Bipolar disorder type I and II show distinct relationships between cortical thickness and executive function.

OBJECTIVE: Frontal cortical abnormalities and executive function impairment co-occur in bipolar disorder. Recent studies have shown that bipolar subtypes differ in the degree of structural and functional impairments. The relationships between cognitive performance and cortical integrity have not been clarified and might differ across patients with bipolar disorder type I, II, and healthy subjects. METHOD: Using a vertex-wise whole-brain analysis, we investigated how cortical integrity, as measured by cortical thickness, correlates with executive performance in patients with bipolar disorder type I, II, and controls (N = 160). RESULTS: We found focal associations between executive function and cortical thickness in the medial prefrontal cortex in bipolar II patients and controls, but not in bipolar I disorder. In bipolar II patients, we observed additional correlations in lateral prefrontal and occipital regions. CONCLUSIONS: Our findings suggest that bipolar disorder patients show altered structure-function relationships, and importantly that those relationships may differ between bipolar subtypes. The findings are line with studies suggesting subtype-specific neurobiological and cognitive profiles. This study contributes to a better understanding of brain structure-function relationships in bipolar disorder and gives important insights into the neuropathophysiology of diagnostic subtypes.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.

Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.

A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Less pronounced response to exercise in healthy relatives to type 2 diabetic subjects compared with controls.

Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility compared with subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared with FH-. Sixteen FH+ and 19 FH- insulin-sensitive men similar in age, peak oxygen consumption (V̇o2 peak), and body mass index completed an exercise intervention with heart rate monitored during exercise for 7 mo. Before and after the exercise intervention, the participants underwent a physical examination and tests for glucose tolerance and exercise capacity, and muscle biopsies were taken for expression analysis. The participants attended, on average, 39 training sessions during the intervention and spent 18.8 MJ on exercise. V̇o2 peak/kg increased by 14%, and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH+ group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on V̇o2 peak, weight, and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation, and cellular respiration increased more in the FH- compared with the FH+ group. This suggests that healthy, insulin-sensitive FH+ and FH- participants with similar age, V̇o2 peak, and body mass index may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals.

Manic episodes are associated with grey matter volume reduction - a voxel-based morphometry brain analysis.

OBJECTIVE: To investigate whether the lifetime number of affective episodes or illness duration is associated with changes in local grey matter volume, in patients with bipolar I disorder without comorbid conditions. METHOD: Magnetic resonance imaging scans of 55 patients with bipolar I disorder were analysed using VBM. RESULTS: Smaller grey matter volume in the inferior frontal gyri of the dorsolateral prefrontal cortices (DLPFC) correlated significantly to the lifetime number of manic episodes. No association between local grey matter volume and the lifetime number of depression episodes or illness duration was found. CONCLUSION: We found strong evidence for a linear correlation between a decrease in DLPFC volume and the lifetime number of manic episodes in patients with bipolar I disorder. Interestingly, DLPFC is known to be important for executive functions and the findings in this study might hence be linked to the executive cognitive deficits associated with bipolar disorder.

Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood.

BACKGROUND: The vitamin K-dependent Gas6 protein (product of growth arrest specific gene 6) binds to, and activates the TAM receptor tyrosine kinases Tyro3, Axl and Mer. It has been suggested that Gas6 and the TAM receptors are important for primary platelet functions, but Gas6 cannot be found in human platelets. However, Gas6 is present in human plasma at a concentration of around 0.2 nM, which is a thousand-fold lower than that of the homologous protein S. The Axl and Mer receptors can be cleaved close to the cell membrane, yielding soluble molecules consisting of the extracellular parts of the receptors. OBJECTIVE: To investigate if soluble Axl (sAxl) is present in human serum and plasma and if Gas6 circulates in complex with sAxl. METHODS: We expressed recombinant sAxl, raised antibodies and developed and validated an ELISA for Axl. Serum and plasma were analyzed using ELISAs for Gas6, Axl and sAxl-Gas6 complexes. Serum was gel filtered and fractions analyzed by the different ELISAs to determine if Gas6 in serum is free or complexed. Immunoprecipitation was used to investigate binding between Gas6 and sAxl in serum. RESULTS: sAxl is present in serum and plasma at around 0.6 nM and all Gas6 is bound to sAxl. No complexes between Gas6 and the soluble forms of Mer and Tyro3 could be detected, indicating that sAxl is the physiological binder of Gas6 in human serum. CONCLUSIONS: Gas6 in circulation is bound to sAxl suggesting circulating Gas6 to be inhibited and incapable of stimulating the TAM receptors.

A model for chronic quantitative studies of colorectal sensitivity using balloon distension in conscious mice -- effects of opioid receptor agonists.

In the current study, colorectal distension (CRD) was performed in conscious mice, in order to study visceral (colon) sensitivity. Electrodes were chronically implanted into the external oblique muscle to obtain the electromyographic (EMG) response to CRD. CRD was performed using a computerized system, which inflated the balloon with air to the desired pressures. An increasing (10-80 mmHg) and a repeated (12 x 55 mmHg) phasic paradigm with distensions lasting 10 s and with 5-min intervals were used. The EMG recordings were linearly correlated to intracolonic pressures between 10 and 80 mmHg, which are characteristic of the visceromotor response (VMR). Repeated phasic distensions at 55 mmHg resulted in a stable VMR in female mice, but an increasing VMR in male mice. Interestingly, the duration of the VMR was about 5 s, which is shorter than the actual duration of the distension. U-69593 and fentanyl (selective kappa and mu opioid receptor agonists) significantly reduced the VMR at subcutaneous doses of 0.5 and 0.05 mg x kg-1, respectively. In conclusion, a CRD model for repetitive quantitative studies of colorectal sensitivity and evaluation of pharmacological modulation of visceral sensitivity in conscious mice is presented.

Use of polytetrafluoroethylene grafts in elderly and high-risk patients.

Despite well established methods of vascular surgery, the elderly patient has not been considered a candidate for operation because of a high operative risk and a limited life expectancy. Simplified surgical procedures and the use of new graft material now permit vascular reconstruction with minimal injury to the tissues, little blood loss, and a short operative time. The immediate postoperative mortality after vascular surgery in 68 patients 70 to 88 years of age threatened with immediate amputation was 3%. Seventy-five percent of the limbs were intact 12 months after operation and 55% after 24 months. Thus when amputation of ischemic extremities seems unavoidable, a vascular reconstruction should always be considered even in elderly patients.

Value of a follow-up study of recurrent carcinoma of the colon and rectum.

The results of our programmed follow-up study of patients with carcinoma of the colon and rectum have been disappointing. This is true also for those patients who have undergone resection with the intention of cure. This is mainly because of the discouraging results of our treatment of recurrent lesions. Chemotherapy or roentgen radiation has not regularly been used. The mean survival time has probably been prolonged in some single instances. Only three out of 36 are still alive. Oour negative results show that a follow-up study of this magnitude has been too extensive when the poor outcome is considered. We believe that a follow-up study of patients who have been operated upon for carcinoma of the colon and rectum is necessary but in a simpler form than we have done.