Deniz Ceylan

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium

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.

Abnormal white matter integrity as a structural endophenotype for bipolar disorder

BACKGROUND Several lines of evidence suggest that bipolar disorder (BD) is associated with white matter (WM) pathology. Investigation of unaffected first-degree relatives of BD patients may help to distinguish structural biomarkers of genetic risk without the confounding effects of burden of illness, medication or clinical state. In the present study, we applied tract-based spatial statistics to study WM changes in patients with BD, unaffected siblings and controls. METHOD A total of 27 euthymic patients with BD type I, 20 unaffected siblings of bipolar patients and 29 healthy controls who did not have any current or past diagnosis of Axis I psychiatric disorders were enrolled in the study. RESULTS Fractional anisotropy (FA) was significantly lower in BD patients than in the control group in the corpus callosum, fornix, bilateral superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, posterior thalamic radiation, cingulum, uncinate fasciculus, superior corona radiata, anterior corona radiata and left external capsule. In region-of-interest (ROI) analyses, we found that both unaffected siblings and bipolar patients had significantly reduced FA in the left posterior thalamic radiation, the left sagittal stratum, and the fornix compared with healthy controls. Average FA for unaffected siblings was intermediate between the healthy controls and bipolar patients within these ROIs. CONCLUSIONS Decreased FA in the fornix, left posterior thalamic radiation and left sagittal stratum in both bipolar patients and unaffected siblings may represent a potential structural endophenotype or a trait-based marker for BD.

Neuroanatomical correlates of genetic risk for bipolar disorder: A voxel-based morphometry study in bipolar type I patients and healthy first degree relatives.

BACKGROUND Bipolar disorder (BD) is a highly heritable mental illness which is associated with neuroanatomical abnormalities. Investigating healthy individuals at high genetic risk for bipolar disorder may help to identify neuroanatomical markers of risk and resilience without the confounding effects of burden of illness or medication. METHODS Structural magnetic resonance imaging scans were acquired from 30 euthymic patients with BD-I (BP), 28 healthy first degree relatives of BD-I patients (HR), and 30 healthy controls (HC). Data was analyzed using DARTEL for voxel based morphometry in SPM8. RESULTS Whole-brain analysis revealed a significant main effect of group in the gray matter volume in bilateral inferior frontal gyrus, left parahippocampal gyrus, left lingual gyrus and cerebellum, posterior cingulate gyrus, and supramarginal gyrus (alphasim corrected (≤0.05 FWE)). Post-hoc t-tests showed that inferior frontal gyrus volumes were bilaterally larger both in BP and HR than in HC. BP and HR also had smaller cerebellar volume compared with HC. In addition, BP had smaller left lingual gyrus volume, whereas HR had larger left parahippocampal and supramarginal gyrus volume compared with HC. LIMITATIONS This study was cross-sectional and the sample size was not large. All bipolar patients were on medication, therefore we were not able to exclude medication effects in bipolar group in this study. CONCLUSIONS Our findings suggest that increased inferior frontal gyrus and decreased cerebellar volumes might be associated with genetic predisposition for bipolar disorder. Longitudinal studies are needed to better understand the predictive and prognostic value of structural changes in these regions.

Response inhibition and interference control in patients with bipolar I disorder and first-degree relatives

The current study aimed to assess both response inhibition (RI) and interference control (IC) in euthymic patients with bipolar disorder (BD‐Ps) as well as asymptomatic first‐degree relatives (BD‐Rs) and healthy controls (HCs) in order to evaluate trait‐as opposed to illness‐associated features of these components.

Regulators of mitochondrial complex I activity: A review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.

Mutation/SNP analysis in EF-hand calcium binding domain of mitochondrial Ca2+ uptake 1 gene in bipolar disorder patients

Calcium signaling is important for synaptic plasticity, generation of brain rhythms, regulating neuronal excitability, data processing and cognition. Impairment in calcium homeostasis contributed to the development of psychiatric disorders such as bipolar disorder (BP). MCU is the most important calcium transporter in mitochondria inner membrane responsible for influx of Ca[Formula: see text]. MICU1 is linked with MCU and has two canonical EF hands that are vital for its activity and regulates MCU-mediated Ca[Formula: see text] influx. In the current study, we aimed to investigate the role of genetic alteration of EF hand calcium binding motifs of MICU1 on the development of BP. We examined patients with BP, first degree relatives of these patients and healthy volunteers for mutations and polymorphisms in EF hand calcium binding motifs of MICU1. The result showed no SNP/mutation in BP patients, in healthy subjects and in first degree relatives. Additionally, alignment of the EF hand calcium binding regions among species (Gallus-gallus, Canis-lupus-familiaris, Bos-taurus, Mus-musculus, Rattus-norvegicus, Pan-troglodytes, Homosapiens and Danio-rerio) showed exactly the same amino acids (DLNGDGEVDMEE and DCDGNGELSNKE) except in one of the calcium binding domain of Danio-rerio that there was only one difference; leucine instead of Methionine. Our results showed that the SNP on EF-hand Ca[Formula: see text] binding domains of MICU1 gene had no effect in phenotypic characters of BP patients.

Neurobiology of Risk for Bipolar Disorder

Opinion statementBipolar disorder (BD) is a chronic mental illness which follows a relapsing and remitting course and requires lifetime treatment. The lack of biological markers for BD is a major difficulty in clinical practice. Exploring multiple endophenotypes to fit in multivariate genetic models for BD is an important element in the process of finding tools to facilitate early diagnosis, early intervention, prevention of new episodes, and follow-up of treatment response in BD. Reviewing of studies on neuroimaging, neurocognition, and biochemical parameters in populations with high genetic risk for the illness can yield an integrative perspective on the neurobiology of risk for BD. The most up-to-date data reveals consistent deficits in executive function, response inhibition, verbal memory/learning, verbal fluency, and processing speed in risk groups for BD. Functional magnetic resonance imaging (fMRI) studies report alterations in the activity of the inferior frontal gyrus, medial prefrontal cortex, and limbic areas, particularly in the amygdala in unaffected first-degree relatives (FDR) of BD compared to healthy controls. Risk groups for BD also present altered immune and neurochemical modulation. Despite inconsistencies, accumulating data reveals cognitive and imaging markers for risk and to a less extent resilience of BD. Findings on neural modulation markers are preliminary and require further studies. Although the knowledge on the neurobiology of risk for BD has been inadequate to provide benefits for clinical practice, further studies on structural and functional changes in the brain, neurocognitive functioning, and neurochemical modulation have a potential to reveal biomarkers for risk and resilience for BD. Multimodal, multicenter, population-based studies with large sample size allowing for homogeneous subgroup analyses will immensely contribute to the elucidation of biological markers for risk for BD in an integrative model.

Neurological soft signs in bipolar disorder in comparison to healthy controls and schizophrenia: A meta-analysis

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.

Oxidatively-induced DNA damage and base excision repair in euthymic patients with bipolar disorder

Oxidatively-induced DNA damage has previously been associated with bipolar disorder. More recently, impairments in DNA repair mechanisms have also been reported. We aimed to investigate oxidatively-induced DNA lesions and expression of DNA glycosylases involved in base excision repair in euthymic patients with bipolar disorder compared to healthy individuals. DNA base lesions including both base and nucleoside modifications were measured using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry with isotope-dilution in DNA samples isolated from leukocytes of euthymic patients with bipolar disorder (n = 32) and healthy individuals (n = 51). The expression of DNA repair enzymes OGG1 and NEIL1 were measured using quantitative real-time polymerase chain reaction. The levels of malondialdehyde were measured using high performance liquid chromatography. Seven DNA base lesions in DNA of leukocytes of patients and healthy individuals were identified and quantified. Three of them had significantly elevated levels in bipolar patients when compared to healthy individuals. No elevation of lipid peroxidation marker malondialdehyde was observed. The level of OGG1 expression was significantly reduced in bipolar patients compared to healthy individuals, whereas the two groups exhibited similar levels of NEIL1 expression. Our results suggest that oxidatively-induced DNA damage occurs and base excision repair capacity may be decreased in bipolar patients when compared to healthy individuals. Measurement of oxidatively-induced DNA base lesions and the expression of DNA repair enzymes may be of great importance for large scale basic research and clinical studies of bipolar disorder.

The relationship between Lithium and cancer proliferation: A case-based review of the literature

BACKGROUND The incidence and mortality rates of cancer in patients with Bipolar Disorder (BD) is higher compared with the general population. The role of Lithium (Li) in cancer proliferation/inhibition is still a controversial issue in the literature. OBJECTIVE Based on a clinical case with lithium intake and development of a renal tumor, we aimed to explore the relationship between Li use and tumor proliferation, with regard to the mechanism of action of Li. METHOD We present evidence of a female patient with bipolar disorder I, who had been on Li for several years, either as monotherapy or in combination with Valproate (VPA). While on Li monotherapy, the patient had undergone unilateral nephrectomy due to a chromophobe cell renal tumor. A literature search was performed using keywords bipolar disorder, medical comorbidity, cancer, renal tumor, lithium, mood stabilizers, valproate and mechanism of action. RESULTS The limited data on the relationship between Li and cancer proliferation in clinical populations support neither a positive relationship between long-term Li use and increased urinary tract cancers nor an overall cancer risk. Growing evidence identifies effects of Li on cancer proliferation through inhibition of glycogen synthase kinase-3β (GSK-3β), modulations of redox status, inflammatory changes, pro-/anti-apoptotic mechanisms, and mitochondrial function changes. CONCLUSION Despite the presence of contradictory data, a substantial body of evidence mainly from molecular studies points to Lis anti-carcinogenic effects. However, the underlying mechanistic pathways remain unclear. Mitochondrial dysfunction and redox modulations are potential areas for research on the relationship between Li and cancer proliferation.