Recent advances in the diagnosis and the treatment of primary CNS lymphoma.

This review focuses on the recent progress in the management of primary central nervous system lymphoma (PCNSL). Multiomic analyses allowed to better understand the tumorigenesis of PCNSL and to establish a molecular classification with prognostic value that will optimize patient management and guide future targeted approaches. Cooperative clinical trials have demonstrated the feasibility and efficacy, in selected fit patients, of high-dose chemotherapy with autologous stem cell transplantation as post-induction consolidation, that will progressively replace whole brain radiotherapy associated with a much higher risk of delayed neurotoxicity. Several novel treatments have shown efficacy and overall good tolerance in PCNSL patients, such as Bruton's tyrosine kinase (BTK) inhibitors, imids, immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR-T). This opens promising therapeutic perspectives to improve the current standard treatment, especially for elderly and unfit patients who represent a growing population.

[Cohort studies in child and adolescent psychiatry]. / Kohortenstudien in der Kinder- und Jugendpsychiatrie.

BACKGROUND: Longitudinal cohort studies with early start and life span perspectives are increasingly recognized as being crucial to uncover developmental trajectories as well as risk and resilience factors of psychiatric disorders. OBJECTIVE: The importance of longitudinal studies is presented and the main findings of the Mannheim study of children at risk (MARS), the adolescent brain cognitive development (ABCD), the pediatric and adolescent health survey (Kinder- und Jugendgesundheitssurvey, KiGGS) and the AIMS longitudinal European autism project (LEAP) cohort studies are described. MATERIAL AND METHODS: A literature search was carried out in MEDLINE. RESULTS: The MARS followed participants with psychosocial and organic risks over more than 30 years starting from birth and showed the importance of early risk factors (prenatal period up to early childhood) for neuropsychosocial development. The ABCD cohort study (start 9-10 years old) underlined the developmental significance of early socioemotional and prenatal risks as well as toxin exposure. The KiGGS cohort followed children and adolescents from age 0-17 years up to the ages of 10-28 years. Main findings underline the importance of the socioeconomic status and gender-specific effects with respect to sensitive periods for the onset and trajectories of psychiatric disorders. The AIMS cohort followed patients with and without autism spectrum disorders aged between 6 and 30 years and first results revealed small effects regarding group differences. Further, cohort studies starting prenatally along with deep phenotyping are warranted to uncover the complex etiology of mental disorders. CONCLUSION: Existing cohort studies on early mental development have shown specific focal points. To identify general and specific risk and resilience factors for psychiatric disorders and to model trajectories, there is a need for multimodal integration of data sets.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

[Wearables for context-triggered assessment in psychiatry]. / Wearables zum kontextgesteuerten Assessment in der Psychiatrie.

The breathtaking technological progress in the field of mobile computing, smartphones and wearables offers new opportunities for psychiatric research and therapy. Wearables enable not only the objective assessment of psychiatric symptoms in real time and everyday life but using continuous monitoring and analysis of relevant parameters can also define important situations, contexts and timing during which extended assessment strategies and real-life interventions can be implemented. The momentary effect of inner city green space exposure on well-being, motivational behavior feedback and geofencing for the detection of drinking episodes are used as examples to illustrate the core benefits of real-time analyses and feedback from wearables for psychiatric research and therapy.

Effects of BDNF Val66Met genotype and schizophrenia familial risk on a neural functional network for cognitive control in humans.

Cognitive control represents an essential neuropsychological characteristic that allows for the rapid adaption of a changing environment by constant re-allocation of cognitive resources. This finely tuned mechanism is impaired in psychiatric disorders such as schizophrenia and contributes to cognitive deficits. Neuroimaging has highlighted the contribution of the anterior cingulate cortex (ACC) and prefrontal regions (PFC) on cognitive control and demonstrated the impact of genetic variation, as well as genetic liability for schizophrenia. In this study, we aimed to examine the influence of the functional single-nucleotide polymorphism (SNP) rs6265 of a plasticity-related neurotrophic factor gene, BDNF (Val66Met), on cognitive control. Strong evidence implicates BDNF Val66Met in neural plasticity in humans. Furthermore, several studies suggest that although the variant is not convincingly associated with schizophrenia risk, it seems to be a modifier of the clinical presentation and course of the disease. In order to clarify the underlying mechanisms using functional magnetic resonance imaging (fMRI), we studied the effects of this SNP on ACC and PFC activation, and the connectivity between these regions in a discovery sample of 85 healthy individuals and sought to replicate this effect in an independent sample of 253 individuals. Additionally, we tested the identified imaging phenotype in relation to schizophrenia familial risk in a sample of 58 unaffected first-degree relatives of schizophrenia patients. We found a significant increase in interregional connectivity between ACC and PFC in the risk-associated BDNF 66Met allele carriers. Furthermore, we replicated this effect in an independent sample and demonstrated its independence of structural confounds, as well as task specificity. A similar coupling increase was detectable in individuals with increased familial risk for schizophrenia. Our results show that a key neural circuit for cognitive control is influenced by a plasticity-related genetic variant, which may render this circuit particular susceptible to genetic and environmental risk factors for schizophrenia.

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala, prefrontal and anterior cingulate cortex reactivity and habituation in a large, healthy fMRI cohort.

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.

Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains.

Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.

Species-conserved reconfigurations of brain network topology induced by ketamine.

Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.

Stratospheric sulfur and its implications for radiative forcing simulated by the chemistry climate model EMAC.

Multiyear simulations with the atmospheric chemistry general circulation model EMAC with a microphysical modal aerosol module at high vertical resolution demonstrate that the sulfur gases COS and SO2, the latter from low-latitude and midlatitude volcanic eruptions, predominantly control the formation of stratospheric aerosol. Marine dimethyl sulfide (DMS) and other SO2 sources, including strong anthropogenic emissions in China, are found to play a minor role except in the lowermost stratosphere. Estimates of volcanic SO2 emissions are based on satellite observations using Total Ozone Mapping Spectrometer and Ozone Monitoring Instrument for total injected mass and Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) on Envisat or Stratospheric Aerosol and Gases Experiment for the spatial distribution. The 10 year SO2 and COS data set of MIPAS is also used for model evaluation. The calculated radiative forcing of stratospheric background aerosol including sulfate from COS and small contributions by DMS oxidation, and organic aerosol from biomass burning, is about 0.07W/m2. For stratospheric sulfate aerosol from medium and small volcanic eruptions between 2005 and 2011 a global radiative forcing up to 0.2W/m2 is calculated, moderating climate warming, while for the major Pinatubo eruption the simulated forcing reaches 5W/m2, leading to temporary climate cooling. The Pinatubo simulation demonstrates the importance of radiative feedback on dynamics, e.g., enhanced tropical upwelling, for large volcanic eruptions.

The effect of saline-induced extracellular volume expansion on the kidney function.

The functional parameters of renal function of non-hydrated and hydrated dogs (saline-infused to an extent of 1-2% of the body weight) have been compared. The directly measured renal blood flow and the total renal vascular resistance were the same in the two groups. No difference has been found in glomerular filtration rate, the Cinulin was the same in the two groups. There was no important difference in the PAH clearance and PAH extraction. In the hypervolaemic group, the sodium and water excretion was about threefold that of the non-hydrated animals. The plasma protein concentration was significantly lower in the hydrated group. In our experiments we did not find glomerular factors responsible for the increase of sodium and water excretion. The decrease of tubular reabsorption is attributed partly to the decreased plasma protein concentration, partly to unknown (perhaps natriuretic) humoral factors.

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the 'missing heritability' of complex phenotypes.

Functional impact of a recently identified quantitative trait locus for hippocampal volume with genome-wide support.

In a large brain-imaging study, a multinational consortium has recently identified a common genetic variation in rs7294919 being associated with hippocampal volume. Here, we explored whether this quantitative trait locus also affects hippocampal function using a previously established reliable neuroimaging paradigm. We observed a significant effect of rs7294919 variation in the right hippocampus showing that hippocampal activation increased with the number of risk alleles. Furthermore, the risk allele was associated with decreased performance in a verbal learning and memory task. By showing that this single-nucleotide polymorphism also relates to behavioral difference and underlying brain activation in memory, our findings support the idea that rs7294919 may affect the individual capacity to resist disease in terms of diminishing or boosting hippocampal resources.

[Functional imaging of neurocognitive dysfunction in attention deficit hyperactivity disorder]. / Bildgebende Darstellung neurokognitiver Dysfunktionen bei der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobiological disorder of early childhood onset. Defining symptoms are chronic impairments of attention, impulse control and motor hyperactivity that frequently persist until adulthood. Miscellaneous causes of the disorder have been discussed. Accumulating evidence from imaging- and molecular genetic studies strengthened the theory of ADHS being a predominantly inherited disorder of neurobiological origin. In the last 15 years, non-invasive brain imaging methods were successfully implemented in pediatric research. Functional magnetic resonance imaging studies gave major insight into the neurobiological correlates of executive malfunction, inhibitory deficits and psychomotoric soft signs. These findings are in good accordance with brain morphometric data indicating a significant volumetric decrease of major components of striato-thalamo-cortical feedback loops, primarily influencing prefrontal executive functioning (e.g. basal ganglia). Empirical evidence points to a broad array of associated behavioral disturbances like deficient visuomotor abilities and oculomotor dysfunctions. This paper reviews the current empirical evidence derived from prior imaging studies. Special emphasis is given to the relevance of oculomotor dysfunctions in clinical and research settings, as well as their assessment in the MR environment.

[One decade of functional imaging in schizophrenia research. From visualisation of basic information processing steps to molecular-genetic oriented imaging]. / Zehn Jahre funktionelle Magnetresonanztomographie in der Schizophrenieforschung. Von der Abbildung einfacher Informationsverarbeitungsprozesse zur molekulargenetisch orientierten Bildgebung.

Modern neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have contributed tremendously to our current understanding of psychiatric disorders in the context of functional, biochemical and microstructural alterations of the brain. Since the mid-nineties, functional MRI has provided major insights into the neurobiological correlates of signs and symptoms in schizophrenia. The current paper reviews important fMRI studies of the past decade in the domains of motor, visual, auditory, attentional and working memory function. Special emphasis is given to new methodological approaches, such as the visualisation of medication effects and the functional characterisation of risk genes.

The renal actions of adenosine.

This study examined the effects of adenosine on the renal function. In ten normal dogs intrarenal adenosine infusion (20 nmol/kg/min) increased the renal blood flow (RBF) from 521 +/- 20 ml/min to 582 +/- 23 ml/min. The extraction of PAH (EPAH) decreased from 0.85 +/- 0.02 to 0.79 +/- 0.02, the Einulin from 0.24 +/- 0.02 to 0.18 +/- 0.02. We conclude that the intrarenal infusion of adenosine modifies the intrarenal redistribution of the blood flow increasing the deep cortical and medullary blood flow. In these experiments the glomerular filtration (GFR) during adenosine infusion calculated from the extraction of the inulin (Einulin) multiplied by the renal plasma flow (RPF) decreased from 79.4 +/- 6.4 ml/min to 62.2 +/- 6.6 ml/min and calculated from the Ecreatinine x RPF from 80.3 +/- 6.3 ml/min to 59.3 +/- 4.9 ml/min. The EPAH x RPF did not change, it was 241 +/- 11 ml/min and 253 +/- 13 ml/min, respectively. While the urinary clearances (the clearance calculated by the classic clearance formula; urinary concentration of the substance multiplied by the urine volume and divided by the plasma concentration) in the control periods did not differ from the direct clearances (Cinulin = 73.3 +/- 3 ml/min, Ccreatinine = 75 +/- 4 ml/min and CPAH = 262 +/- 15 ml/min) during the adenosine infusion there are considerable differences: the Cinulin = 40 +/- 6 ml/min, the Ccreatine = 42 +/- 6 ml/min and the CPAH = 164 +/- 22 ml/min. The differences are mathematically significant (p < 0.01). During the postinfusion periods the urinary clearances did not differ from the direct clearances. These results show that during adenosine infusion there is a definitive loss of the clearance substances somewhere in the nephron between the glomeruli and the pyelon. These observations suggest that during adenosine infusion there is a back-diffusion of the clearance substances because the permeability of the tubuli changes in the medullary part. The rediffused substances will be retransported into the circulation by the renal lymph flow and that is why they do not appear in the renal venous blood. The rediffusion can explain that the intrarenal adenosine infusion decreases considerably the excretion of the sodium and water in the kidney when there is no or only a small reduction of the glomerular filtration rate.