Biology subjects

Cervenka, S.

Publications and source records attributed to Cervenka, S..

8 recordsLinked to original sources

bioRxiv2018

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk.

ImportanceBetween-subject variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients. However, such group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature\n\nObjectiveTo compare brain structural variability between individuals with SZ and healthy controls (HC) and to test if respective variability reflects the polygenic risk for SZ (PRS) in HC.\n\nDesign, Setting, and ParticipantsWe compared MRI derived cortical thickness and subcortical volumes between 2,010 healthy controls and 1,151 patients with SZ across 16 cohorts. Secondly, we tested for associations between PRS and MRI features in 12,490 participants from UK Biobank.\n\nMain Outcomes and MeasuresWe modeled mean and dispersion effects of SZ and PRS using double generalized linear models. We performed vertex-wise analyses for thickness, and region-of-interest analysis for cortical, subcortical and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, controlling for intracranial volume and population covariates, test of robustness of PRS threshold, and outlier removal.\n\nResultsCompared to controls, patients with SZ showed higher heterogeneity in cortical thickness, cortical and ventricle volumes, and hippocampal subfields. Higher PRS was associated with thinner frontal and temporal cortices, as well as smaller left CA2/3, but was not significantly associated with dispersion.\n\nConclusion and relevanceSZ is associated with substantial brain structural heterogeneity beyond the mean differences. These findings possibly reflect higher differential sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of SZ. Higher PRS for SZ was associated with thinner fronto-temporal cortices and smaller subcortical volumes, but there were no significant associations with the heterogeneity in these measures, i.e. the variability among individuals with high PRS were comparable to the variability among individuals with low PRS. This suggests that brain variability in SZ results from interactions between environmental and genetic factors that are not captured by the PGR. Factors contributing to heterogeneity in fronto-temporal cortices and hippocampus are thus key to further our understanding of how genetic and environmental factors shape brain biology in SZ.\n\nKey PointsQuestion: Is schizophrenia and its polygenic risk associated with brain structural heterogeneity in addition to mean changes?\n\nFindings: In a sample of 1151 patients and 2010 controls, schizophrenia was associated with increased heterogeneity in fronto-temporal thickness, cortical, ventricle, and hippocampal volumes, besides robust reductions in mean estimates. In an independent sample of 12,490 controls, polygenic risk for schizophrenia was associated with thinner fronto-temporal cortices and smaller CA2/3 of the left hippocampus, but not with heterogeneity.\n\nMeaning: Schizophrenia is associated with increased inter-individual differences in brainstructure, possibly reflecting clinical heterogeneity, gene-environment interactions, or secondary disease factors.

neuroscience↗

bioRxiv2018

Accuracy and reliability of PBR28 specific binding estimated without the use of a reference region

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28.\n\nThe Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans.\n\nThe simulation experiments showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values.\n\nThe results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

neuroscience↗

bioRxiv2018

Dopamine D1 receptor availability is not associated with delusional ideation measures of psychosis proneness

The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however the exact nature of this involvement is not clear. Positron emission tomography studies comparing D1R between patients and control subjects have produced inconsistent results. An important confounding factor in most clinical studies is previous exposure to antipsychotic treatment, which is thought to influence the density of D1R. To circumvent some of the limitations of clinical studies, an alternative approach for studying the relationship between D1R and psychosis is to examine individuals at increased risk for psychotic disorders, or variation in subclinical psychotic symptoms such as delusional ideation within the general population, referred to as psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls using data from 76 individuals measured with PET using [11C]SCH23390 and 217 individuals who completed delusional ideation questionnaires, belonging to three different study cohorts. We first performed exploratory, hypothesis-generating, analyses by creating and evaluating a new measure of delusional ideation (n=132 and n=27), which was then found to show a negative association with D1R availability (n=24). Next, we performed confirmatory analyses using Bayesian statistical modelling, in which we first attempted to replicate this result (n=20), and then evaluated the association of Peters Delusion Inventory scores with D1R availability in two independent cohorts (n=41 and 20). Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R availability in healthy controls. If differences in D1R can be confirmed in drug-naive schizophrenia patients compared to controls, further studies are needed to ascertain whether these changes occur at the onset of psychotic symptoms or if they are associated with specific behavioural or genetic aspects of psychosis proneness other than delusional ideation.

neuroscience↗

bioRxiv2018

Genetics of brain age suggest an overlap with common brain disorders

Numerous genetic and environmental factors contribute to psychiatric disorders and other brain disorders. Common risk factors likely converge on biological pathways regulating the optimization of brain structure and function across the lifespan. Here, using structural magnetic resonance imaging and machine learning, we estimated the gap between brain age and chronological age in 36,891 individuals aged 3 to 96 years, including individuals with different brain disorders. We show that several disorders are associated with accentuated brain aging, with strongest effects in schizophrenia, multiple sclerosis and dementia, and document differential regional patterns of brain age gaps between disorders. In 16,269 healthy adult individuals, we show that brain age gap is heritable with a polygenic architecture overlapping those observed in common brain disorders. Our results identify brain age gap as a genetically modulated trait that offers a window into shared and distinct mechanisms in different brain disorders.

neuroscience↗

bioRxiv2018

Test-retest reliability and convergent validity of (R)-PK11195 outcome measures without arterial input function

BackgroundThe positron emission tomography radioligand (R)-[11C]PK11195 can be used to quantify the expression of translocator protein (TSPO), which is considered a marker for activation of glial cells. TSPO is expressed throughout the brain, and for this reason no true reference region exists. When a radioligand does not have a reference region, an arterial input function (AIF) is usually required in order to quantify binding. However, obtaining an AIF can be difficult as well as uncomfortable for participants. Alternative methods have therefore been proposed with the aim of estimating (R)-[11C]PK11195 binding without arterial measurements, such as standardized uptake values (SUVs), supervised-cluster analysis (SVCA), or the use of a pseudo-reference region. The objective of this study was to evaluate the test-retest reliability and convergent validity of these techniques.\n\nMethodsData from a previously published (R)-[11C]PK11195 test-retest study in six healthy male subjects were reanalysed. Non-displaceable binding potential (BPND) was calculated for a set of cortical and subcortical brain regions using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using SVCA. SUVs were estimated for the time interval of 40-60 minutes. For comparison, total distribution volume (VT), specific distribution volume (VS) and BPND were estimated from the two-tissue-compartment model (2TCM) using AIF. Test-retest reliability was then assessed for all outcome measures. Convergent validity was examined by correlating all measures derived without an AIF to those derived using 2TCM.\n\nResultsTest-retest reliability for BPND estimates were poor (80% of all regional ICCs<0.5). SUVs showed, on average, moderate reliability. BPND estimates derived without an AIF were not correlated with VT, VS or BPND from the 2TCM (all R2<12%). SUVs were not correlated with any other outcome (all R2<9%).\n\nDiscussionBPND estimated using cerebellum or SVCA as reference input showed poor reliability and little to no convergent validity with outcomes derived using an AIF. SUVs showed moderate reliability but no convergent validity with any other outcome. Caution is warranted for interpreting patient-control comparisons employing (R)-[11C]PK11195 outcome measures obtained without an AIF.

neuroscience↗

bioRxiv2017

PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data

BackgroundAccumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels as compared to healthy control subjects.\n\nMethodsPubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (VT), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no-change of TSPO levels in patients as compared to healthy controls.\n\nResultsFive studies, with 75 patients with first-episode psychosis or schizophrenia and 77 healthy control subjects were included. BF showed strong support for lower patient VT relative to no-change (all BF>32) or relative to an increase (all BF>422) in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25).\n\nDiscussionThe observed reduction of TPSO in compared to control subjects in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.

immunology↗

bioRxiv2017

Serotonin 5-HT1A receptor binding and self-transcendence in healthy control subjects - a replication study using Bayesian hypothesis testing

ObjectiveA putative relationship between markers for the serotonin system and the personality scale self-transcendence (ST) and its subscale spiritual acceptance (SA) has been demonstrated in a previous PET study of 5-HT1A receptor binding in healthy control subjects. The results could however not be replicated in a subsequent PET study at an independent centre. In this study, we performed a replication of our original study in a larger sample using Bayesian hypothesis testing to evaluate relative evidence both for and against this hypothesis.\n\nMethodsRegional 5-HT1A receptor binding potential (BPND) was examined in 50 healthy male subjects using PET with the radioligand [11C]WAY100635. 5-HT1A availability was calculated using the simplified reference tissue model (SRTM) yielding regional BPND. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5-HT1A BPND in frontal cortex, hippocampus and raphe nuclei were examined by calculation of default correlation Bayes factors (BFs) and replication BFs.\n\nResultsThere were no significant correlations between 5-HT1A receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT1A availability and ST/SA, while the remaining BF provided only weak evidence.\n\nConclusionWe could not replicate our previous findings of an association between 5-HT1A availability and the personality trait ST/SA. Rather, the Bayesian analysis provided evidence for a lack of correlation. Further research should focus on whether other components of the serotonin system may be related to ST or SA. This study also illustrates how Bayesian hypothesis testing allows for greater flexibility and more informative conclusions than traditional p-values, suggesting that this approach may be advantageous for analysis of molecular imaging data.

neuroscience↗

bioRxiv2017

Is dopamine D1 receptor availability related to social behavior? A positron emission tomography replication study

BackgroundAssociations between dopamine receptor levels and pro- and antisocial behavior have previously been demonstrated in human subjects using positron emission tomography (PET) and self-rated measures of personality traits. So far, only one study has focused on the D1-dopamine receptor (D1-R), [fi]nding a positive correlation with the trait social desirability, which is characterized by low dominant and high af[fi]liative behavior, while physical aggression showed a negative correlation. The aim of the present study was to replicate these previous [fi]ndings using a new independent sample of subjects.\n\nMethodsTwenty-six healthy males were examined with the radioligand [11C]SCH-23390, and completed the Swedish universities Scales of Personality (SSP) which includes measures of social desirability and physical trait aggression. The simpli[fi]ed reference tissue model with cerebellum as reference region was used to calculate BPND values in the whole striatum and limbic striatum. The two regions were selected since they showed strong association between D1-R availability and personality scores in the previous study. Pearsons correlation coef[fi]cients and replication Bayes factors were then employed to assess the replicability and robustness of previous results.\n\nResultsThere were no signi[fi]cant correlations (all p values > 0.3) between regional BPND values and personality scale scores. Replication Bayes factors showed strong to moderate evidence in favor no relationship between D1-receptor availability and social desirability (striatum BF01 = 12.4; limbic striatum BF01 = 7.2) or physical aggression scale scores (limbic striatum BF01 = 3.3), compared to the original correlations.\n\nDiscussionWe could not replicate the previous [fi]ndings of associations between D1-R availability and either pro- or antisocial behavior as measured using the SSP. Rather, there was evidence in favor of failed replications of associations between BPND and scale scores. Potential reasons for these results are restrictive variance in both PET and personality outcomes due to high sample homogeneity, or that the previous [fi]ndings were false positives.

neuroscience↗