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Author: Andre Altmann (33)


Feb
2018

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Brain 2018 Feb;141(2):391-408
Christopher D Whelan, Andre Altmann, Juan A Botía, Neda Jahanshad, Derrek P Hibar, Julie Absil, Saud Alhusaini, Marina K M Alvim, Pia Auvinen, Emanuele Bartolini, Felipe P G Bergo, Tauana Bernardes, Karen Blackmon, Barbara Braga, Maria Eugenia Caligiuri, Anna Calvo, Sarah J Carr, Jian Chen, Shuai Chen, Andrea Cherubini, Philippe David, Martin Domin, Sonya Foley, Wendy França, Gerrit Haaker, Dmitry Isaev, Simon S Keller, Raviteja Kotikalapudi, Magdalena A Kowalczyk, Ruben Kuzniecky, Soenke Langner, Matteo Lenge, Kelly M Leyden, Min Liu, Richard Q Loi, Pascal Martin, Mario Mascalchi, Marcia E Morita, Jose C Pariente, Raul Rodríguez-Cruces, Christian Rummel, Taavi Saavalainen, Mira K Semmelroch, Mariasavina Severino, Rhys H Thomas, Manuela Tondelli, Domenico Tortora, Anna Elisabetta Vaudano, Lucy Vivash, Felix von Podewils, Jan Wagner, Bernd Weber, Yi Yao, Clarissa L Yasuda, Guohao Zhang, Nuria Bargalló, Benjamin Bender, Neda Bernasconi, Andrea Bernasconi, Boris C Bernhardt, Ingmar Blümcke, Chad Carlson, Gianpiero L Cavalleri, Fernando Cendes, Luis Concha, Norman Delanty, Chantal Depondt, Orrin Devinsky, Colin P Doherty, Niels K Focke, Antonio Gambardella, Renzo Guerrini, Khalid Hamandi, Graeme D Jackson, Reetta Kälviäinen, Peter Kochunov, Patrick Kwan, Angelo Labate, Carrie R McDonald, Stefano Meletti, Terence J O'Brien, Sebastien Ourselin, Mark P Richardson, Pasquale Striano, Thomas Thesen, Roland Wiest, Junsong Zhang, Annamaria Vezzani, Mina Ryten, Paul M Thompson, Sanjay M Sisodiya
Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls.

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Oct
2017

The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total= 1586, behavioral total= 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor α4β2 (rs1044396 on thegene) previously implicated in behavioral and nicotine-related studies (albeit with inconsistent major/minor allele impacts).

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Dec
1969

Microarray technologies are established approaches for high throughput gene expression, methylation and genotyping analysis. An accurate mapping of the array probes is essential to generate reliable biological findings. However, manufacturers of the microarray platforms typically provide incomplete and outdated annotation tables, which often rely on older genome and transcriptome versions that differ substantially from up-to-date sequence databases.

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Dec
2015

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease.

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Jun
2015

During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set.

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Jun
2015

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells.

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Dec
1969

Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array-based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.

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Jul
2014

Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity.

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Apr
2014

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.

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Jun
2014

Alzheimer's disease (AD) is an increasingly prevalent, fatal neurodegenerative disease that has proven resistant, thus far, to all attempts to prevent it, forestall it, or slow its progression. The ε4 allele of the Apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial AD. While the link between APOE4 and AD is strong, many expected effects, like increasing the risk of conversion from MCI to AD, have not been widely replicable.

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Dec
1969

SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder.

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May
2013

Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%).

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Jan
2013

Recent advances in massively parallel sequencing (MPS) have had an extensive impact on research in medical genomics. In particular, the analysis of rare variants using MPS promises to lead to a better understanding of complex disorders. Nevertheless, for meaningful studies that address the genetic basis for neuropsychiatric disorders, at least hundreds of patient samples have to be analyzed.

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Dec
1969

Due to recent advances in genotyping technologies, mapping phenotypes to single loci in the genome has become a standard technique in statistical genetics. However, one-locus mapping fails to explain much of the phenotypic variance in complex traits. Here, we present GLIDE, which maps phenotypes to pairs of genetic loci and systematically searches for the epistatic interactions expected to reveal part of this missing heritability.

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Dec
2012

Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures.

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Oct
2012

High-throughput DNA sequencing (HTS) is of increasing importance in the life sciences. One of its most prominent applications is the sequencing of whole genomes or targeted regions of the genome such as all exonic regions (i.e.

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Dec
1969

Highly active antiretroviral therapy (HAART) has been shown to be effective in many recent trials. However, there is limited data on time trends of HAART efficacy after treatment change.
Data from different European cohorts were compiled within the EuResist Project.

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Dec
1969

For a long time, the clinical management of antiretroviral drug resistance was based on sequence analysis of the HIV genome followed by estimating drug susceptibility from the mutational pattern that was detected. The large number of anti-HIV drugs and HIV drug resistance mutations has prompted the development of computer-aided genotype interpretation systems, typically comprising rules handcrafted by experts via careful examination of in vitro and in vivo resistance data. More recently, machine learning approaches have been applied to establish data-driven engines able to indicate the most effective treatments for any patient and virus combination.

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Jul
2011

Genotype-derived drug resistance profiles are a valuable asset in HIV-1 therapy decisions. Therapy decisions could be further improved, both in terms of predicting length of current therapy success and in preserving followup therapy options, through better knowledge of mutational pathways- here defined as specific locations on the viral genome which, when mutant, alter the risk that additional specific mutations arise. We limit the search to locations in the reverse transcriptase region of the HIV-1 genome which host resistance mutations to nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors (as listed in the 2008 International AIDS Society report), or which were mutant at therapy start in 5% or more of the therapies studied.

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Jul
2011

High-throughput-sequencing (HTS) technologies are the method of choice for screening the human genome for rare sequence variants causing susceptibility to complex diseases. Unfortunately, preparation of samples for a large number of individuals is still very cost- and labor intensive. Thus, recently, screens for rare sequence variants were carried out in samples of pooled DNA, in which equimolar amounts of DNA from multiple individuals are mixed prior to sequencing with HTS.

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Dec
1969

Infections with the human immunodeficiency virus type 1 (HIV-1) are treated with combinations of drugs. Unfortunately, HIV responds to the treatment by developing resistance mutations. Consequently, the genome of the viral target proteins is sequenced and inspected for resistance mutations as part of routine diagnostic procedures for ensuring an effective treatment.

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Oct
2010

Although genotypic resistance testing (GRT) is recommended to guide combination antiretroviral therapy (cART), funding and/or facilities to perform GRT may not be available in low to middle income countries. Since treatment history (TH) impacts response to subsequent therapy, we investigated a set of statistical learning models to optimise cART in the absence of GRT information.
The EuResist database was used to extract 8-week and 24-week treatment change episodes (TCE) with GRT and additional clinical, demographic and TH information.

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Sep
2010

As there exists no cure or vaccine for the infection with human immunodeficiency virus (HIV), the standard approach to treating HIV patients is to repeatedly administer different combinations of several antiretroviral drugs. Because of the large number of possible drug combinations, manually finding a successful regimen becomes practically impossible. This presents a major challenge for HIV treatment.

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May
2010

In life sciences, interpretability of machine learning models is as important as their prediction accuracy. Linear models are probably the most frequently used methods for assessing feature relevance, despite their relative inflexibility. However, in the past years effective estimators of feature relevance have been derived for highly complex or non-parametric models such as support vector machines and RandomForest (RF) models.

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Feb
2010

Replication capacity (RC) of specific HIV isolates is occasionally blamed for unexpected treatment responses. However, the role of viral RC in response to antiretroviral therapy is not yet fully understood.
We developed a method for predicting RC from genotype using support vector machines (SVMs) trained on about 300 genotype-RC pairs.

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Dec
1969

The extreme flexibility of the HIV type-1 (HIV-1) genome makes it challenging to build the ideal antiretroviral treatment regimen. Interpretation of HIV-1 genotypic drug resistance is evolving from rule-based systems guided by expert opinion to data-driven engines developed through machine learning methods.
The aim of the study was to investigate linear and non-linear statistical learning models for classifying short-term virological outcome of antiretroviral treatment.

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Jul
2009

We investigated the prevalence of raltegravir resistance-associated mutations at baseline and their evolution during raltegravir therapy in patients infected with different HIV-1 subtypes.
At pre-treatment screening, the integrase gene from plasma samples from patients infected with subtype B and non-B viruses was analysed. Raltegravir resistance evolution was further evaluated in 10 heavily pre-treated patients.

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Dec
1969

Inferring response to antiretroviral therapy from the viral genotype alone is challenging. The utility of an intermediate step of predicting in vitro drug susceptibility is currently controversial. Here, we provide a retrospective comparison of approaches using either genotype or predicted phenotypes alone, or in combination.

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Apr
2009

Expert-based genotypic interpretation systems are standard methods for guiding treatment selection for patients infected with human immunodeficiency virus type 1. We previously introduced the software pipeline geno2pheno-THEO (g2p-THEO), which on the basis of viral sequence predicts the response to treatment with a combination of antiretroviral compounds by applying methods from statistical learning and the estimated potential of the virus to escape from drug pressure.
We retrospectively validated the statistical model used by g2p-THEO in approximately 7600 independent treatment-sequence pairs extracted from the EuResist integrated database, ranging from 1990 to 2007.

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Dec
1969

Analysis of the viral genome for drug resistance mutations is state-of-the-art for guiding treatment selection for human immunodeficiency virus type 1 (HIV-1)-infected patients. These mutations alter the structure of viral target proteins and reduce or in the worst case completely inhibit the effect of antiretroviral compounds while maintaining the ability for effective replication. Modern anti-HIV-1 regimens comprise multiple drugs in order to prevent or at least delay the development of resistance mutations.

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Oct
2008

In genetics, many evolutionary pathways can be modeled by the ordered accumulation of permanent changes. Mixture models of mutagenetic trees have been used to describe disease progression in cancer and in HIV. In cancer, progression is modeled by the accumulation of chromosomal gains and losses in tumor cells; in HIV, the accumulation of drug resistance-associated mutations in the viral genome is known to be associated with disease progression.

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Jul
2008

Optimizing HIV therapies is crucial since the virus rapidly develops mutations to evade drug pressure. Recent studies have shown that genotypic information might not be sufficient for the design of therapies and that other clinical and demographical factors may play a role in therapy failure. This study is designed to assess the improvement in prediction achieved when such information is taken into account.

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Dec
1969

The outcome of antiretroviral combination therapy depends on many factors involving host, virus, and drugs. We investigate prediction of treatment response from the applied drug combination and the genetic constellation of the virus population at baseline. The virus's evolutionary potential for escaping from drug pressure is explored as an additional predictor.

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