Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites

Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ?4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aβ???? levels, suggesting a role for the CR1 protein in Aβ metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.     

Complement receptor 1 coding variant p.Ser1610Thr in Alzheimer's disease and related endophenotypes

We previously described an intragenic functional copy number variation (CNV) in complement receptor 1 (CR1) that is associated with Alzheimer disease (AD) risk. A recent study, however, reported a rare CR1 coding variant p.Ser1610Thr (rs4844609) associated with AD susceptibility, explaining the effect of genome wide association (GWA) top single nucleotide polymorphism rs6656401. We assessed the role of the Ser1610Thr variant in AD pathogenesis and the effect on AD-related endophenotypes in a Flanders-Belgian cohort. We evaluated whether this rare variant rather than the CR1 CNV could explain the association of CR1 in our population. The Ser1610Thr variant was not associated with AD, memory impairment, total tau, amyloid β_1–42 or tau phosphorylated at threonine 181 levels. It did not explain (part of) the association of genome wide association top single-nucleotide polymorphisms rs3818361/rs6656401, nor of the CR1 CNV, with AD in our cohort, whereas the CR1 CNV and rs3818361/rs6656401 represented the same association signal. These findings question a role for the Ser1610Thr variant in AD risk and related endophenotypes, and reaffirm our previous observation that the CR1 CNV could be the true functional risk factor explaining the association between CR1 and AD.     

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment

C9orf72 G₄C₂ repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G₄C₂ pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G₄C₂ repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G₄C₂ repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.     

Pros and cons of an illicit drug users' registration system by means of judicial data in Flanders (Belgium)

The main objective of this study was to evaluate the advantages and shortcomings of a new kind of registration of illicit drug users in Flanders, Belgium. Data about the profile of drug users who have come into contact with the law were collected by examining the records kept by the District Courts. On the one hand, published data on illicit drug users in Flanders are scarce. On the other hand, a lot of unused judicial information is available. All District Courts in Flanders (n=13) and Brussels (n=1) participated in the study. The data show that a simple registration of verbalised drug users with a short questionnaire can provide useful information for prevention campaigns and police investigation and shows the importance of prevention programmes starting at school. Notwithstanding some shortcomings, the illicit drug users' registration system by means of judicial data in Flanders forms a solid basis upon which an integrated registration of illicit drug use can be built.     

The contribution of preschool playground factors in explaining children's physical activity during recess

Background  

Low levels of physical activity are characteristic in preschoolers. To effectively promote physical activity, it is necessary to understand factors that influence young children's physical activity. The present study aimed to investigate how physical activity levels are influenced by environmental factors during recess in preschool.     

Structure-activity study of the ORL1 antagonist Ac-Arg-D-Cha-Qaa-D-Arg-D-p-ClPhe-NH2

The structure-activity requirements of the ORL1 antagonist Ac-Arg-D-Cha-Qaa-D-Arg-D-p-ClPhe-NH(2) 4 were investigated by varying the position, structure, and charge of the Arg residues. Attempts to abridge the peptide by removal of the Arg, D-Cha, and D-p-ClPhe residues abolished affinity for the ORL1 receptor, whereas deletion of the acetamido N-terminus maintained receptor affinity and selectivity. This series of analogues has provided an improved potent and selective ORL1 receptor antagonist, Ac-Cit-D-Cha-Qaa-D-Arg-D-p-ClPhe-NH(2).     

Within- and between-day variability of objectively measured physical activity in preschoolers

In this study, physical activity (PA) was objectively measured in 213 Belgian preschoolers (M(age) = 4.98, SD = .88 years) over 4 consecutive days including two weekend days. Within-day variability in PA showed a typical activity pattern during weekdays and weekend days. Weekdays clearly reflected a preschool attending day with more peaks and troughs than weekend days and after-school hours were characterized by a decrease in activity. Between-day variability in PA was identified in preschool girls above the age of four, suggesting that the lack of a structured preschool environment is already related with a decrease in PA in this sex-specific age group. The results of this study are informative for the development of future PA interventions and indicate that both the preschool and the home environment should be targeted in the promotion of preschoolers' PA.     

Epidemiologic survey of functional conditions of the masticatory system in Belgian children aged 3–6 years

In this epidemiologic survey 510 children aged 3-6 yr were investigated. Several occlusal and functional parameters were measured: the maximal interincisal distance, the frequency of lateral and frontal crossbite, open bite, the number of tooth contacts on lateral excursions of 3 mm, the wear facets, deviations in opening, pain in muscles and in the TM-joints, TMJ sounds, parafunctional habits. The interincisal distance varied between 25 and 55 mm. This distance increased with age. Only five children had a hypermobility of the mandible (opening more than 55 mm) and 11 a restricted opening movement (less than 30 mm). 7.2% showed a lateral crossbite on the right, and 8.9% on the left, side. The percentage of an open bite decreased with age from 66.7% in the 3-yr-olds to 20.0% in the 6-yr-olds. 33% of the children had only one contact on the working side. As reported by the parents 7.7% had regularly bruxism but 21.8% showed wear facets on the molars and 40.7% on the front teeth. Only in three girls were the TMJ painful to palpation. Dysfunction only occurred in 3.5% of the sample.