Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ 1-40 and Aβ 1 -42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10 - 5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ 1 -42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ 1 -42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites

Intensity of human prion disease surveillance predicts observed disease incidence

BACKGROUND: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt-Jakob disease (CJD) and whether such measures correlate with disease incidence. METHOD: From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17 610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28 780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. RESULTS: Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. CONCLUSIONS: Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries