Lack of effect of pravastatin on cerebral blood flow or parenchymal volume loss in elderly at risk for vascular disease

<p><b>Background and Purpose:</b> Ageing is associated with a decline in cerebral blood flow. Animal studies have shown that cholesterol-lowering therapy with statins might preserve cerebral blood flow (CBF). We examined the effect of 40 mg pravastatin on the decline in CBF and brain volume in a subset of elderly subjects participating in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial.</p> <p><b>Methods:</b> Randomization was not stratified according to whether or not subjects participated in the MRI substudy. In 391 men (n=226) and women (n=165) aged 70 to 82 years (mean±SD, 75±3.2), we measured total CBF (in mL/min) at baseline and after a mean±SD follow-up of 33±1.4 months with a gradient-echo phase-contrast MRI technique. Total CBF was defined as the summed flows in both internal carotid and vertebral arteries. Parenchymal volume (whole brain) was segmented with the use of in-house–developed semiautomatic software.</p> <p><b>Results:</b> Total CBF significantly declined in the placebo-allocated group, from 521±83 to 504±92 mL/min (P=0.0036) and in the pravastatin-allocated group from 520±94 to 506±92 mL/min (P=0.018). This decline was not significantly different between treatment groups (P=0.56). There was also a significant reduction in brain volume over time (P<0.001), which was not different between the treatment groups (P=0.47). When expressed per unit of parenchymal volume, the decline in CBF over time was no longer statistically significant.</p> <p><b>Conclusions:</b> Elderly people at risk for cerebral vascular disease had a significant decline in CBF with increasing age that was explained by a concomitant reduction in brain volume. Treatment with 40 mg pravastatin daily had no beneficial effect on total CBF.</p&gt

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

<p><b>Background:</b> Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.</p> <p><b>Methods and Findings:</b> In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).</p> <p><b>Conclusions:</b> In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.</p&gt

Genetic risk factors for amyotrophic lateral sclerosis : focusing on copy number variation

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, for which there is no adequate therapy. The majority of ALS patients are sporadic (i.e. they have no relatives with the disease). Sporadic ALS is considered to be a complex disease that is the result of an interplay of genetic and environmental risk factors, which act together to cause disease. Identifying the implicated genes will lead to a better understanding of the pathogenesis and will facilitate the development of novel therapies. This thesis describes several genetic studies that were aimed to identify genetic risk factors that are associated with ALS susceptibility, including genome-wide association studies (GWAS) to identify associated single-nucleotide polymorphisms (SNPs) and candidate gene studies, investigating the role of suspected genes. The focus of this thesis was the role of copy-number variation as a source of increased risk for ALS. We studied this in a genome-wide manner performed association analyses on rare and common CNVs. We identified several novel genetic loci that confer an increased risk for ALS, including a locus on chromosome 9p and UNC13A. Additionally, we found suggestive evidence for an association of NIPA1 deletions with an increased risk for ALS. We then examined this gene in more detail in a follow-up study. This study showed that expansions of a polyalanine repeat in this gene are associated with a higher risk of ALS and, in addition, with a shorter survival and with a lower age at onset of the disease. In another candidate gene study, we examined the role of SMN1, the causative gene for spinal muscular atrophy, a congenital motor neuron disease with some familiarities with ALS. Previous studies have shown that CNVs in this gene are associated with ALS, but results were contradictory. We found firm evidence for an association of SMN1 duplications and ALS susceptibility. We found no association with SMN1 deletions, which has been suggested previously. In conclusion, this thesis describes several novel risk loci for ALS, together with firm evidence for the implication of the previously suspected gene SMN1 in ALS pathogenesis. These findings are a starting point for functional studies investigating the underlying pathogenic pathways and will hopefully lead to better treatment strategies for this devastating diseas

SMN1 gene duplications are associated with sporadic ALS

OBJECTIVE: To investigate the role of SMN1 and SMN2 copy number variation and point mutations in amyotrophic lateral sclerosis (ALS) pathogenesis in a large population. METHODS: We conducted a genetic association study including 847 patients with ALS and 984 controls. We used multiplexed ligation-dependent probe amplification (MLPA) assays to determine SMN1 and SMN2 copy numbers and examined effects on disease susceptibility and disease course. Furthermore, we sequenced SMN genes to determine if SMN mutations were more prevalent in patients with ALS. A meta-analysis was performed with results from previous studies. RESULTS: SMN1 duplications were associated with ALS susceptibility (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.34-3.20, p = 0.001). A meta-analysis with previous data including 3,469 individuals showed a similar effect: OR 1.85, 95% CI 1.18-2.90, p = 0.008). SMN1 deletions and SMN2 copy number status were not associated with ALS. SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. We found no enrichment of SMN point mutations in patients with ALS. CONCLUSIONS: Our data provide firm evidence for a role of common SMN1 duplications in ALS, and raise new questions regarding the disease mechanisms involved

NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis

Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of NIPA1 have been associated with a higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role of genetic variation in NIPA1 in ALS susceptibility and disease course is, however, not known. We sequenced the entire coding sequence of NIPA1 and genotyped a polyalanine repeat located in the first exon of NIPA1. A total of 2292 ALS patients and 2777 controls from three independent European populations were included. We identified two sequence variants that have a potentially damaging effect on NIPA1 protein function. Both variants were identified in ALS patients; no damaging variants were found in controls. Secondly, we found a significant effect of 'long' polyalanine repeat alleles on disease susceptibility: odds ratio = 1.71, P = 1.6 x 10(-4). Our analyses also revealed a significant effect of 'long' alleles on patient survival [hazard ratio (HR) = 1.60, P = 4.2 x 10(-4)] and on the age at onset of symptoms (HR = 1.37, P = 4.6 x 10(-3)). In patients carrying 'long' alleles, median survival was 3 months shorter than patients with 'normal' genotypes and onset of symptoms occurred 3.6 years earlier. Our data show that NIPA1 polyalanine repeat expansions are a common risk factor for ALS and modulate disease course

ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis

Forensic Dental Identification: Towards A Simplified Computerised System

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group

A large genome scan for rare CNVs in amyotrophic lateral sclerosis.

Contains fulltext : 89076.pdf (publisher's version ) (Closed access)Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 x 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 x 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 x 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 x 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

Contains fulltext : 95644.pdf (publisher's version ) (Closed access)OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973.1 december 201110 p