Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases.

BACKGROUND: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. CASE REPORT: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5-6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. CONCLUSION: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

MaRCoS, an open-source electronic control system for low-field MRI.

Every magnetic resonance imaging (MRI) device requires an electronic control system that handles pulse sequences and signal detection and processing. Here we provide details on the architecture and performance of MaRCoS, a MAgnetic Resonance COntrol System developed by an open international community of low-field MRI researchers. MaRCoS is inexpensive and can handle cycle-accurate sequences without hard length limitations, rapid bursts of events, and arbitrary waveforms. It has also been readily adapted to meet the requirements of the various academic and private institutions participating in its development. We describe the MaRCoS hardware, firmware and software that enable all of the above, including a Python-based graphical user interface for pulse sequence implementation, data processing and image reconstruction.

Benchmarking the performance of a low-cost magnetic resonance control system at multiple sites in the open MaRCoS community.

PURPOSE: To describe the current properties and capabilities of an open-source hardware and software package that is being developed by many sites internationally with the aim of providing an inexpensive yet flexible platform for low-cost MRI. METHODS: This article describes three different setups from 50 to 360 mT in different settings, all of which used the MaRCoS console for acquiring data, and different types of software interface (custom-built GUI or Pulseq overlay) to acquire it. RESULTS: Images are presented both from phantoms and in vivo from healthy volunteers to demonstrate the image quality that can be obtained from the MaRCoS hardware/software interfaced to different low-field magnets. CONCLUSIONS: The results presented here show that a number of different sequences commonly used in the clinic can be programmed into an open-source system relatively quickly and easily, and can produce good quality images even at this early stage of development. Both the hardware and software will continue to develop, and it is an aim of this article to encourage other groups to join this international consortium.

Portable magnetic resonance imaging of patients indoors, outdoors and at home.

Mobile medical imaging devices are invaluable for clinical diagnostic purposes both in and outside healthcare institutions. Among the various imaging modalities, only a few are readily portable. Magnetic resonance imaging (MRI), the gold standard for numerous healthcare conditions, does not traditionally belong to this group. Recently, low-field MRI technology companies have demonstrated the first decisive steps towards portability within medical facilities and vehicles. However, these scanners' weight and dimensions are incompatible with more demanding use cases such as in remote and developing regions, sports facilities and events, medical and military camps, or home healthcare. Here we present in vivo images taken with a light, small footprint, low-field extremity MRI scanner outside the controlled environment provided by medical facilities. To demonstrate the true portability of the system and benchmark its performance in various relevant scenarios, we have acquired images of a volunteer's knee in: (i) an MRI physics laboratory; (ii) an office room; (iii) outside a campus building, connected to a nearby power outlet; (iv) in open air, powered from a small fuel-based generator; and (v) at the volunteer's home. All images have been acquired within clinically viable times, and signal-to-noise ratios and tissue contrast suffice for 2D and 3D reconstructions with diagnostic value. Furthermore, the volunteer carries a fixation metallic implant screwed to the femur, which leads to strong artifacts in standard clinical systems but appears sharp in our low-field acquisitions. Altogether, this work opens a path towards highly accessible MRI under circumstances previously unrealistic.

Glutamatergic and GABA-ergic abnormalities in First-episode depression. A 1-year follow-up 1H-MR spectroscopic study.

BACKGROUND: Previous magnetic resonance spectroscopic (MRS) studies have reported brain metabolic abnormalities in Major Depressive Disorder (MDD). Nevertheless, results have been inconsistent, focusing on fully developed major depression neglecting first episode patients (FED). Longitudinal studies have also been rare and with short follow-up periods. The aim of the current study was to investigate the differences between healthy controls and first episode patients at baseline, together with changes of metabolites after 1 year follow-up in the ventromedial prefrontal cortex. METHODS: 1H-MRS images were obtained from 64 healthy controls and 31 FED patients using a 3T Philips Achieva scanner and processed with TARQUIN software at baseline and after 1 year. Examined metabolites included Glx (corresponding to Glu+Gln-peak), Glu, NAAG, myo-Ins, Cr, GSH and GABA. Clinical improvement was assessed by HDRS-17 scale. Differences in the concentrations of metabolites were evaluated by MANOVA/MANCOVA and GLM repeated measures for longitudinal changes. RESULTS: FED patients had significantly decreased glutamate levels at baseline (p < 0.05) along with significantly elevated GABA (p < 0.01) compared to healthy controls. At the follow up, myo- Ins levels were significantly increased compared to baseline (p < 0.05) LIMITATIONS: The limited sample size, together with the unexpectedly high response rate after treatment (83%) might suggest decreased representativeness of the sample. CONCLUSIONS: Results indicate glutamatergic and GABAergic changes taking place within the ventromedial prefrontal region even at the early stage of depression prior to any medication treatment.

Classification model based on strain measurements to identify patients with arrhythmogenic cardiomyopathy with left ventricular involvement.

BACKGROUND AND OBJECTIVE: A heterogenous expression characterizes arrhythmogenic cardiomyopathy (AC). The evaluation of regional wall movement included in the current Task Force Criteria is only qualitative and restricted to the right ventricle. However, a strain-based approach could precisely quantify myocardial deformation in both ventricles. We aim to define and modelize the strain behavior of the left ventricle in AC patients with left ventricular (LV) involvement by applying algorithms such as Principal Component Analysis (PCA), clustering and naïve Bayes (NB) classifiers. METHODS: Thirty-six AC patients with LV involvement and twenty-three non-affected family members (controls) were enrolled. Feature-tracking analysis was applied to cine cardiac magnetic resonance imaging to assess strain time series from a 3D approach, to which PCA was applied. A Two-Step clustering algorithm separated the patients' group into clusters according to their level of LV strain impairment. A statistical characterization between controls and the new AC subgroups was done. Finally, a NB classifier was built and new data from a small evolutive dataset was predicted. RESULTS: 60% of AC-LV patients showed mildly affected strain and 40% severely affected strain. Both groups and controls exhibited statistically significant differences, especially when comparing controls and severely affected AC-LV patients. The classification accuracy of the strain NB classifier reached 82.76%. The model performance was as good as to classify the individuals with a 100% sensitivity and specificity for severely impaired strain patients, 85.7% and 81.1% for mildly impaired strain patients, and 69.9% and 91.4% for normal strain, respectively. Even when the severely affected LV-AC group was excluded, LV strain showed a good accuracy to differentiate patients and controls. The prediction of the evolutive dataset revealed a progressive alteration of strain in time. CONCLUSIONS: Our LV strain classification model may help to identify AC patients with LV involvement, at least in a setting of a high pretest probability, such as family screening.

Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Left ventricular myocardial dysfunction in arrhythmogenic cardiomyopathy with left ventricular involvement: A door to improving diagnosis.

BACKGROUND: Diagnostic Task Force Criteria (TFC) for arrhythmogenic cardiomyopathy (AC) exhibit poor performance for left dominant forms. TFC only include right ventricular (RV) dysfunction (akinesia, dyssynchrony, volumes and ejection fraction). Moreover, cardiac magnetic resonance imaging (CMRI) assessment of left ventricular (LV) dyssynchrony has hitherto not been described. Thus, we aimed to comprehensively characterize LV CMRI behavior in AC patients. METHODS: Thirty-five AC patients with LV involvement and twenty-three non-affected family members (controls) were enrolled. Feature-tracking analysis was applied to cine CMRI to assess LV ejection fraction (LVEF), LV end-systolic and end-diastolic volume indexes, strain values and dyssynchrony. Regions with more frequent strain and dyssynchrony impairment were also studied. RESULTS: Radial dyssynchrony and LVEF were selected (sensitivities 54.3% and 48.6%, respectively at 100% specificity), with a threshold of 70 ms for radial dyssynchrony and 48.5% for LVEF. 71.4% of patients exceeded these thresholds (31.4% both, 22.9% only dyssynchrony and 17.1% only LVEF). Considering these cut-off values as a novel combined criterion, 30% of patients with 'borderline' or 'possible' AC following 2010 TFC would move to a 'definite' AC diagnosis. Strain was globally impaired whereas dyssynchronous regions were more often apical and located at the inferolateral wall. CONCLUSIONS: Mirroring the RV evaluation, we suggest including LVEF and LV dyssynchrony to improve the diagnosis of AC. Two independent mechanisms can be claimed in AC patients with LV involvement: 1) decreased myocardial deformation with global LV affectation and 2) delayed myocardial contraction at localized regions.

Depression and Anxiety Scores Are Associated with Amygdala Volume in Cushing's Syndrome: Preliminary Study.

INTRODUCTION: Cushing's syndrome (CS) has repeatedly been associated with hippocampal volume reductions, while little information is available on the amygdala, another structure rich in glucocorticoid receptors. The aim of the study was to analyze amygdala volume in patients with CS and its relationship with anxiety, depression, and hormone levels. MATERIAL AND METHODS: 39 CS patients (16 active and 23 patients in remission) and 39 healthy controls matched for age, sex, and education level completed anxiety (STAI) and depression tests (BDI-II) and underwent a 3 Tesla brain MRI and endocrine testing. Amygdala volumes were analysed with FreeSurfer software. RESULTS: Active CS patients had smaller right (but not left) amygdala volumes when compared to controls (P = 0.045). Left amygdala volumes negatively correlated with depression scores (r = -0.692, P = 0.003) and current anxiety state scores (r = -0.617, P = 0.011) in active CS patients and with anxiety trait scores (r = -0.440, P = 0.036) in patients in remission. No correlations were found between current ACTH, urinary free cortisol or blood cortisol levels, and amygdala volumes in either patient group. CONCLUSION: Patients with active CS have a smaller right amygdala volume in comparison to controls, while left amygdala volumes are associated with mood state in both patient groups.

White matter involvement on DTI-MRI in Cushing's syndrome relates to mood disturbances and processing speed: a case-control study.

PURPOSE: Cushing's syndrome (CS) is an endocrine disorder due to prolonged exposure to cortisol. Recently, microstructural white matter (WM) alterations detected by diffusion tensor imaging (DTI) have been reported in CS patients, and related to depression, but other functional significances. remain otherwise unclear. We aimed at investigating in more depth mood symptoms in CS patients, and how these relate to cognition (information processing speed), and to WM alterations on DTI. METHODS: The sample comprised 35 CS patients and 35 healthy controls. Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, State-Trait Anxiety Inventory (STAI) to assess anxiety, and processing speed was measured by the Symbol Digit Modalities Test (SDMT). DTI studies were acquired using a 3-Tesla Philips-Achieva MR-facility. Voxelwise statistical analysis of fractional anisotropy (FA), mean, axial and radial diffusivities (MD, AD, RD) data were performed using FMRIB Software Library. Correlation analysis were obtained between mood and processing speed variables, and FA, MD, AD and RD values, taking both CS patients and healthy controls. RESULTS: Active, controlled and cured CS patients showed greater depression (F = 12.4, p < 0.001), anxious state (F = 4.8, p = 0.005) and anxious trait (F = 9.6, p < 0.001) scores, than controls. Using the entire sample, depression scores correlated negatively to FA and positively to RD values. Although there were no differences in processing speed between groups, SDMT scores correlated positively to both FA and AD values. CONCLUSIONS: There were greater depressive and anxious symptoms in CS patients than in healthy controls, but no difference in processing speed. However, DTI is related to depression and information processing speed in CS.

Altered amplitude of low frequency fluctuations in schizophrenia patients with persistent auditory verbal hallucinations.

The aim of this study is to analyze the differences in low frequency fluctuation (LFF) values between schizophrenia patients with and without auditory verbal hallucinations (AVH). Nineteen schizophrenia patients with persistent AVH (HP), fourteen non-hallucinating schizophrenia patients (nHP) and twenty healthy controls (HC) underwent R-fMRI. LFF values were calculated in the slow frequency band (0.01-0.08Hz). By means of group level contrasts, we performed direct voxel-wise group comparisons. Both groups of patients showed decreased amplitude LFF (ALFF) values in the occipital pole and lingual gyrus compared to HC, whereas increased ALFF values were found in the temporal pole and fusifom gyrus. Schizophrenia patients exhibited decreased fractional ALFF (fALFF) values in the precuneus, occipital pole and bilateral occipital cortex, and increased fALFF in the insula compared to HC. There were also differences between patients with and without AVH. (Ok to start with lower case?) fALFF values were higher in the putamen and insular cortex and lower in the frontal pole in HP compared to nHP and HC. ALFF increased in HP patients in the bilateral thalamus and bilateral parahippocampal gyrus, compared to nHP patients and HC. Our results suggest that altered dynamics in low-frequency fluctuations may play a key role in the neurophysiology of auditory hallucinations.

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

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.

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

BACKGROUND: 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). METHODS: Forty-nine MDD patients were grouped into one of four different CO categories according to their trajectory: recovery, partial remission, remission recurrence, and chronic depression. Regression models including baseline demographic, clinical, and sMRI data were used for predicting patients' COs and symptom severity 5 years later. RESULTS: The model including only clinical data explained 32.4% of the variance in COs and 55% in HDRS, whereas the model combining clinical and sMRI data increased up to 52/68%, respectively. A bigger volume of right anterior cingulate gyrus was the variable that best predicted COs. CONCLUSIONS: The findings suggest that the addition of sMRI brain data to clinical information in depressive patients can significantly improve the prediction of their COs. The dorsal part of the right anterior cingulate gyrus may act as a potential biomarker of long-term clinical trajectories.

Brain metabolite abnormalities in ventromedial prefrontal cortex are related to duration of hypercortisolism and anxiety in patients with Cushing's syndrome.

Chronic exposure to excessive glucocorticoid (GC) concentration in Cushing's syndrome (CS) can affect the brain structurally and functionally; ventromedial prefrontal cortex (vmPFC) is rich in GC receptors and therefore particularly vulnerable to excessive GC concentration. Proton magnetic resonance spectroscopy ((1)H-MRS) is a sensitive, non-invasive imaging technique that provides information on brain metabolites in vivo. Our aim was to investigate metabolite concentrations in vmPFC of CS patients and their relationship with clinical outcome. Twenty-two right-handed CS patients (7 active/15 in remission, 19 females, 41.6 ± 12.3 years) and 22 right-handed healthy controls (14 females, 41.7 ± 11 years) underwent brain MRI and (1)H-MRS exams at 3 Tesla. Concentrations of glutamate (Glu), glutamate + glutamine (Glx), creatine (Cr), N-Acetyl-aspartate (NAA), N-Acetyl-aspartate + N-acetylaspartylglutamate (total NAA), choline-containing compounds (Cho) and myoinositol (MI) were determined. Moreover, anxiety and depressive symptoms were evaluated with the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory-II (BDI-II) test, respectively. CS patients had lower concentrations of glutamate and total NAA in the vmPFC than healthy controls (8.6 ± 1.2 vs. 9.3 ± 0.7 mmol/L, and 6.4 ± 0.8 vs. 6.8 ± 0.4 mmol/L, respectively; p < 0.05). Duration of hypercortisolism was negatively correlated with total NAA (r = -0.488, p < 0.05). Moreover, the concentration of total NAA was negatively correlated with anxiety state (r = -0.359, p < 0.05). Brain metabolites are abnormal in the vmPFC of patients with CS. Decreased total NAA and glutamate concentrations indicate neuronal dysfunction that appear to be related with duration of hypercortisolism and anxiety.

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

OBJECTIVE: Cushing's 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 Cushing's 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 Cushing's syndrome.

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.

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.