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University of Manchester, U.S. National Institute on Aging, University of Cardiff, VU University Amsterdam, Ucl Business Plc and Hospital District Of Helsinki And Uusimaa | Date: 2017-08-09

The present invention relates to methods of assessing whether a subject has or is likely to develop a neurodegenerative disease comprising determining whether the subject has a mutation in the C9orf72 gene wherein said mutation prevents or disrupts C9orf72 expression relative to expression in a reference from subjects without the mutation.


Awh E.,University of Oregon | Belopolsky A.V.,VU University Amsterdam | Theeuwes J.,VU University Amsterdam
Trends in Cognitive Sciences | Year: 2012

Prominent models of attentional control assert a dichotomy between top-down and bottom-up control, with the former determined by current selection goals and the latter determined by physical salience. This theoretical dichotomy, however, fails to explain a growing number of cases in which neither current goals nor physical salience can account for strong selection biases. For example, equally salient stimuli associated with reward can capture attention, even when this contradicts current selection goals. Thus, although 'top-down' sources of bias are sometimes defined as those that are not due to physical salience, this conception conflates distinct - and sometimes contradictory - sources of selection bias. We describe an alternative framework, in which past selection history is integrated with current goals and physical salience to shape an integrated priority map. © 2012 Elsevier Ltd.


Schomaker J.,Justus Liebig University | Meeter M.,VU University Amsterdam
Neuroscience and Biobehavioral Reviews | Year: 2015

When one encounters a novel stimulus this sets off a cascade of brain responses, activating several neuromodulatory systems. As a consequence novelty has a wide range of effects on cognition; improving perception and action, increasing motivation, eliciting exploratory behavior, and promoting learning. Here, we review these benefits and how they may arise in the brain. We propose a framework that organizes novelty's effects on brain and cognition into three groups. First, novelty can transiently enhance perception. This effect is proposed to be mediated by novel stimuli activating the amygdala and enhancing early sensory processing. Second, novel stimuli can increase arousal, leading to short-lived effects on action in the first hundreds of milliseconds after presentation. We argue that these effects are related to deviance, rather than to novelty per se, and link them to activation of the locus-coeruleus norepinephrine system. Third, spatial novelty may trigger the dopaminergic mesolimbic system, promoting dopamine release in the hippocampus, having longer-lasting effects, up to tens of minutes, on motivation, reward processing, and learning and memory. © 2015 Elsevier Ltd.


Van Ooyen A.,VU University Amsterdam
Nature Reviews Neuroscience | Year: 2011

The development of the nervous system is an extremely complex and dynamic process. Through the continuous interplay of genetic information and changing intra- and extracellular environments, the nervous system constructs itself from precursor cells that divide and form neurons, which migrate, differentiate and establish synaptic connections. Our understanding of neural development can be greatly assisted by mathematical and computational modelling, because it allows us to bridge the gap between system-level dynamics and the lower level cellular and molecular processes. This Review shows the potential of theoretical models to examine many aspects of neural development. © 2011 Macmillan Publishers Limited. All rights reserved.


Penninx B.W.J.H.,VU University Amsterdam
Neuroscience and Biobehavioral Reviews | Year: 2017

Depression's burden of disease goes beyond functioning and quality of life and extends to somatic health. Results from longitudinal cohort studies converge in illustrating that major depressive disorder (MDD) subsequently increases the risk of cardiovascular morbidity and mortality with about 80%. The impact of MDD on cardiovascular health may be partly explained by mediating mechanisms such as unhealthy lifestyle (smoking, excessive alcohol use, physical inactivity, unhealthy diet, therapy non-compliance) and unfavorable pathophysiological disturbances (autonomic, HPA-axis, metabolic and immuno-inflammatory dysregulations). A summary of the literature findings as well as relevant results from the large-scale Netherlands Study of Depression and Anxiety (N = 2981) are presented. Persons with MDD have significantly worse lifestyles as well as more pathophysiological disturbances as compared to healthy controls. Some of these differences seem to be specific for (typical versus ‘atypical’, or antidepressant treated versus drug-naive) subgroups of MDD patients. Alternative explanations are also present, namely undetected confounding, iatrogenic effects or ‘third factors’ such as genetics. © 2016 Elsevier Ltd


Paulus W.J.,VU University Amsterdam | Tschope C.,Franklin University
Journal of the American College of Cardiology | Year: 2013

Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity. © 2013 by the American College of Cardiology Foundation.


The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.Molecular Psychiatry advance online publication, 30 June 2015; doi:10.1038/mp.2015.69. © 2015 Macmillan Publishers Limited


Stam C.J.,VU University Amsterdam
Nature Reviews Neuroscience | Year: 2014

Modern network science has revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, hubs and rich clubs. The next challenge is to use this knowledge to gain a better understanding of brain disease. Recent developments in the application of network science to conditions such as Alzheimer's disease, multiple sclerosis, traumatic brain injury and epilepsy have challenged the classical concept of neurological disorders being either 'local' or 'global', and have pointed to the overload and failure of hubs as a possible final common pathway in neurological disorders. © 2014 Macmillan Publishers Limited. All rights reserved.


Romero E.,VU University Amsterdam
Nature Physics | Year: 2014

The crucial step in the conversion of solar to chemical energy in photosynthesis takes place in the reaction centre, where the absorbed excitation energy is converted into a stable charge-separated state by ultrafast electron transfer events. However, the fundamental mechanism responsible for the near-unity quantum efficiency of this process is unknown. Here we elucidate the role of coherence in determining the efficiency of charge separation in the plant photosystem II reaction centre by comprehensively combining experiment (two-dimensional electronic spectroscopy) and theory (Redfield theory). We reveal the presence of electronic coherence between excitons as well as between exciton and charge-transfer states that we argue to be maintained by vibrational modes. Furthermore, we present evidence for the strong correlation between the degree of electronic coherence and efficient and ultrafast charge separation. We propose that this coherent mechanism will inspire the development of new energy technologies.


Gooren L.J.,VU University Amsterdam
New England Journal of Medicine | Year: 2011

A healthy and successful 40-year-old man finds it increasingly difficult to live as a male. In childhood he preferred playing with girls and recalls feeling that he should have been one. Over time he has come to regard himself more and more as a female personality inhabiting a male body. After much agonizing, he has concluded that only sex reassignment can offer the peace of mind he craves. What would you advise? Copyright © 2011 Massachusetts Medical Society.

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