Marcus V. Zanetti

State-dependent microstructural white matter changes in bipolar I depression

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

Voxel-based morphometry in Alzheimer’s disease

Recent morphometric MRI studies have investigated brain volume abnormalities associated with the diagnosis of Alzheimer’s disease (AD) using voxel-based morphometry (VBM). This technique allows the assessment of gray matter volumes in subjects with AD or related conditions compared with healthy controls in an automated fashion, across the whole brain. This article reviews VBM findings related to different AD stages and its prodrome, mild cognitive impairment. These findings include not only gray matter deficits in medial temporal structures as seen in former MRI studies of AD conducted using manual region-of-interest measurements, but also volume changes in several other brain regions not assessed in previous MRI studies. We also discuss potential applications of VBM to improve AD diagnostic accuracy in routine clinical practice. Finally, we highlight future research directions in this field, including: investigations on the relationship between VBM findings of multifocal gray matter deficits and changes in white matter tracts that interconnect such regions; the need for population-based VBM studies using large AD samples; and the potential of studies combining VBM measurements with other potential biological markers (such as brain imaging indices of amyloid-β deposition and cerebrospinal fluid AD markers) to further advance our knowledge about the physiopathology of AD.

Age-related gray matter volume changes in the brain during non-elderly adulthood

Previous magnetic resonance imaging (MRI) studies described consistent age-related gray matter (GM) reductions in the fronto-parietal neocortex, insula and cerebellum in elderly subjects, but not as frequently in limbic/paralimbic structures. However, it is unclear whether such features are already present during earlier stages of adulthood, and if age-related GM changes may follow non-linear patterns at such age range. This voxel-based morphometry study investigated the relationship between GM volumes and age specifically during non-elderly life (18–50 years) in 89 healthy individuals (48 males and 41 females). Voxelwise analyses showed significant (p < 0.05, corrected) negative correlations in the right prefrontal cortex and left cerebellum, and positive correlations (indicating lack of GM loss) in the medial temporal region, cingulate gyrus, insula and temporal neocortex. Analyses using ROI masks showed that age-related dorsolateral prefrontal volume decrements followed non-linear patterns, and were less prominent in females compared to males at this age range. These findings further support for the notion of a heterogeneous and asynchronous pattern of age-related brain morphometric changes, with region-specific non-linear features.

Increased rates of white matter hyperintensities in late-onset bipolar disorder

OBJECTIVES Magnetic resonance imaging (MRI) studies have reported an increased frequency of white matter hyperintensities (WMH) in association with late-onset (LO) depression, and this has supported the notion that vascular-related mechanisms may be implicated in the pathophysiology of LO mood disorders. Recent clinical studies have also suggested a link between LO bipolar disorder (LO-BD) and cerebrovascular risk factors, but this has been little investigated with neuroimaging techniques. In order to ascertain whether there could be a specific association between WMH and LO-BD, we directly compared WMH rates between LO-BD subjects (illness onset >or= 60 years), early-onset BD subjects (EO-BD, illness onset <60 years), and elderly healthy volunteers. METHODS T2-weighted MRI data were acquired in LO-BD subjects (n = 10, age = 73.60 +/- 4.09), EO-BD patients (n = 49, age = 67.78 +/- 4.44), and healthy subjects (n = 24, age = 69.00 +/- 7.22). WMH rates were assessed using the Scheltens scale. RESULTS There was a greater prevalence of WMH in LO-BD patients relative to the two other groups in the deep parietal region (p = 0.018) and basal ganglia (p < 0.045). When between-group comparisons of mean WMH scores were conducted taking account of age differences (ANCOVA), there were more severe scores in LO-BD patients relative to the two other groups in deep frontal and parietal regions, as well as in the putamen (p < 0.05). CONCLUSIONS Our results provide empirical support to the proposed link between vascular risk factors and LO-BD. If extended in future studies with larger samples, these findings may help to clarify the pathophysiological distinctions between bipolar disorder emerging at early and late stages of life.

A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects

OBJECTIVES Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent-onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first-onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls. METHODS A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM-IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel-based morphometry. RESULTS The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right-sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left-sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p=0.01, corrected for multiple comparisons). CONCLUSIONS These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.

White-matter hyperintensities in first-episode psychosis

Background White-matter hyperintensities have been associated with both schizophrenia and mood disorders, particularly bipolar disorder, but results are inconsistent across studies. Aims To examine whether white-matter hyperintensities are a vulnerability marker for psychosis or are specifically associated with bipolar disorder. Method T2-weighted magnetic resonance imaging data were acquired in 129 individuals with first-episode psychosis (either affective or non-affective psychoses) and 102 controls who were randomly selected from the same geographical areas. Visual white-matter hyperintensity ratings were used for group and subgroup comparisons. Results There were no statistically significant between-group differences in white-matter hyperintensity frequency or severity scores. No significant correlations were found between white-matter hyperintensity scores and duration of illness, duration of untreated psychosis, or severity of psychotic, manic or depressive symptoms. Conclusions White-matter hyperintensities are not associated with vulnerability to psychosis in general, or specifically with affective psychoses. Further, first-episode psychosis investigations using more quantitative methods are warranted to confirm these findings.

Neuroanatomical Classification in a Population-Based Sample of Psychotic Major Depression and Bipolar I Disorder with 1 Year of Diagnostic Stability

The presence of psychotic features in the course of a depressive disorder is known to increase the risk for bipolarity, but the early identification of such cases remains challenging in clinical practice. In the present study, we evaluated the diagnostic performance of a neuroanatomical pattern classification method in the discrimination between psychotic major depressive disorder (MDD), bipolar I disorder (BD-I), and healthy controls (HC) using a homogenous sample of patients at an early course of their illness. Twenty-three cases of first-episode psychotic mania (BD-I) and 19 individuals with a first episode of psychotic MDD whose diagnosis remained stable during 1 year of followup underwent 1.5 T MRI at baseline. A previously validated multivariate classifier based on support vector machine (SVM) was employed and measures of diagnostic performance were obtained for the discrimination between each diagnostic group and subsamples of age- and gender-matched controls recruited in the same neighborhood of the patients. Based on T1-weighted images only, the SVM-classifier afforded poor discrimination in all 3 pairwise comparisons: BD-I versus HC; MDD versus HC; and BD-I versus MDD. Thus, at the population level and using structural MRI only, we failed to achieve good discrimination between BD-I, psychotic MDD, and HC in this proof of concept study.

Leukocyte mitochondrial DNA copy number in bipolar disorder

BACKGROUND Evidence supports the role for mitochondrial impairment in the pathophysiology of bipolar disorder (BD). BD has been associated with decreased mitochondrial electron transport chain activity and increased oxidative stress. Also, mitochondrial DNA (mtDNA) encodes mitochondrial electron transport chain proteins and has been associated with altered oxidative stress. Preclinical studies showed that lithium treatment increased mtDNA content, but no study has directly assessed mtDNA content in subjects with BD in vivo. Also, the effects of lithium treatment on mtDNA content have never been evaluated in humans. METHODS Leukocyte mtDNA content using real time-PCR was evaluated in subjects with BD (n=23) in a depressive episode (≥18 in the 21-item Hamilton Depression Rating Scale) before and after 6-week lithium treatment versus healthy controls (n=24). RESULTS mtDNA content showed no significant difference between subjects with BD at baseline and controls (p=0.46); also no difference was observed when comparing before and after lithium treatment. A trend for decreased mtDNA content was specifically observed in BD type I compared to controls and BD type II (p=0.05). Importantly, endpoint mtDNA copy number was significantly correlated with age. CONCLUSION In BD subjects who were younger, unmedicated and had a shorter duration of illness, no change was observed in mtDNA copy number. More studies with larger samples are warranted to evaluate mtDNA content changes in BD and its potential role as a treatment target, especially in BD type I and its association with aging.

Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder

Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.

Lithium decreases plasma adiponectin levels in bipolar depression.

Lithium, a first line treatment for bipolar disorder (BD), has been associated with significant weight gain, but the mechanisms underlying this phenomenon are still unclear. It has been suggested that changes in production/release of adipokines - molecules secreted by adipose tissue presenting anti-inflammatory (adiponectin) and pro-inflammatory (leptin, resistin) properties - might be implicated. Adiponectin, resistin and leptin were assessed in 25 acutely depressed BD individuals (88% medication-free and 68% treatment-naive) at baseline and after 6 weeks of lithium therapy, and in 23 healthy controls matched by age. The 21-item Hamilton Depression Rating Scale was used to assess depression severity. Levels of adiponectin significantly decreased after lithium monotherapy, while the levels of resistin and leptin remained stable after the follow-up period. Adipokine levels during depressive episodes in BD did not differ compared to controls. Pretreatment levels of leptin were higher in remitters and changes in resistin levels were negatively correlated to improvement of depressive symptoms with lithium. Our findings shed light in this pathophysiological process, which might be associated with metabolic syndrome, inflammation and other medical comorbidities in BD.