targeting the assemblies of α-synuclein and propagation from pre-motor phase of the disease. Despite this prion-like progression, there is currently no argument indicating a risk of human transmission of Parkinson's disease.L'accumulation d'une protéine spécifique sous forme agrégée est un phénomène commun aux maladies neurodégénératives humaines. Dans la maladie de Parkinson, cette protéine est l'α-synucléine qui est une protéine neuronale de 143 acides aminés. De conformation monomérique en solution, elle possède également une capacité naturelle à s'agréger en structures amyloïdes (dimères, oligomères, fibrilles puis corps ou neurites de Lewy). Elle détient donc les caractéristiques d'une protéine prion (différentes conformations, initiation et dissémination d'un processus transconformationnel). De nombreux arguments expérimentaux in vitro et in vivo sur des animaux transgéniques ou sauvages sont en faveur d'une progression prion-like de la maladie de Parkinson. La diffusion séquentielle et prédictive de l'α-synucléine mise en évidence par Braak et al. et sa corrélation avec les signes non moteurs vont tout à fait dans le sens de cette progression prion-like. Même si le facteur déclenchant à l'origine du mauvais repliement et de l'agrégation de la protéine cible reste inconnu, la maladie de Parkinson est un modèle très pertinent pour l'étude de ces mécanismes et aussi pour tester des traitements spécifiques ciblant les assemblages d'α-synucléine et leur propagation dès la phase pré-motrice de la maladie. Malgré cette progression prion-like, il n'existe actuellement aucun argument indiquant un risque de transmission interhumaine de la maladie de Parkinson

Intérêt des données de remboursement de l’assurance-maladie pour l’étude des disparités territoriales de la prévalence de l’asthme : une étude en Provence-Alpes-Côte d’Azur

International audienceBackground.-Data on asthma prevalence at a small-area level would be useful to set up and monitor French local public health policies. This study, based on drug reimbursement databases in southeastern France, aimed to (1) compare asthma-like disorders prevalence estimated by using three different indicators; (2) study sociodemographic characteristics associated with these indicators; (3) verify whether these indicators are equivalent to study geographical disparities of the asthma-like disorders prevalence at a small-area level. Methods.-The study was conducted among the beneficiaries of the National Health Insurance Fund aged 18-44 years residing in southeastern France in 2010 (n = 1,371,816). Using data on asthma drugs reimbursements (therapeutic class R03), we built three indicators to assess asthma-like disorders prevalence: at least 1, 2 or 3 purchase(s) in 2010. We analyzed sociodemographic characteristics associated with these indicators, and their geographical disparities at a small-area level using multilevel logistic regression models. Results.-The crude asthma-like disorders prevalence varied between 2.6% and 8.4% depending on the indicator. It increased with age, was higher for women than for men, and among low-income people for all three indicators. We measured significant geographical disparities. Areas with high prevalence rates were the same regardless of the indicator. Conclusion.-The indicators built in this study can be useful to identify high prevalence areas. They could contribute to launch discussion on environmental health issues at the local level