Unraveling Molecular Mechanisms Underlying Alzheimer’s disease and its Related Endophenotypes

Dementia and its most common type, Alzheimer’s disease (AD) is a devastating disease that afflicts millions worldwide. Still, there are no targeted preventive interventions or pharmacological treatments for AD available. This makes further unraveling the pathophysiology of AD to find new targets for treatment a global research priority. Genetic research has played a pivotal role to identify novel insights in the pathophysiology of AD and has influenced clinical diagnostics and treatment developments. Therefore, the overarching aim of the studies included in this thesis is to gain novel insights in the molecular and biological mechanisms underlying AD and its related endophenotypes using genetic research. The studies that make up this thesis are organized in chapters that all approach this goal from a different angle

Personalized versus standard cognitive behavioral therapy for fear of cancer recurrence, depressive symptoms or cancer-related fatigue in cancer survivors:Study protocol of a randomized controlled trial (MAtCH-study)

© 2021, The Author(s).Background: Fear of cancer recurrence, depressive symptoms, and cancer-related fatigue are prevalent symptoms among cancer survivors, adversely affecting patients’ quality of life and daily functioning. Effect sizes of interventions targeting these symptoms are mostly small to medium. Personalizing treatment is assumed to improve efficacy. However, thus far the empirical support for this approach is lacking. The aim of this study is to investigate if systematically personalized cognitive behavioral therapy is more efficacious than standard cognitive behavioral therapy in cancer survivors with moderate to severe fear of cancer recurrence, depressive symptoms, and/or cancer-related fatigue. Methods: The study is designed as a non-blinded, multicenter randomized controlled trial with two treatment arms (ratio 1:1): (a) systematically personalized cognitive behavioral therapy and (b) standard cognitive behavioral therapy. In the standard treatment arm, patients receive an evidence-based diagnosis-specific treatment protocol for fear of cancer recurrence, depressive symptoms, or cancer-related fatigue. In the second arm, treatment is personalized on four dimensions: (a) the allocation of treatment modules based on ecological momentary assessments, (b) treatment delivery, (c) patients’ needs regarding the symptom for which they want to receive treatment, and (d) treatment duration. In total, 190 cancer survivors who experience one or more of the targeted symptoms and ended their medical treatment with curative intent at least 6 months to a maximum of 5 years ago will be included. Primary outcome is limitations in daily functioning. Secondary outcomes are level of fear of cancer recurrence, depressive symptoms, fatigue severity, quality of life, goal attainment, therapist time, and drop-out rates. Participants are assessed at baseline (T0), and after 6 months (T1) and 12 months (T2). Discussion: To our knowledge, this is the first randomized controlled trial comparing the efficacy of personalized cognitive behavioral therapy to standard cognitive behavioral therapy in cancer survivors. The study has several innovative characteristics, among which is the personalization of interventions on several dimensions. If proven effective, the results of this study provide a first step in developing an evidence-based framework for personalizing therapies in a systematic and replicable way. Trial registration: The Dutch Trial Register (NTR) NL7481 (NTR7723). Registered on 24 January 2019

Blood-based metabolic signatures in Alzheimer's disease

Introduction Identification of blood-based metabolic changes might provide early and easy-to-obtain biomarkers. Methods We included 127 Alzheimer's disease (AD) patients and 121 control subjects with cerebrospinal fluid biomarker-confirmed diagnosis (cutoff tau/amyloid β peptide 42: 0.52). Mass spectrometry platforms determined the concentrations of 53 amine compounds, 22 organic acid compounds, 120 lipid compounds, and 40 oxidative stress compounds. Multiple signatures were assessed: differential expression (nested linear models), classification (logistic regression), and regulatory (network extraction). Results Twenty-six metabolites were differentially expressed. Metabolites improved the classification performance of clinical variables from 74% to 79%. Network models identified five hubs of metabolic dysregulation: tyrosine, glycylglycine, glutamine, lysophosphatic acid C18:2, and platelet-activating factor C16:0. The metabolite network for apolipoprotein E (APOE) ε4 negative AD patients was less cohesive compared with the network for APOE ε4 positive AD patients. Discussion Multiple signatures point to various promising peripheral markers for further validation. The network differences in AD patients according to APOE genotype may reflect different pathways to AD

Selangor administration report, 1913 (September 25)

Supplement to the Government Gazette, 191

Crystallization of the ordered vortex phase in high temperature superconductors

The Landau-Khalatnikov time-dependent equation is applied to describe the crystallization process of the ordered vortex lattice in high temperature superconductors after a sudden application of a magnetic field. Dynamic coexistence of a stable ordered phase and an unstable disordered phase, with a sharp interface between them, is demonstrated. The transformation to the equilibrium ordered state proceeds by movement of this interface from the sample center toward its edge. The theoretical analysis dictates specific conditions for the creation of a propagating interface, and provides the time scale for this process.Comment: 8 pages and 3 figures; to be published in Phys. Rev. B (Rapid Communications section

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10 '5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10 '9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10 '5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-I 4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice

Anomalous Hopping Exponents of Ultrathin Films of Metals

The temperature dependence of the resistance R(T) of ultrathin quench-condensed films of Ag, Bi, Pb and Pd has been investigated. In the most resistive films, R(T)=Roexp(To/T)^x, where x=0.75. Surprisingly, the exponent x was found to be constant for a wide range of Ro and To in all four materials, possibly implying a consistent underlying conduction mechanism. The results are discussed in terms of several different models of hopping conduction.Comment: 6 pages, 5 figure

Heritability of the shape of subcortical brain structures in the general population

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures

A priori collaboration in population imaging: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium

Introduction: Virchow-Robin spaces (VRS), or perivascular spaces, are compartments of interstitial fluid enclosing cerebral blood vessels and are potential imaging markers of various underlying brain pathologies. Despite a growing interest in the study of enlarged VRS, the heterogeneity in rating and quantification methods combined with small sample sizes have so far hampered advancement in the field. Methods: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement (UNIVRSE) consortium was established with primary aims to harmonize rating and analysis (www.uconsortium.org). The UNIVRSE consortium brings together 13 (sub)cohorts from five countries, totaling 16,000 subjects and over 25,000 scans. Eight different magnetic resonance imaging protocols were used in the consortium. Results: VRS rating was harmonized using a validated protocol that was developed by the two founding members, with high reliability independent of scanner type, rater experience, or concomitant brain pathology. Initial analyses revealed risk factors for enlarged VRS including increased age, sex, high blood pressure, brain infarcts, and white matter lesions, but this varied by brain region. Discussion: Early collaborative efforts between cohort studies with respect to data harmonization and joint analyses can advance the field of population (neuro)imaging. The UNIVRSE consortium will focus efforts on other potential correlates of enlarged VRS, including genetics, cognition, stroke, and dementia