Search

Background and purpose A strong association between time to generalization ( TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis ( ALS). Thus, TTG may be used as an early to intermediate end-point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS. Methods This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5-year follow-up period. Results In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval ( CI) 0.53-0.70; P < 0.001]. In a time-to-event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio ( HR) 0.98, 95% CI 0.97-0.99] and multivariate Cox analyses ( HR 0.98, 95% CI 0.96-0.99). TTG predicted death/tracheostomy at 4 years ( C-statistic 0.58; 95% CI 0.53-0.63) and at 5 years ( C-statistic 0.58; 95% CI 0.53-0.62). Conclusions Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end-point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The human apoE gene ( APOE, GenBank accession AF261279) shows a common polymorphism, with the three ℇ2, ℇ3 and ℇ4 alleles resulting from the haplotypes of two C→T SNPs. However, whereas the three common T-T, T-C and C-C haplotypes corresponding to the ℇ2, ℇ3 and ℇ4 alleles are well known, the last C-T haplotype (GenBank accession AY077451), encoding a fourth apoE allele, has rarely been reported. We detected this fourth allele in a Caucasian patient with motor neuron disease (MND). According to the literature we refer to this allele as ℇ3r. Although several explanations may be proposed for its formation, the existence of this fourth allele is consistent with the evolutionary hypothesis generally accepted for the apoE alleles. The rarity and physiological role of ℇ3r remains to be explained, and requires further investigation. [ABSTRACT FROM AUTHOR]

Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of β-amyloid (Aβ) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating Aβ formation from amyloid precursor protein (APP). This article briefly reviews the profile of γ-secretase inhibitors, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, and that have reached the clinic., Discussion: Several classes of potent γ-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain Aβ concentrations and, in some cases, reduce Aβ plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced Aβ levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma Aβ levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated Aβ in the CSF after single oral doses., Conclusions: Unfortunately, γ-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising γ-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD., (© 2010 Blackwell Publishing Ltd.)