Structural dysconnectivity in offspring of individuals with bipolar disorder: The effect of co-existing clinical-high-risk for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) might be associated in disturbances in brain networks. However, little is known about the abnormalities in structural brain connectivity which might be related to vulnerability to BD and predictive of the emergence of manic symptoms. No previous study has investigated the effect of subthreshold syndromes on structural dysconnectivity in offspring of parents with BD (BDoff). METHODS: We investigated diffusion weighted images of 70 BDoff and 48 healthy controls (HC). Nineteen of the 70 BDoff had presented with subthreshold syndromes indicating a clinical high-risk (BDoff-CHR) and other 51 BDoff had no such history (BDoff-non-CHR). Global and regional network properties, rich club organization and inter-regional connectivity in BDoff and healthy controls were investigated using graph analytical methods and network-based-statistics (NBS). RESULTS: Global properties of WM networks appeared to be intact in BDoff-CHR and BDoff-non-CHR. However, decreased regional connectivity in right occipito-parietal areas and cerebellum was a common feature of both BDoff groups. Importantly, decreased interregional connectivity between nodes in right and left prefrontal regions, nodes in right prefrontal lobe and right temporal lobe and nodes in left occipital area and left cerebellum were evident in BDoff-CHR but not BDoff-non-CHR. LIMITATIONS: The cross-sectional nature of the study was the main consideration. CONCLUSION: Decreased regional connectivity in right posterior brain regions might be related to vulnerability to BD. On the other hand, interregional dysconnectivity in anterior frontal and limbic regions and left posterior brain regions might be evident in individuals genetically at risk for developing BD who had experienced subthreshold mood symptoms.

Neurocognition in young offspring of individuals with bipolar disorder: The role of co-existing familial and clinical high-risk for bipolar disorder.

Bipolar disorder (BD) is associated with cognitive dysfunction which has also been reported in offspring of individuals with BD (BDoff). However, it remains unclear whether cognitive underperformance in BDoff is associated with the presence of history of subclinical syndromes associated with risk for BD. To address this knowledge gap we assessed executive function, visual and verbal memory, working memory, processing speed and verbal fluency in 21 offspring with clinical high risk (CHR; BDoff+CHR), 54 offspring without CHR (BDoff-non-CHR), and 50 healthy individuals without familial risk of BD. BDoff underperformed compared to controls in most cognitive tasks. There was no significant neurocognitive difference between BDoff+CHR and BDoff-non-CHR except in the fluency/central executive domain (Cohen's d = 0.60, p = 0.03). Our results suggest that cognitive dysfunction in multiple domains is associated with familial predisposition to BD regardless of CHR status. On the other hand, abnormalities in central executive processes might be more pronounced in BDoff+CHR than BDoff-non-CHR. Further longitudinal studies investigating cognitive trajectory of BDoff and its interaction with the emergence of subclinical syndromes are needed to fully characterize the relationship between cognition and mood dysregulation in BD.

Neurocognitive heterogeneity in young offspring of patients with bipolar disorder: The effect of putative clinical stages.

BACKGROUND: Bipolar disorder (BD) is associated with significant cognitive heterogeneity. In recent years, a number of studies have investigated cognitive subgroups in BD using data-driven methods and found that BD includes several subgroups including a severely impaired and a neurocognitively intact cluster. Studies in offspring of BD (BDoff) are particularly important to establish the timing of emergence of cognitive subgroups but studies investigating cognitive heterogeneity in BDoff are lacking. Our aim was to investigate cognitive heterogeneity in BDoff and the relationship between cognitive heterogeneity and putative clinical stages of BD. METHODS: Seventy-one euthymic BDoff and 50 healthy controls were assessed using clinical measures and a battery of neuropsychological tests. Neurocognitive subgroups were investigated using latent class analysis. RESULTS: Three neurocognitive subgroups, including a severe impairment group, a good performance cluster, and a subgroup characterized by intermediate/selective impairment was found. Both severe and intermediate level impairment subgroups underperformed healthy controls in processing speed, verbal fluency, visual memory and working memory. Deficits in verbal memory and executive functions were only evident in severe impairment subgroup. The putative stage of the illness had no significant effect on cognitive clustering of BDoff. Trait impulsivity scores were significantly increased in severe and intermediate impairment clusters but not in the cognitively good functioning subgroup of BDoff. LIMITATIONS: The cross-sectional nature of the study was the main consideration. CONCLUSION: These results suggest that cognitive heterogeneity is premorbid characteristic of BD and cognitive subgroups of BDoff emerge prior to the onset of illness and prodromal symptoms.

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.

DNA redox modulations and global DNA methylation in bipolar disorder: Effects of sex, smoking and illness state.

DNA redox modulations and methylation have been associated with bipolar disorder (BD) pathophysiology. We aimed to investigate DNA redox modulation and global DNA methylation and demethylation levels in patients with BD during euthymia, mania or depression in comparison to non-psychiatric controls. The roles of sex and smoking as susceptibility factors for DNA redox modulations and global DNA methylation and demethylation were also explored. Levels of 5-methylcytosine (5-mC), 5-hydroxymethylcytosine (5-hmC) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were assessed in DNA samples of 75 patients with DSM-IV BD type I (37 euthymic, 18 manic, 20 depressive) in comparison to 60 non-psychiatric controls. Levels of 5-mC and 5-hmC were assessed using Dot Blot as a screening process, and verified using ELISA. Levels of 8-OHdG were assessed using ELISA. The levels of 8-OHdG significantly differed among non-psychiatric control, euthymia, mania and depression groups [F (3,110) = 2.771, p = 0.046], whereas there were no alterations in the levels of 5-hmC and 5-mC. Linear regression analyses revealed the significant effects of smoking (p = 0.031) and sex (p = 0.012) as well as state of illness on the levels of 8-OHdG (p = 0.025) in patients with BD. Our results suggest that levels of 8-OHdG may be affected by sex, illness states and smoking in BD.

Neurobiology of Risk for Bipolar Disorder.

Bipolar 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.

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.