Creutzfeldt-Jakob disease : update

Although rare, human diseases induced by non-conventional transmissible agents (NCTA or prions) are under constant scrutiny and associated with sometimes irrational fears. This article reviews briefly the clinical, biological, neuro-imaging, genetic and neuropathology data on the different variants of Creutzfeldt-Jakob disease. The recent leads on their pathogenesis, the resulting public health challenges, the running of French surveillance networks, and the recent diagnostic and therapeutic hopes are summarised.La rareté des maladies humaines à Agents Transmissibles Non Conventionnels (ATNC ou prions) ne doit pas faire sous-estimer l'intérêt constant et les craintes, parfois irrationnelles, qu'elles entraînent. Les données concernant la clinique, la biologie, l'imagerie, la génétique et la neuropathologie des différentes variantes de la maladie de Creutzfeldt-Jakob, sont brièvement mises en perspective. Les pistes récentes concernant leur mécanisme, les nouveaux défis pour la santé publique qu'apportent ces affections, les principales mesures mises en oeuvre pour les prévenir, les modalités de fonctionnement des réseaux de surveillance français et les espoirs diagnostiques et thérapeutiques récents sont résumés

Automated Analysis of Basal Ganglia Intensity Distribution in Multisequence MRI of the Brain - Application to Creutzfeldt-Jakob Disease

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence MRI of the brain. One common feature of most forms of prion protein infections is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted MR images. We employ T1, T2 and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data is registered to a probabilistic atlas and normalised in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas is employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance to the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (CJD), in agreement with the histological data. The algorithm permitted to classify the intensities of abnormal signals in sporadic CJD patient FLAIR images with a more significant hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Using normalised measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sporadic CJD and new-variant CJD patients, as a first attempt towards an automatic classification tool of human spongiform encephalopathies

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

Dopamine transporter messenger RNA in Parkinson's disease and control substantia nigra neurons

Dopamine transporter messenger RNA (mRNA) expression was assessed by in situ hybridization over individual pigmented neurons from the substantia nigra pars compacta in midbrain sections from 7 parkinsonian and 7 age‐matched, neurologically normal patients. In the normal control brains, high levels of expression of dopamine transporter mRNA were noted over pigmented neurons in the substantia nigra pars compacta; neurons in the adjacent nucleus paranigralis of the ventral tegmental area displayed less hybridization. Nigra compacta neurons surviving in brains of patients with Parkinson's disease displayed only 57% of the dopamine transporter mRNA hybridization intensity displayed by nigral neurons in normal control brains. The disease‐related decrease in the apparent level of dopamine transporter mRNA expression in remaining neurons could reflect neuronal dysfunction. Conceivably, it might also reflect differential vulnerability of those neurons that initially expressed higher levels of this transporter to the insult of parkinsonism

Truncated PrP(c) in mammalian brain: interspecies variation and location in membrane rafts.

A key molecular event in prion diseases is the conversion of cellular prion protein (PrP(c)) into an abnormal misfolded conformer (PrP(sc)). The PrP(c) N-terminal domain plays a central role in PrP(c) functions and in prion propagation. Because mammalian PrP(c) is found as a full-length and N-terminally truncated form, we examined the presence and amount of PrP(c) C-terminal fragment in the brain of different species. We found important variations between primates and rodents. In addition, our data show that the PrP(c) fragment is present in detergent-resistant raft domains, a membrane domain of critical importance for PrP(c) functions and its conversion into PrP(sc)

Intérêt de l'IRM Multimodalitaire dand le Diagnostic des Maladies à Prions

National audienceno abstrac

Early diagnosis of human TSE by multimodality MRI: Spectroscopic detection of thalamic gliosis in a patient with FFI and normal FLAIR and diffusion-weighted imaging

International audienceRecently, several reports underlined the usefulness of brain MRI for the diagnosis ofCreutzfeldt-Jakob dis ease. FLAIR sequence and diffusion-weighted imaging (DWI) areconsidered as high sensitive sequences to detect signal alteration of the cortex and thedeep grey matter. Recent advances in therapeutic approach of patients with prion diseaseshave emphasized the need for earlier diagnostic markers that would authorize the onset oftreatment before massive and irreversible lesions of the brain have occurred.Consequently, we designed a radio -clinical study using a multimodality MRIstandardized procedure that aimed to estimate differential sensitivity of FLAIR, DWI andMR spectroscopy for the diagnosis of human TSE. Here we report a case of familial fatalinsomnia with the D178N-129M mutation. FLAIR and diffusion-weighted sequenceswere normal in the whole brain notably in both thalami. However, spectroscopic studyshowed a striking increase of the peak of myo-inositol (mI) and of the mI/NAA ratio inthe thalamus when compared to the other studied brain regions of the patient (frontalisocortex, lenticular nucleus and cerebellar vermis) and to the thalami of control cases (n= 10). This metabolite pattern is indicating of gliosis. Because the MRI study wasperformed only two days before death, we were able to strictly correlate the spectroscopicdata with the neuropathological lesions (including the severity of astrogliosis andmicroglial activation) observed in the thalamus. From this observation, we can concludethat 1) MR spectroscopy can detect prion-related lesions even when other sequencesappear normal 2) spectroscopic metabolite pattern well correlates with theneuropathological one