Abstract Cognitive impairment is evident euthymic patients with bipolar disorder (BP) and in their first-degree relatives (BP-Rel). Increasing evidence suggests that BP is also associated with social ...cognitive impairment. It is important to establish whether social cognitive impairment is also evident in BP-Rel. A novel meta-analysis of theory of mind (ToM) and facial emotion recognition in BP-Rel including 16 studies (728 first-degree relatives of patients with BP and 865 healthy controls) was conducted. ToM ( d =0.34, CI =0.16–0.52) was significantly impaired in BP-Rel. The effect size for the difference between BP-Rel and healthy controls was smaller for facial emotion recognition ( d =0.17, CI =0.16–0.29) and could be nonsignificant after the effect of publication bias was taken into account. First-degree relatives of patients with BP underperform healthy subjects in social cognitive abilities, particularly in ToM. However, the effect size for between-group difference is small. ToM impairment might be a vulnerability marker of BP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•MiR-484, −652–3p, −142–3p were downregulated and miR-185–5p was upregulated in plasma derived exosomal samples of patients with BD in comparison to those of healthy controls.•Expression levels of ...the altered miRNAs were similar among manic, depressive and euthymic states of BD.•The ROC analyses confirmed that combination of the 4 miRNAs (miR-484,−652–3p, −185–5p,−142–3p)show high sensitivity but moderate specificity for BD diagnosis.•Dysregulated miRNAs were enriched several target pathways including PI3K/Akt signaling, fatty acid biosynthesis/metabolism, extracellular matrix and adhesion pathways.
Emerging evidence suggests central roles of miRNAs in the pathogenesis of bipolar disorder (BD). Exosomes are membrane-bound vesicles acting as “biological cargo carriers” of various types of molecules including microRNAs. In this study, we aimed to investigate circulating exosomal microRNAs as potential diagnostic biomarkers for BD.
The exosomes were precipitated from plasma samples of patients with BD (n = 69; 15 depressed, 27 manic, 27 euthymic) and healthy controls (n = 41). Total RNA was extracted from the exosomes and the levels of miRNAs were assayed by qPCR. Dysregulated miRNAs were subjected to Kyoto Encyclopedia of Genes and Genomes” (KEGG) pathway analysis by DIANA-miRPath v3.0 to identify the predicted targets and the related pathways.
Thirteen miRNAs showed significant differences between patients with BD and healthy individuals; among these, MiR-484, -652–3p, -142–3p remained significantly downregulated and miR-185–5p remained significantly upregulated after accounting for multiple comparisons and adjustments for potential confounders. There were no significant alterations among different states of BD. The KEEG analysis of four dysregulated miRNAs highlighted several target pathways including PI3K/Akt signaling, fatty acid biosynthesis/metabolism, extracellular matrix and adhesion pathways.
Our findings suggest that dysregulation of miRNAs might be involved in the underlying pathophysiology of BD through several biological pathways; and highlight the importance of the exosomal miRNAs for biomarker research in BD. Further longitudinal studies may clarify the roles of exosomal miRNAs and their targets in the neurobiology of BD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Neurological soft signs (NSS) are subtle deficits in motor coordination, sensory integration, and sequencing of complex motor acts. Increased NSS is a well-established feature of patients with ...schizophrenia but a relatively smaller number of studies have investigated NSS in bipolar disorder (BD). Some authors but not others suggested that NSS can distinguish schizophrenia from BD. We conducted a meta-analysis of 18 studies to quantitatively review NSS in BD in comparison to schizophrenia and healthy controls. The current meta-analysis compared NSS scores of 725 BD patients and 634 healthy controls, and 391 BD and 471 schizophrenia patients. Patients with BD had significantly higher NSS scores (d = 1.14, CI = 0.89–1.44) than healthy controls and increased scores in BD was evident in all aspects of NSS (d = 0.88–0.99). BD was associated with a less severe increase in NSS compared to schizophrenia, however, between-group difference was modest (d = 0.42, CI = 0.18–0.65). The results of this meta-analysis demonstrated that BD is characterized by a robust increase in NSS which is only moderately less severe than schizophrenia. Increased NSS is a common feature of both disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Patients with depression have higher urine levels of 8-oxo-dG, lower expression levels of OGG1 than healthy controls.•Patients with unipolar and bipolar depression did not differ with respect to ...urine 8-oxo-dG and OGG1 expression levels.•Patients presented decreased urine levels of 8-oxo-dG, increased expression levels of OGG1 by remission of depression.
Previous studies showed significant increases in DNA base damage markers and significant alterations in base excision repair enzymes in patients with unipolar and bipolar depression. We aimed to investigate changes in urine 8-Oxo-2′-deoxyguanosine (8-oxo-dG) and gene expression levels of 8-Oxoguanine DNA glycosylase 1 (OGG1) during a current depressive episode and after remission in bipolar and unipolar disorders.
Twenty-four acutely depressed bipolar (BD), 33 unipolar depression (UD) patients and 61 healthy controls were included in the study. Clinical evaluations, blood and urine sampling were completed at baseline and at remission after eight weeks. The urine 8-oxo-dG levels were assessed by liquid chromatography tandem mass spectrometry and adjusted for urine creatinine levels. The gene expression levels of OGG1 were determined from cDNA extracted from blood samples, using real time-polymerase chain reaction.
At baseline, patients presented significantly higher levels of 8-oxo-dG (p = 0.008), and lower gene expression of OGG1 (p = 0.024) compared to controls. Levels of either 8-oxo-dG or OGG1 expression did not differ between BD and UD. In patients who remitted by the 8th week (n = 30), 8-oxo-dG decreased significantly (p = 0.001), and gene expression levels of OGG1 increased by 2.95 times compared to baseline levels (p = 0.001). All comparisons were adjusted for age, sex, smoking status and body mass index.
Our results suggest that patients with bipolar and unipolar mood disorders present increased 8-oxo-dG and decreased gene expression levels of OGG1 in current depressive episodes, and that these changes might be reversed by the resolution of depressive symptoms. The causal relationship between DNA damage and repair requires further exploration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Coherent object perception in patients with schizophrenia is known to be impaired. Oscillatory brain dynamics constitute a fundamental mechanism for the coordinated communication of neural circuits. ...Such dynamics have been proposed to reflect impaired spatio-temporal integration of sensory and cognitive processes during object perception in schizophrenia.
EEG recordings of patients with schizophrenia (n = 23) and control participants (n = 23) were examined. Presented were either an ambiguous (multistable) stimulus, endogenously inducing switching between two perceptual alternatives, or a slightly modified unambiguous control stimulus, during which perceptual reversals were triggered by a minor change in the stimulus configuration. Event-related amplitude modulation induced by perceptual reversals was analyzed for theta (3–8 Hz) and gamma band oscillations (28–48 Hz).
Patients displayed increased reaction times and more errors when indicating unambiguous reversals. The patients´ amplitude enhancement of theta oscillations was diminished in both task conditions. During the control task were gamma amplitudes larger in patients than in healthy participants.
The results indicate that impairments in generating coherent percepts are reflected in alterations of multiple frequency bands and time windows. Changes in gamma band oscillations may reflect the patients' impairments in perceptuo-cognitive integration processes. Diminished theta amplitude modulation in patients further emphasize diminished top-down cognitive control during perceptual reversals.
This study provides insight into how theta and gamma oscillations underlie changes in object perception, and thereby possibly the generation of core symptoms, in schizophrenia.
This paper is dedicated to Prof. Dr. Erol Başar, a pioneer in research on oscillatory braindynamics. He was tireless in his effort to understand brain functions and integratedphilosophy, physics, biology and psychology in his research. His vision on how informationis coded in brain networks inspired many researchers in the last 40 years. With him, we not only lose an exceptional researcher, but also a supportive academic teacher and mentor with a persistent, prolific enthusiasm for international and collaborative projects.
•Gamma and Theta oscillations seem particularly important for altered perceptual experiences in schizophrenia•Reduced theta amplitude modulation in patients with schizophrenia emphasize diminished top-down cognitive control during perceptual reversals.•Changes in gamma band oscillations may reflect the patients' impairments in perceptuo-cognitive integration processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lithium is a mood stabilizing agent commonly used for the treatment of bipolar disorder. Here, we investigated the potential neuroprotective effect of lithium against paraquat toxicity and its ...underlying mechanisms in vitro. SH-SY5Y human neuroblastoma cells were treated with paraquat (PQ) 0.5 mM concentration after lithium pretreatment to test lithium's capability in preventing cell toxicity. Cell death was evaluated by LDH, WST-8, and tryphan blue assays. Apoptosis was analyzed using DNA fragmentation, Annexin V immunostaining, Sub G1 cell cycle analysis, and caspase-3 activity assays. BCL2, BAX, and NRF2 protein expression were evaluated by Western-blotting and the BDNF protein level was determined with ELISA. mRNA levels of BCL2, BAX, BDNF, and NRF2 target genes (HO-1, GCS, NQO1), as well as miR-34a expression were analyzed by qPCR assay. Functional experiments were done via transfection with NRF2 siRNA and miR-34a mimic. Lithium treatment prevented paraquat induced cell death and apoptosis. Lithium treated cells showed increased anti-apoptotic protein BCL2 and decreased pro-apoptotic protein BAX expression. Lithium exerted a neurotrophic effect by increasing BDNF protein expression. It also diminished reactive oxygen species production and activated the redox sensitive transcription factor NRF2 and increased its target genes expression. Knockdown of NRF2 abolished neuroprotective, anti-apoptotic, and anti-oxidant effects of lithium. Furthermore, lithium significantly decreased both basal and PQ-induced expression of miR-34a. Transfection of miR-34a specific mimic reversed neuroprotective, anti-apoptotic, and anti-oxidant effects of lithium against PQ-toxicity. Our results revealed two novel mechanisms of lithium neuroprotection, namely NRF2 activation and miR-34a suppression.
Abstract Objective Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived ...neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. Method BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Results Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Limitations Small sample size in different episodes and drug-free patients was the limitation of thestudy. Conclusion Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Aims
Long‐term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and ...progression among BD patients receiving LTLT.
Methods
We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney‐related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR.
Results
Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type‐2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow‐up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers).
Conclusion
CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow‐up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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