Sporadic human prion diseases: molecular insights and diagnosis

Human prion diseases can be sporadic, inherited, or acquired by infection. Distinct clinical and pathological characteristics separate sporadic diseases into three phenotypes: Creutzfeldt-Jakob disease (CJD), fatal insomnia, and variably protease-sensitive prionopathy. CJD accounts for more than 90% of all cases of sporadic prion disease; it is commonly categorised into five subtypes that can be distinguished according to leading clinical signs, histological lesions, and molecular traits of the pathogenic prion protein. Three subtypes affect prominently cognitive functions whereas the other two impair cerebellar motor activities. An accurate and timely diagnosis depends on careful clinical examination and early performance and interpretation of diagnostic tests, including electroencephalography, quantitative assessment of the surrogate markers 14-3-3, tau, and of the prion protein in the CSF, and neuroimaging. The reliability of CSF tests is improved when these tests are interpreted alongside neuroimaging data

A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report

<p>Abstract</p> <p>Background</p> <p>Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrP^Sc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion.</p> <p>Case presentation</p> <p>We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrP^Scshowed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrP^Scwas estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine.</p> <p>Conclusions</p> <p>A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were compatible with sporadic Creutzfeldt-Jakob disease, the molecular subtype with the abnormal prion protein isoforms showing enhanced protease sensitivity was reminiscent of the "protease-sensitive prionopathy". It remains to be established whether the differences found between the latter and this case are due to the polymorphism at codon 129. Different degrees of proteinase K susceptibility were easily determined with the chemical polymer detection system which could help to detect proteinase-susceptible pathologic prion protein in diseases other than the classical ones.</p

Effect of electronic interactions on the persistent current in one-dimensional disordered rings

The persistent current is here studied in one-dimensional disordered rings that contain interacting electrons. We used the density matrix renormalization group algorithms in order to compute the stiffness, a measure that gives the magnitude of the persistent currents as a function of the boundary conditions for different sets of both interaction and disorder characteristics. In contrast to its non-interacting value, an increase in the stiffness parameter was observed for systems at and off half-filling for weak interactions and non-zero disorders. Within the strong interaction limit, the decrease in stiffness depends on the filling and an analytical approach is developed to recover the observed behaviors. This is required in order to understand its mechanisms. Finally, the study of the localization length confirms the enhancement of the persistent current for moderate interactions when disorders are present at half-filling. Our results reveal two different regimes, one for weak and one for strong interactions at and off half-filling.Comment: 16 pages, 21 figures; minor changes (blanks missing, sentences starting with a mathematical symbol

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study

BACKGROUND: Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. METHODS: A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. RESULTS: Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. CONCLUSION: The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies

Artificial intelligence and cognitive psychology: How to solve mathematical problems

That a computer might autonomously solve mathematical puzzles described in natural language text and diagrams is still an open challenge in the field of Artificial Intelligence. Conversely, primary school children, aged 9/10 years, can solve them without any advanced computational skills, or a huge quantity of data. In this paper, we have tried to apply the AI approach to mathematical puzzles with models and terms from psychological cognitive studies, such as the Cattell-Horn-Carroll theory of cognitive abilities. We considered 147 ma thematical puzzles, used by Bocconi University for mathematical games among students in the 4th and 5th years of primary school, and we found that they can be viewed, in most cases, as Constraint-Based problems. In order to study the problem-solving process used by school children, some mathematical puzzles with a specific number of variables, domains and constraints, were created ad hoc for the study and were administered to 37 students in the 4th year of primary school. Results showed that problems with the same number of variables as domains were more easily solved than problems with a different number of variables and domains. These results were discussed from the viewpoints of Artificial Intelligence and of Cognitive Psychology in order to provide new insights into the definition of fully-fledged, intelligent agents able to solve mathematical puzzles