Midlife vascular risk factors and risk of incident dementia:Longitudinal cohort and Mendelian randomization analyses in the UK Biobank

Introduction Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Methods Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. Results Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI;0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). Discussion These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk

Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.</p> <p>Methods</p> <p>CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals.</p> <p>Results</p> <p>The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: <it>CYP3A4*1B</it>, 4.8 % (95% C.I. 2.6–7.0), 3.7 % (0.8–6.6) 4.3% (2.0–6.6) and 4.3% (2.1–6.5); <it>CYP3A5*3</it>, 91.8 % (93.0–97.4), 95.7% (92.6–98.8), 91.7% (88.6–94.8) and 90.8% (87.7–93.9). The association between <it>CYP3A4*1B </it>and <it>CYP3A5*3 </it>variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage.</p> <p>Conclusion</p> <p>Common polymorphisms on <it>CYP3A4 </it>and <it>CYP3A5 </it>genes do not modify the risk of developing digestive cancers in Western Europe.</p

Optimality of Human Contour Integration

For processing and segmenting visual scenes, the brain is required to combine a multitude of features and sensory channels. It is neither known if these complex tasks involve optimal integration of information, nor according to which objectives computations might be performed. Here, we investigate if optimal inference can explain contour integration in human subjects. We performed experiments where observers detected contours of curvilinearly aligned edge configurations embedded into randomly oriented distractors. The key feature of our framework is to use a generative process for creating the contours, for which it is possible to derive a class of ideal detection models. This allowed us to compare human detection for contours with different statistical properties to the corresponding ideal detection models for the same stimuli. We then subjected the detection models to realistic constraints and required them to reproduce human decisions for every stimulus as well as possible. By independently varying the four model parameters, we identify a single detection model which quantitatively captures all correlations of human decision behaviour for more than 2000 stimuli from 42 contour ensembles with greatly varying statistical properties. This model reveals specific interactions between edges closely matching independent findings from physiology and psychophysics. These interactions imply a statistics of contours for which edge stimuli are indeed optimally integrated by the visual system, with the objective of inferring the presence of contours in cluttered scenes. The recurrent algorithm of our model makes testable predictions about the temporal dynamics of neuronal populations engaged in contour integration, and it suggests a strong directionality of the underlying functional anatomy

Genetic factors associated with higher segregation of brain networks and cognition mediated by cardiovascular health: GWAS and Mendelian randomization analyses in the UK Biobank and Rotterdam Study

BACKGROUND: Higher segregation of functional networks in the brain has been associated with better cognitive abilities in aging (Chan, PNAS, 2014) and higher cognitive resilience against Alzheimer's disease (Ewers, Brain, in press). Here, we elucidated for the first time the genetic and environmental (i.e. cardiovascular) determinants of system segregation (SyS) in two large population-based cohorts. METHOD: We included 16,635 UK Biobank (UKB) participants (45-81y, discovery-sample) and 2,414 Rotterdam-Study participants (52-90y, replication-sample). Resting-state-fMRI SyS was computed as the ratio of between-network to within-network connectivity, where networks (N=55) were defined by independent component analysis. Genome-wide association study (GWAS) of SyS was performed in UKB, controlling for twenty principal components, age, sex, genotype-array and assessment center. For out-of-sample prediction, a polygenic risk score (PRS) of SyS was tested in Rotterdam-Study participants. In both cohorts, we determined the effect of cardiovascular health (adherence to Life's simple 7) on SyS. We estimated age-dependent and -independent effects of SyS on cognition (multi-domain factor score) in both cohorts and, in a subsample of 2,113 UKB participants, on cognitive decline over time. To explore causal effects, Mendelian Randomization (MR) analyses were performed. RESULT: GWAS of SyS in UKB yielded 659 genome-wide significant single-nucleotide polymorphisms (SNPs; P<5e-08, h2 =0.144, Fig. 1). Nine independent risk loci were detected implicated 59 genes. Lead SNPs with highest likelihood to have deleterious consequences were located near the INPP5A and PLCE1 genes. In Rotterdam-Study participants, PRS explained 1.4% of variance in SyS. We found overall better cardiovascular health to be associated with higher SyS, while higher blood pressure alone was a significant predictor of lower SyS (UKB:βstd =-0.059(0.007), P<0.001; Rotterdam-Study:βstd (SE)=-0.060(0.020), P=0.003; Fig. 2). MR analysis in UKB confirmed that genetically elevated levels of blood pressure were associated with lower SyS (β(CI95%)=-0.003(-0.002,-0.001), P=0.002). We found higher SyS to be associated with better cognition across all ages in UKB (βstd (SE)=-0.031(0.012), P=0.005) and in older, but not younger Rotterdam-Study participants (βstd (SE)=0.038(0.016), P=0.0026, Fig. 3). In MR analysis, genetically elevated levels of SyS were associated with better cognition (β(CI95)=0.104(0.03-0.18), P=0.008). CONCLUSION: The current study highlights the importance of cardiovascular health for maintaining segregated brain systems what in turn was shown to benefit cognitive functions during aging

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the central nervous system caused by the polyomavirus JC (JCV) that can occur in multiple sclerosis (MS) patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not the least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether TSPO positron emission tomography (PET) imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from MS lesions. For this monocenter pilot study we followed 8 patients with natalizumab-associated PML with PET imaging using the TSPO radioligand [18F]GE-180 combined with frequent 3 T MRI imaging. In addition we compared TSPO PET signals in PML lesions with the signal pattern of MS lesions from 17 independent MS patients. We evaluated the standardized uptake value ratio (SUVR) as well as the morphometry of the TSPO uptake for putative PML and MS lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/MS). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogenous distribution in putative MS lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3-dimensional diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated more than 96% of PML and MS lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active MS lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent MS activity from PML progression