Human prion diseases are characterized by the conversion of the normal prion protein (PrP C ) into a pathogenic isomer (PrP Sc ). Distinct PrP Sc conformers are associated with different subtypes of prion diseases. PrP C binds copper and has antioxidation activity. Changes in metal-ion occupancy can lead to signi®cant decline of the antioxidation activity and changes in conformation of the protein. We studied the trace element status of brains from patients with sporadic Creutzfeldt±Jakob disease (sCJD). We found a decrease of up to 50% of copper and an increase in manganese of approximately 10-fold in the brain tissues from sCJD subjects. We have also studied the metal occupancy of PrP in sCJD patients. We observed striking elevation of manganese and, to a lesser extent, of zinc accompanied by signi®cant reduction of copper bound to puri®ed PrP in all sCJD variants, determined by the PrP genotype and PrP Sc type, combined.Both zinc and manganese were undetectable in PrP C preparations from controls. Copper and manganese changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrP Sc type-1. Anti-oxidation activity of puri®ed PrP was dramatically reduced by up to 85% in the sCJD variants, and correlated with increased in oxidative stress markers in sCJD brains. These results suggest that altered metal-ion occupancy of PrP plays a pivotal role in the pathogenesis of prion diseases. Since the metal changes differed in each sCJD variants, they may contribute to the diversity of PrP Sc and disease phenotype in sCJD. Finally, this study also presented two potential approaches in the diagnosis of CJD; the signi®cant increase in brain manganese makes it potentially detectable by MRI, and the binding of manganese by PrP in sCJD might represent a novel diagnostic marker.

The Creutzfeldt-Jakob disease clinical subtype should be considered when interpreting results of the 14-3-3 test.

Epidemiological data show a higher prevalence of late-onset Alzheimer's disease (AD) in women. The estrogenic deficiency in the post-menopausal period is suspected to be the cause of the gender-related risk of the disease, but studies on the estrogenic therapy and occurrence of AD were not consistent and sometimes contradicting. The aim of this study is to investigate whether a higher exposure to endogenous estrogens is associated with lower risk of dementia or not. Two hundred and four AD patients and 201 control women were considered. By interviews, we evaluated different variables, indirectly correlated to estrogenic natural exposure, as well as educational level and head trauma. These data were correlated in the AD group with the disease progression, as well as with the age at onset. Unexpectedly, we found a significant higher number of pregnancies in the AD than in the control group. Within the AD cases, the number of lifetime pregnancies is related to an earlier onset of the disease. As previously reported, we confirmed that the educational level is a protective factor and that major head trauma represents a risk factor in developing AD. The higher number of pregnancies and a less frequency of nulliparous women, indirectly relate the AD group to a higher estro-progestinic exposure. These findings suggest that it is the increase of progesterone or estrogens level--and not the estrogens decrease, as previously indicated by other authors--that could play a role in the Alzheimer's pathology.

The elevation of Abeta42 plasma levels in women with MCI may represent a biologic explanation for the sex-dependent increased incidence of late-onset AD in women identified by epidemiologic studies.

The phenotype of human sporadic prion diseases is affected by patient genotype at codon 129 of the prion protein (PrP) gene, the site of a common methionine/ valine polymorphism, and by the type of the scrapie PrP (PrP Sc ), which likely reflects the prion strain. However, two distinct disease phenotypes, identified as sporadic Creutzfeldt-Jakob disease (M/M2 sCJD) and sporadic fatal insomnia (sFI), share methionine homozygosity at codon 129 and PrP Sc type 2. One-dimensional gel electrophoresis and immunoblotting reveal no difference between the M/M2 sCJD and sFI species of PrP Sc in gel mobility and glycoform ratio. In contrast, the two-dimensional immunoblot demonstrates that in M/M2 sCJD the full-length PrP Sc form is overrepresented and carries glycans that are different from those present in the PrP Sc of sFI. Because the altered glycans are detectable only in the PrP Sc and not in the normal or cellular PrP (PrP C ), they are likely to result from preferential conversion to PrP Sc of rare PrP C glycoforms. This is the first evidence that a qualitative difference in glycans contributes to prion diversity.