The project follows up our previous magnetic resonance imaging (MRI) study with the affected, unaffected offspring of parents with bipolar disorder (BP) and healthy controls and consists of : 1) prospective study arm, in which we will aquire a second batch of MRI scans after at least 5 years from the first examination to assess the changes in the volumes of gray matter in the regions of interest (subgenual cingulate, amygdala, hippocampus): 2) cross-sectional study arm in which we will perform diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) to investigate white matter abnormalities and functional connectivity in the circuit associated with regulation of emotions (including amygdala and subgenual cingulate) in a group of offspring from the previous study extended by new subjects at risk of BP. A priori-defined abnormalities in gray and white matter will be tested as the candidate biological risk factors for bipolar disorder.

Projekt navazuje na předchozí průřezovou studii se strukturální magnetickou rezonancí (MR) u zdravých a poruchou nálady postižených potomků rodičů s bipolární poruchou (BP) a sestává z části 1) prospektivní s druhým vyšetřením MR u stejného souboru s odstupem 5 let od prvního vyšetření k zachycení průběhových změn objemů šedé hmoty v regionech zájmu (subgenuální cingulum, amygdala, hipokampus) a 2) průřezové s vyšetřením pomocí zobrazení tenzorů difuze (DTI) a klidové funkční magnetické rezonance (resting state fMRI) s cílem zkoumat abnormity anatomické a funkční konektivity mezi oblastmi spojenými s regulací emocí (zahrnující subgenuální cungulum a amygdalu) u souboru potomků z předchozího projektu rozšířeném o nové subjekty. A priori definované abnormity v šedé a bílé hmotě specifických oblastí mozku spojených s regulací emocí budou testovány jako kandidátní biologické rizikové faktory po BP s uplatněním v časné diagnostice u osob s rizikem rozvoje onemocnění.

• MeSH
• biologické faktory MeSH
• bipolární porucha MeSH
• časná diagnóza MeSH
• dítě postižených rodičů MeSH
• endofenotypy MeSH
• genetická predispozice k nemoci MeSH
• magnetická rezonanční tomografie MeSH
• neurozobrazování MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• zobrazování difuzních tenzorů MeSH

• Konspekt
• Psychiatrie
• NLK Obory
• psychiatrie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

• MeSH
• bipolární porucha farmakoterapie   genetika   MeSH
• celogenomová asociační studie MeSH
• fenotyp MeSH
• genetická variace MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• receptory GDNF genetika   MeSH
• sloučeniny lithia terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

BACKGROUND: Brain imaging is of limited diagnostic use in psychiatry owing to clinical heterogeneity and low sensitivity/specificity of between-group neuroimaging differences. Machine learning (ML) may better translate neuroimaging to the level of individual participants. Studying unaffected offspring of parents with bipolar disorders (BD) decreases clinical heterogeneity and thus increases sensitivity for detection of biomarkers. The present study used ML to identify individuals at genetic high risk (HR) for BD based on brain structure. METHODS: We studied unaffected and affected relatives of BD probands recruited from 2 sites (Halifax, Canada, and Prague, Czech Republic). Each participant was individually matched by age and sex to controls without personal or family history of psychiatric disorders. We applied support vector machines (SVM) and Gaussian process classifiers (GPC) to structural MRI. RESULTS: We included 45 unaffected and 36 affected relatives of BD probands matched by age and sex on an individual basis to healthy controls. The SVM of white matter distinguished unaffected HR from control participants (accuracy = 68.9%, p = 0.001), with similar accuracy for the GPC (65.6%, p = 0.002) or when analyzing data from each site separately. Differentiation of the more clinically heterogeneous affected familiar group from healthy controls was less accurate (accuracy = 59.7%, p = 0.05). Machine learning applied to grey matter did not distinguish either the unaffected HR or affected familial groups from controls. The regions that most contributed to between-group discrimination included white matter of the inferior/middle frontal gyrus, inferior/middle temporal gyrus and precuneus. LIMITATIONS: Although we recruited 126 participants, ML benefits from even larger samples. CONCLUSION: Machine learning applied to white but not grey matter distinguished unaffected participants at high and low genetic risk for BD based on regions previously implicated in the pathophysiology of BD.

• MeSH
• bílá hmota anatomie a histologie   patologie   MeSH
• bipolární porucha diagnóza   genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• kohortové studie MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurozobrazování * MeSH
• prefrontální mozková kůra anatomie a histologie   patologie   MeSH
• rizikové faktory MeSH
• šedá hmota anatomie a histologie   patologie   MeSH
• spánkový lalok anatomie a histologie   patologie   MeSH
• strojové učení * MeSH
• support vector machine MeSH
• temenní lalok anatomie a histologie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH
• Kanada MeSH

• Publikační typ
• abstrakt z konference MeSH

OBJECTIVES: Impaired response inhibition underlies symptoms and altered functioning in patients with bipolar disorders (BD). The interpretation of fMRI studies requires an accurate estimation of neurocognitive performance, for which individual studies are typically underpowered. Thus, we performed the first combined meta-analysis of fMRI activations and neurocognitive performance in studies investigating response inhibition in BD. METHODS: We used signed differential mapping to combine anatomical coordinates of activation and standardized differences between means to evaluate neurocognitive performance in 30 fMRI studies of response inhibition comparing controls (n = 667) and patients with BD (n = 635). RESULTS: Relative to controls, BD patients underactivated the right inferior frontal gyrus (rIFG) regardless of current mood state and behavioral performance. Unique to euthymia were cortical hyperactivations (left superior temporal, right middle frontal gyri) combined with subcortical hypoactivations (basal ganglia), whereas unique to mania were subcortical hyperactivations (bilateral basal ganglia), combined with cortical hypoactivations (right inferior and medial frontal gyri). The fMRI changes in euthymia were associated with normal cognitive performance, whereas manic patients committed more errors during response inhibition. CONCLUSIONS: The rIFG hypoactivations were congruent with a BD trait, which may underlie the impaired response inhibition in mania. Euthymic BD subjects may compensate for the rIFG hypoactivations by hyperactivations of adjacent cortical areas, yielding comparable performance in inhibitory functions and suggesting possibilities for neuromodulation treatment of these cognitive impairments. The reversal of the activation pattern between mania and euthymia has implications for monitoring of treatment response and identification of imminent relapse.

• MeSH
• bipolární porucha komplikace   patologie   MeSH
• čelní lalok krevní zásobení   patologie   MeSH
• databáze bibliografické statistika a číselné údaje   MeSH
• inhibice (psychologie) * MeSH
• kognitivní poruchy komplikace   patologie   MeSH
• kyslík krev   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• počítačové zpracování obrazu MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH