Amphotericin B: a novel class of antiscrapie drugs

Amphotericin B (AmB) has been able to lengthen the incubation period of intracerebrally (ic) scrapie-injected hamsters to 45 d. This article reports a linear relationship between AmB doses and the duration of the incubation periods of ic-treated animals compared with controls, a greater effect of AmB treatment administered 2 w before or the same day of ic scrapie incubation, and the ineffectiveness of mepartricin, an AmB analogue, in prolonging the incubation period of ic scrapie-injected hamsters. The beneficial effect of AmB appears due to a delay in the replication of the scrapie agent in the brain of infected hamsters. Moreover, AmB suppresses scrapie replication in the spleen of treated animals. Three hypotheses may explain these results: (1) AmB alters a hypothetical scrapie receptor, preventing the entry of the agent into central nervous system (CNS) target cells; (2) AmB interferes with mechanisms involved in scrapie replication; (3) AmB prevents the formation and accumulation of a scrapie-specific amyloid protein responsible for the disease. Whatever the mechanism of action, AmB is the only currently available drug to modify experimental CNS scrapie infection, so AmB is proposed as a novel class of antiscrapie drugs.     

Increased brain synthesis of prostaglandin E2 and F2-isoprostane in human and experimental transmissible spongiform encephalopathies

The levels of 2 arachidonic acid metabolites formed either by enzymatic activity of cyclooxygenase, i.e. prostaglandin E2 (PGE2), or by free radical-catalyzed peroxidation, i.e. F2-isoprostane 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha), were measured in the CSF of subjects with sporadic and familial Creutzfeldt-Jakob disease (CJD) and in brain homogenates of scrapie-infected mice. The CSF levels of both metabolites were increased in sporadic CJD (n = 52) and familial CJD (n = 10) patients when compared with a group of patients with noninflammatory disorders. Similarly, PGE2 and 8-epi-PGF2alpha levels were higher in brain homogenates obtained from C57BL/6J mice infected with the ME7 scrapie strain than in brain homogenates from control animals. As PGE2 is 1 of the most abundant prostaglandins released during inflammation and 8-epi-PGF2alpha is a quantitative marker of lipid peroxidation, our results provide in vivo biochemical evidence for the occurrence of inflammation and oxidative stress in human and experimental transmissible spongiform encephalopathies (TSEs), a concept so far based mainly on histopathological and in vitro evidence. Interestingly, in sporadic CJD patients, high CSF levels of PGE2, but not 8-epi-PGF2alpha, correlated with short survival time, suggesting that the inflammatory response correlates with the clinical duration of disease.     

Creutzfeldt-Jakob disease and other human forms of transmissible spongiform encephalopathy in Italy: a mortality study carried out from different data sources

Creutzfeldt-Jakob Disease (CJD) is a rare pathology (about 1 case per million) but it has a great importance for Public Health; the Italian National CJD register has been established in the Istituto Superiore di Sanita (ISS) since 1993, and epidemiological studies on CJD have been carried out as well. This paper reports a mortality study carried out comparing and integrating data from the two available sources: the National CJD Register and the Italian Data Base on Mortality, processed by the ISS Statistics Unit, on the data collected by the Italian Census Bureau (ISTAT). The study allowed to estimate: the underreporting of CJD mortality to both sources, the misclassification of ISTAT data and the integrated mortality rates from CJD in Italy: 1.58 per million persons aged 25 or more, average rate during the period 1993-1999.     

Mortality trend from sporadic Creutzfeldt-Jakob disease (CJD) in Italy, 1993-2000

The objective was to identify any possible cases of variant Creutzfeldt-Jakob disease (CJD) in Italy, and to estimate the trends in mortality from sporadic CJD for 1993-2000. CJD cases were ascertained through direct notification to the Registry; 382 definite or probable sporadic CJD patients, but no cases of variant CJD were identified. The average yearly mortality rate was 1.04 cases per million inhabitants, with an increase in deaths in the 60-69 and > or =70 year age groups. Survival was shorter in male respect to female and in patients with an age at onset > or =65 years. CJD cases were uneven distributed among different regions in the period 1993-1995, but not herein after. The rise in mortality from sporadic CJD in Italy likely reflects increased awareness and better diagnosis during the years. However, continuous notification and postmortem examination of all suspected cases are recommended for optimal surveillance.     

Cerebrospinal fluid real‐time quaking‐induced conversion is a robust and reliable test for sporadic creutzfeldt–jakob disease: An international study

Real‐time quaking‐induced conversion (RT‐QuIC) has been proposed as a sensitive diagnostic test for sporadic Creutzfeldt–Jakob disease; however, before this assay can be introduced into clinical practice, its reliability and reproducibility need to be demonstrated. Two international ring trials were undertaken in which a set of 25 cerebrospinal fluid samples were analyzed by a total of 11 different centers using a range of recombinant prion protein substrates and instrumentation. The results show almost complete concordance between the centers and demonstrate that RT‐QuIC is a suitably reliable and robust technique for clinical practice. Ann Neurol 2016;80:160–165     

Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies

The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10–15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.     

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.