Yolanda Vives-Gilabert

Microstructural white-matter abnormalities associated with treatment resistance, severity and duration of illness in major depression

BACKGROUND Although white-matter abnormalities have been reported in middle-aged patients with major depressive disorder (MDD), few data are available on treatment-resistant MDD and the influence of relevant variables related to clinical burden of illness is far from being well established. METHOD The present study examined white-matter microstructure in a sample of 52 patients with MDD in different stages (treatment-resistant/chronic MDD, n = 18; remitted-recurrent MDD, n = 15; first-episode MDD, n = 19) and 17 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. Groups were comparable in age and gender distribution, and results were corrected for familywise error (FWE) rate. RESULTS Widespread significant reductions of fractional anisotropy (FA) - including the cingulum, corpus callosum, superior and inferior longitudinal fascicule - were evident in treatment-resistant/chronic MDD compared with first-episode MDD and controls (p < 0.05, FWE-corrected). Decreased FA was observed within the ventromedial prefrontal region in treatment-resistant/chronic MDD even when compared with the remitted-recurrent MDD group (p < 0.05, FWE-corrected). Longer duration of illness (β = -0.49, p = 0.04) and higher depression severity (at a trend level: β = -0.26, p = 0.06) predicted lower FA in linear multiple regression analysis at the whole-brain level. The number of previous episodes and severity of symptoms were significant predictors when focused on the ventromedial prefrontal area (β = -0.28, p = 0.04; and β = -0.29, p = 0.03, respectively). Medication effects were controlled for in the analyses and results remained unaltered. CONCLUSIONS Our findings support the notion that disruptions of white-matter microstructure, particularly in fronto-limbic networks, are associated with resistance to treatment and higher current and past burden of depression.

Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations.

Effects of illness duration and treatment resistance on grey matter abnormalities in major depression

BACKGROUND Findings of brain structural changes in major depressive disorder are still inconsistent, partly because some crucial clinical variables have not been taken into account. AIMS To investigate the effect of major depressive disorder on grey matter volumes. METHOD Voxel-based morphometry was used to compare 66 patients with depression at different illness stages (22 each with first-episode, remitted-recurrent and treatment resistant/chronic depression) with 32 healthy controls. Brain volumes were correlated with clinical variables. RESULTS Voxel-based morphometry showed a significant group effect in right superior frontal gyrus, left medial frontal gyrus and left cingulate gyrus (P<0.05, family wise error-corrected). Patients whose condition was treatment resistant/chronic exhibited the smallest volumes in frontotemporal areas. Longer illness duration was negatively correlated with decreases in right medial frontal cortex and left insula. CONCLUSIONS Frontotemporolimbic areas are smaller in the patients with severe depression and are associated with duration of illness, but not with medication patterns, suggesting negative effects of long-lasting major depressive disorder on grey matter.

Small cerebellar cortex volume in patients with active Cushing's syndrome

OBJECTIVE Cushings syndrome (CS) is associated with neuropsychological deficits. As the cerebellum plays a key role in neuropsychological functions it may be affected in CS. The aim of this study was to investigate whether patients with CS have a smaller cerebellar volume than healthy controls, and to analyse whether cerebellar volume is associated with neuropsychological performance and clinical parameters. DESIGN A cross-sectional study was performed. METHODS Thirty-six CS patients (15 with active CS and 21 with CS in remission) and 36 controls matched for age, sex, and education underwent neuropsychological testing, quality of life assessment, clinical evaluation, and magnetic resonance imaging brain scan. Cerebellar volumes (white matter and cortex, bilateral) were calculated using FreeSurfer Software. RESULTS Patients with active CS showed smaller bilateral cerebellar cortex volumes than controls (left, P=0.035 and right, P=0.034), as well as a trend toward smaller right cerebellar cortex volumes than patients in remission CS (P=0.051). No differences were observed in the volume of cerebellar white matter between the three groups. Both right and left cerebellar cortex volumes correlated negatively with triglyceride levels (right: r=-0.358, P=0.002 and left: r=-0.317, P=0.005) and age at diagnosis (right: r=-0.433, P=0.008 and left: r=-0.457, P=0.005). Left cerebellar cortex volume also correlated positively with visual memory performance (r=0.245, P=0.038). Right cerebellar cortex volume positively correlated with quality-of-life scores (r=0.468, P=0.004). CONCLUSIONS The cerebellar cortex volume is smaller in active CS patients than in controls. This finding is associated with poor visual memory and quality of life and is mostly pronounced in patients with higher triglyceride levels and older age at diagnosis.

Predicting dementia development in Parkinson's disease using Bayesian network classifiers

Parkinsons disease (PD) has broadly been associated with mild cognitive impairment (PDMCI) and dementia (PDD). Researchers have studied surrogate, neuroanatomic biomarkers provided by magnetic resonance imaging (MRI) that may help in the early diagnosis of this condition. In this article, four classification models (naïve Bayes, multivariate filter-based naïve Bayes, filter selective naïve Bayes and support vector machines, SVM) have been applied to evaluate their capacity to discriminate between cognitively intact patients with Parkinsons disease (PDCI), PDMCI and PDD. For this purpose, the MRI studies of 45 subjects (16 PDCI, 15 PDMCI and 14 PDD) were acquired and post-processed with Freesurfer, obtaining 112 variables (volumes of subcortical structures and thickness of cortical parcels) per subject. A multivariate filter-based naïve Bayes model was found to be the best classifier, having the highest cross-validated sensitivity, specificity and accuracy. Additionally, the most relevant variables related to dementia in PD, as predicted by our classifiers, were cerebral white matter, and volumes of the lateral ventricles and hippocampi.

Volumetric MRI study of the habenula in first episode, recurrent and chronic major depression.

The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD.

Reduced DNA methylation of FKBP5 in Cushing’s syndrome

FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing’s syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing’s syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing’s syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.

Cardiovascular risk and white matter lesions after endocrine control of Cushing's syndrome

OBJECTIVE Cushings syndrome (CS) is associated with high cardiovascular risk. White matter lesions (WML) are common on brain magnetic resonance imaging (MRI) in patients with increased cardiovascular risk. AIM To investigate the relationship between cardiovascular risk, WML, neuropsychological performance and brain volume in CS. DESIGN/METHODS Thirty-eight patients with CS (23 in remission, 15 active) and 38 controls sex-, age- and education-level matched underwent a neuropsychological and clinical evaluation, blood and urine tests and 3Tesla brain MRI. WML were analysed with the Scheltens scale. Ten-year cardiovascular risk (10CVR) and vascular age (VA) were calculated according to an algorithm based on the Framingham heart study. RESULTS Patients in remission had a higher degree of WML than controls and active patients (P<0.001 and P=0.008 respectively), which did not correlate with cognitive performance in any group. WML severity positively correlated with diastolic blood pressure (r=0.659, P=0.001) and duration of hypertension (r=0.478, P=0.021) in patients in remission. Both patient groups (active and in remission) had higher 10CVR (P=0.030, P=0.041) and VA than controls (P=0.013, P=0.039). Neither the 10CVR nor the VA correlated with WML, although both negatively correlated with cognitive function and brain volume in patients in remission (P<0.05). Total brain volume and grey matter volume in both CS patient groups were reduced compared to controls (total volume: active P=0.006, in remission P=0.012; grey matter: active P=0.001, in remission P=0.003), with no differences in white matter volume between groups. CONCLUSIONS Patients in remission of Cushings syndrome (but not active patients) have more severe white matter lesions than controls, positively correlated with diastolic pressure and duration of hypertension. Ten-year cardiovascular risk and vascular age appear to be negatively correlated with the cognitive function and brain volume in patients in remission of Cushings syndrome.

NATURALISTIC COURSE OF MAJOR DEPRESSIVE DISORDER PREDICTED BY CLINICAL AND STRUCTURAL NEUROIMAGING DATA: A 5‐YEAR FOLLOW‐UP

Despite its high recurrence rate, major depression disorder (MDD) still lacks neurobiological markers to optimize treatment selection. The aim of this study was to examine the prognostic potential of clinical and structural magnetic resonance imaging (sMRI) in the long‐term MDD clinical outcomes (COs).

Alterations in Cerebral White Matter and Neuropsychology in Patients with Cirrhosis and Falls

Background & Aim Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. Patients and methods Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson’s Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson’s Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. Results The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson’s Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). Conclusions With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment.