Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo

Modeling of craton stability using a viscoelastic rheology

Archean cratons belong to the most remarkable features of our planet since they represent continental crust that has avoided reworking for several billions of years. Even more, it has become evident from both geophysical and petrological studies that cratons exhibit deep lithospheric keels which equally remained stable ever since the formation of the cratons in the Archean. Dating of inclusions in diamonds from kimberlite pipes gives Archean ages, suggesting that the Archean lithosphere must have been cold soon after its formation in the Archean (in order to allow for the existence of diamonds) and must have stayed in that state ever since. Yet, although strong evidence for the thermal stability of Archean cratonic lithosphere for billions of years is provided by diamond dating, the long-term thermal stability of cratonic keels was questioned on the basis of numerical modeling results. We devised a viscoelastic mantle convection model for exploring cratonic stability in the stagnant lid regime. Our modeling results indicate that within the limitations of the stagnant lid approach, the application of a sufficiently high temperature-dependent viscosity ratio can provide for thermal craton stability for billions of years. The comparison between simulations with viscous and viscoelastic rheology indicates no significant influence of elasticity on craton stability. Yet, a viscoelastic rheology provides a physical transition from viscously to elastically dominated regimes within the keel, thus rendering introduction of arbitrary viscosity cutoffs, as employed in viscous models, unnecessary

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction:Plasma biomarkers for Alzheimer’s disease (AD) diagnosis/stratification are a“Holy Grail” of AD research and intensively sought; however, there are no well-established plasmamarkers.Methods:A hypothesis-led plasma biomarker search was conducted in the context of internationalmulticenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL;259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results:Ten analytes showed significant intergroup differences. Logistic regression identified five(FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD andCTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI(AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Twoanalytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion:Plasma markers of inflammation and complement dysregulation support diagnosis andoutcome prediction in AD and MCI. Further replication is needed before clinical translatio

Spatial distribution of malignant tissue in gliomas:correlations of ¹¹C-L-methionine positron emission tomography and perfusion- and diffusion-weighted magnetic resonance imaging

Background The prognosis of glioma patients is contingent on precise target selection for stereotactic biopsies and the extent of tumor resection. 11C-L-methionine (MET) positron emission tomography (PET) demonstrates tumor heterogeneity and invasion with high diagnostic accuracy. Purpose To compare the spatial tumor distribution delineated by MET PET with that by perfusion- and diffusion-weighted magnetic resonance imaging (MRI), in order to understand the diagnostic value of these MRI methods, when PET is not available. Material and Methods Presurgical MET PET and MRI, including perfusion- and diffusion-weighted MRI, were acquired in 13 patients (7 high-grade gliomas, 6 low-grade gliomas). A quantitative volume of interest analysis was performed to compare the modalities objectively, supplemented by a qualitative evaluation that assessed the clinical applicability. Results The inaccuracy of conventional MRI was confirmed (area under the curve for predicting voxels with high MET uptake = 0.657), whereas cerebral blood volume (CBV) maps calculated from perfusion data improved accuracy (area under the curve = 0.760). We considered CBV maps diagnostically comparable to MET PET in 5/7 cases of high-grade gliomas, but insufficient in all cases of low-grade gliomas when evaluated subjectively. Cerebral blood flow and apparent diffusion coefficient maps did not contribute to further accuracy. Conclusion Adding perfusion-weighted MRI to the presurgical protocol can increase the diagnostic accuracy of conventional MRI and is a simple and well-established method compared to MET PET. However, the definition of low-grade gliomas with subtle or no alterations on cerebral blood volume maps remains a diagnostic challenge for stand-alone MRI. </jats:sec

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Tricuspid Annulus Disjunction: Novel Findings by Cardiac Magnetic Resonance in Patients With Mitral Annulus Disjunction

Objectives This study aimed to assess whether patients with MAD also have disjunction of the tricuspid annulus. Background Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral annulus. Whether the disjunction extends to the right side of the heart is not known. Methods In a cohort of patients with MAD, we assessed the presence of tricuspid annulus disjunction (TAD) with the use of cardiac magnetic resonance. We explored the associations between TAD and MAD characteristics and the relationship to ventricular arrhythmias (nonsustained/sustained ventricular tachycardias and aborted cardiac arrest). Results We included 84 patients (mean age: 48 ± 16 years; 63% female). We observed TAD in 42 (50%). Patients with TAD were older (age 52 ± 16 years vs. 43 ± 15 years; p = 0.02), had greater circumferential extent of MAD (164 ± 57° vs. 115 ± 58°; p = 0.002), greater maximum longitudinal MAD distance (9.4 ± 2.9 mm vs. 6.2 ± 2.8 mm; p < 0.001), and more frequent mitral valve prolapse (n = 39 [92%] vs. n = 24 [57%]; p < 0.001). Ventricular arrhythmias had occurred in 34 patients (41%), who were younger (age 39 ± 14 years vs. 54 ± 14 years; p < 0.001) and had lower prevalence of TAD (n = 22 [29%] vs. n = 12 [52%]; p = 0.03). TAD was not associated with ventricular arrhythmias when adjusted for age (odds ratio adjusted for age: 0.54; 95% confidence interval: 0.20 to 1.45; p = 0.22). Conclusions We report for the first time the existence of right-sided annulus disjunction as a common finding in patients with MAD. TAD was associated with more severe left-sided annulus disjunction and mitral valve prolapse, but not with ventricular arrhythmias

Vigorous exercise in patients with hypertrophic cardiomyopathy

Background: We aimed to investigate if history of vigorous exercise was associated with changes in left ventricular morphology, left ventricular function and ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy genotype positive, phenotype negative (Genotype+ LVH−) and in phenotype positive (HCM LVH+). Methods: In this cross sectional study we included 187 subjects (age 49 ± 16 years, 89(48%) female, 121(65%) HCM LVH+ and 66 (35%) Genotype+ LVH-) who answered a questionnaire on physical activity history. Exercise ≥6 metabolic equivalents was defined as vigorous. Subjects with a history of vigorous exercise ≥4 h/week during ≥6 years were defined as athletes. All underwent echocardiography and Holter monitoring. VAs were defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia. Results: In both Genotype+ LVH− and HCM LVH+, lifetime vigorous exercise correlated with larger left ventricular end-diastolic volume (rho 0.44 and 0.38 respectively, both p b 0.001). Lifetime vigorous exercise correlated with increased left ventricular mass in Genotype+ LVH− (rho 0.28, p = 0.03), but not in HCM LVH+ (p = 0.53). Left ventricular systolic function was similar between athletes and non-athletes in Genotype+ LVH− and HCM LVH+. HCM LVH+ athletes had lower E/e' (p = 0.03) and higher e' (p = 0.02) compared to non-athletes, while this difference was not observed in Genotype+ LVH−. Lifetime vigorous exercise was similar among HCM LVH+ with and without VAs (p = 0.89). Conclusions: Increased lifetime vigorous exercise was associated with larger left ventricular volumes in hypertrophic cardiomyopathy, but correlated to left ventricular mass only in Genotype+ LVH−. Vigorous exercise was associated with favorable diastolic function in HCM LVH+, and was not associated with VAs

Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy

Data presented in this paper are supplementary material to our study âVigorous exercise in patients with hypertrophic cardiomyopathyâ [1]. The current article presents supplementary data on collection and analyses of exercise parameters and genetic data in the original research article. Keywords: Hypertrophic cardiomyopathy, Exercise, Genetics, Arrhythmi