Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis.

Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naïve first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular.

Lithium increases platelet serine-9 phosphorylated GSK-3ß levels in drug-free bipolar disorder during depressive episodes.

BACKGROUND: Glycogen synthase kinase-3 ß (GSK3ß) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3ß is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3ß becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3ß (phospho-GSK3ß) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3ß has never been studied in humans. METHODS: In 27 patients with bipolar depression, total GSK3ß and phospho-GSK3ß were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. RESULTS: No differences in phospho-GSK3ß or total GSK3ß were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3ß and total GSK3ß levels. From baseline to endpoint, lithium treatment inactivated GSK3ß by significantly increasing phospho-GSK3ß levels (p = 0.010). Clinical improvement (baseline HAM-D - endpoint HAM-D) negatively correlated with the increase in phospho-GSK3ß (p = 0.03). CONCLUSION: The present results show that lithium inactivates platelet GSK3ß in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3ß as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3ß in other neuropsychiatric disorders and as a new therapeutic target per se.

Classification of MRI under the Presence of Disease Heterogeneity using Multi-Task Learning: Application to Bipolar Disorder.

Heterogeneity in psychiatric and neurological disorders has undermined our ability to understand the pathophysiology underlying their clinical manifestations. In an effort to better distinguish clinical subtypes, many disorders, such as Bipolar Disorder, have been further sub-categorized into subgroups, albeit with criteria that are not very clear, reproducible and objective. Imaging, along with pattern analysis and classification methods, offers promise for developing objective and quantitative ways for disease subtype categorization. Herein, we develop such a method using learning multiple tasks, assuming that each task corresponds to a disease subtype but that subtypes share some common imaging characteristics, along with having distinct features. In particular, we extend the original SVM method by incorporating the sparsity and the group sparsity techniques to allow simultaneous joint learning for all diagnostic tasks. Experiments on Multi-Task Bipolar Disorder classification demonstrate the advantages of our proposed methods compared to other state-of-art pattern analysis approaches.

Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium.

BACKGROUND: Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6 weeks of lithium monotherapy and matched with healthy controls. METHODS: Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score ≥18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and endpoint using ELISA method. RESULTS: Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p=0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p=0.032 and 0.034, respectively). CONCLUSION: Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD.

Multimodal magnetic resonance imaging study of treatment-naïve adults with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication. METHODS: A newly validated method named optimally-discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naïve ADHD adults and 19 age- and gender-matched healthy controls (HC). RESULTS: Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus. CONCLUSIONS: Our results suggest that adult ADHD is associated with neuroanatomical abnormalities mainly affecting the WM microstructure in fronto-parieto-temporal circuits that have been implicated in cognitive, emotional and visuomotor processes.

Volume reduction of the corpus callosum and its relationship with deficits in interhemispheric transfer of information in recent-onset psychosis.

The present study aimed to investigate the presence of corpus callosum (CC) volume deficits in a population-based recent-onset psychosis (ROP) sample, and whether CC volume relates to interhemispheric communication deficits. For this purpose, we used voxel-based morphometry comparisons of magnetic resonance imaging data between ROP (n =122) and healthy control (n = 94) subjects. Subgroups (38 ROP and 39 controls) were investigated for correlations between CC volumes and performance on the Crossed Finger Localization Test (CFLT). Significant CC volume reductions in ROP subjects versus controls emerged after excluding substance misuse and non-right-handedness. CC reductions retained significance in the schizophrenia subgroup but not in affective psychoses subjects. There were significant positive correlations between CC volumes and CFLT scores in ROP subjects, specifically in subtasks involving interhemispheric communication. From these results, we can conclude that CC volume reductions are present in association with ROP. The relationship between such deficits and CFLT performance suggests that interhemispheric communication impairments are directly linked to CC abnormalities in ROP.

Volumetric reduction of the corpus callosum in Alzheimer's disease in vivo as assessed with voxel-based morphometry.

Several recent magnetic resonance imaging studies have employed voxel-based morphometry (VBM) to detect regional gray matter volume abnormalities in Alzheimer's disease (AD). However, investigations of corpus callosum (CC) abnormalities in AD using this automated methodology have been scarce, and no VBM study investigated correlations between regional CC atrophy and cognitive measurements in AD subjects at mild disease stages. We used VBM to compare the topography of CC volume differences between 14 AD subjects (MMSE 14-25) and 14 healthy volunteers. Images were acquired using a 1.5-Telsa scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. Significant CC atrophy was detected in the antero-superior portion of the splenium, the isthmus, the anterior and posterior portions of the CC body, and the rostral portion of the genu. Voxels showing peak statistical difference were all left-sided (P<0.001, uncorrected for multiple comparisons). A cluster of significant positive correlation with MMSE scores was seen on the left anterior CC body. Our results confirm previous findings of diffuse volumetric CC reductions early in the course of AD, and warrant further evaluation of the relevance of atrophic changes in anterior CC portions to the cognitive impairments that characterize the disorder.