Beatriz Gómez-Ansón

Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression

Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: A prospective study with time-dependent analysis

OBJECTIVES:The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis.METHODS:A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1H-magnetic resonance spectroscopy.RESULTS:Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium <130 mEq/l), history of overt HE, serum bilirubin, and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels.CONCLUSIONS:In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.

Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia

Parkinsons disease (PD) involves neuropathological changes in the limbic system that lead to neuronal loss and volumetric reductions of several nuclei. We investigated possible volumetric reductions of the amygdala and hippocampus associated to PD. We carried out magnetic resonance imaging (MRI) volumetric studies in 16 patients with PD and dementia (PDD), 16 patients with PD without dementia (PD), and 16 healthy subjects. The general analysis of variance (ANOVA) showed a significant group effect (for the amygdala, P = 0.01; for the hippocampus, P = 0.005). A post‐hoc test demonstrated that the differences were due to PDD and control group comparisons for the amygdala (P = 0.008) and for the hippocampus (P = 0.004). In nondemented PD subjects, we observed an 11% reduction in the amygdala and a 10% reduction in the hippocampus compared with that in controls. In summary, demented PD patients have clear amygdalar and hippocampal atrophy that remains statistically significant after controlling for global cerebral atrophy. Nondemented PD patients also showed a degree of volumetric reduction in these structures although the differences were not statistically significant.

Longitudinal evaluation of cerebral morphological changes in Parkinson's disease with and without dementia

AbstractObjectiveTo investigate the pattern of brain atrophy across time in a sample of Parkinsons disease (PD) patients with and without dementia using voxelbased morphometry (VBM) analysis.MethodsThe initial sample comprised thirteen non–demented PD patients and sixteen demented patients. Longitudinal cognitive assessment and structural MRI were performed. The mean follow–up period was 25 months (SD = 5.2). From this initial group, eight PD patients with dementia (5 men and 3 women) and eleven PD patients without dementia (7 men and 4 women) were reevaluated. MRI 3D structural images were acquired and analyzed by means of the optimized VBM procedure with Statistical Parametric Mapping (SPM2).ResultsVBM analysis showed a progressive grey matter volume decrease in patients with PD without dementia in limbic, paralimbic and neocortical associative temporooccipital regions. In patients with dementia the loss mainly involved neocortical regions.ConclusionVBM revealed a significant loss of grey matter volume in PD patients with and without dementia with disease progression. The decrease in limbic and paralimbic regions is widespread in non–demented patients. Neocortical volume reduction is the most relevant finding in patients with dementia. This suggests that the neocortex is a substrate for dementia in Parkinson disease.

Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis.

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo‐inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo‐osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by 1H–magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline‐containing compounds, creatine/phosphocreatine, and N‐acetyl‐aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients. (HEPATOLOGY 2004;39:1613‐1622.)

Manual validation of FreeSurfer's automated hippocampal segmentation in normal aging, mild cognitive impairment, and Alzheimer Disease subjects

Hippocampal volume is reduced in Alzheimer Disease (AD) and has been proposed as a possible surrogate biomarker to aid early diagnosis. Whilst automated methods to segment the hippocampus from magnetic resonance images are available, manual segmentation, in spite of being time-consuming and unsuitable for large samples, is still the standard. In order to study the validity of FreeSurfers automated method, we compared hippocampal automated measures with manual tracing in a sample composed of healthy elderly (N=41), Mild Cognitive Impairment (MCI) (N=23), and AD (N=25) subjects. Percent volume overlap, percent volume difference, correlations, and Bland-Altman plots were studied. Automated measures were slightly larger than hand tracing ones (mean difference 10%). Percent volume overlap showed good results, but was far from perfect (78%). Manual and automated volume correlations were approximately 0.84 and the Bland-Altman analysis showed acceptable interchangeability of methods. Within-group analysis demonstrated that patient samples obtained smaller values in validity indexes than controls. Globally, FreeSurfers automated hippocampal volumetry showed adequate validity when compared to manual tracing, with a tendency to overestimation. Nevertheless, the greater difference between automated and manual segmentation in atrophic brains suggests that studies in AD based on this software could be more likely to produce false negatives.

Verbal and Visual Memory Performance and Hippocampal Volumes, Measured by 3-Tesla Magnetic Resonance Imaging, in Patients with Cushing's Syndrome

CONTEXT Cushings syndrome (CS) affects cognition and memory. OBJECTIVE Our objective was to evaluate memory and hippocampal volumes (HV) on 3-tesla magnetic resonance imaging (3T MRI) in CS patients and controls. PATIENTS AND METHODS Thirty-three CS patients (11 active, 22 cured) and 34 controls matched for age, sex, and education underwent Rey Auditory Verbal Learning Test and Rey-Osterrieth Complex Figure memory tests. Gray matter and HV were calculated on 3T MRI, using FreeSurfer image analyses software. RESULTS No differences in HV were observed between active and cured CS or controls. Memory performance was worse in CS patients than controls (P < 0.04 in active; P < 0.03 in cured CS) but did not differ among CS groups, which were therefore analyzed together; they performed worse for verbal (P = 0.02) and visual memory (P = 0.04) than controls. In 12 CS patients, memory was below normative cutoff values for verbal (n = 6, cured), visual memory (n = 10, six cured) or both (n = 4); these patients with severe memory impairments showed smaller HV compared with their matched controls (P = 0.02 with verbal impairment; P = 0.03 with visual impairment). They were older (P = 0.04), had shorter education (P = 0.02), and showed a trend toward longer duration of hypercortisolism (P = 0.07) than the remaining CS patients. Total (P = 0.004) and cortical (P = 0.03) brain gray matter volumes were decreased in CS compared with controls, indicating brain atrophy, whereas subcortical gray matter (which includes HV) was reduced only in the 12 patients with severe memory impairment. CONCLUSION Verbal and visual memory is worse in CS patients than controls, even after biochemical cure. HV was decreased only in those whose memory scores were below normative cutoff values.

Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease.

Background Dementia is a frequent and devastating complication in Parkinson’s disease (PD). There is an intensive search for biomarkers that may predict the progression from normal cognition (PD-NC) to dementia (PDD) in PD. Mild cognitive impairment in PD (PD-MCI) seems to represent a transitional state between PD-NC and PDD. Few studies have explored the structural changes that differentiate PD-NC from PD-MCI and PDD patients. Objectives and Methods We aimed to analyze changes in cortical thickness on 3.0T Magnetic Resonance Imaging (MRI) across stages of cognitive decline in a prospective sample of PD-NC (n = 26), PD-MCI (n = 26) and PDD (n = 20) patients, compared to a group of healthy subjects (HC) (n = 18). Cortical thickness measurements were made using the automatic software Freesurfer. Results In a sample of 72 PD patients, a pattern of linear and progressive cortical thinning was observed between cognitive groups in cortical areas functionally specialized in declarative memory (entorhinal cortex, anterior temporal pole), semantic knowledge (parahippocampus, fusiform gyrus), and visuoperceptive integration (banks of the superior temporal sulcus, lingual gyrus, cuneus and precuneus). Positive correlation was observed between confrontation naming and thinning in the fusiform gyrus, parahippocampal gyrus and anterior temporal pole; clock copy with thinning of the precuneus, parahippocampal and lingual gyrus; and delayed memory with thinning of the bilateral anteromedial temporal cortex. Conclusions The pattern of regional decreased cortical thickness that relates to cognitive deterioration is present in PD-MCI patients, involving areas that play a central role in the storage of prior experiences, integration of external perceptions, and semantic processing.

Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy

BACKGROUND & AIMS We applied advanced magnetic resonance imaging and Voxed based Morphometry analysis to assess brain tissue density in patients with cirrhosis. METHODS Forty eight patients with cirrhosis without overt hepatic encephalopathy (17 Child A, 13 Child B, and 18 Child C) and 51 healthy subjects were matched for age and sex. Seventeen patients had history of overt hepatic encephalopathy, eight of them had minimal hepatic encephalopathy at inclusion, 10 other patients had minimal hepatic encephalopathy at inclusion but without history of previous overt hepatic encephalopathy, and 21 patients had none of these features. RESULTS Patients with cirrhosis presented decreased brain density in many areas of the grey and white matter. The extension and size of the affected areas were greater in patients with alcoholic cirrhosis than in those with post-hepatitic cirrhosis and correlated directly with the degree of liver failure and cerebral dysfunction (as estimated by neuropsychological tests and the antecedent of overt hepatic encephalopathy). Twelve additional patients with cirrhosis who underwent liver transplantation were explored after a median time of 11months (7-50months) after liver transplant. At the time of liver transplantation, three patients belonged to class A of the Child-Pugh classification, five to class B and four to class C. Compared to healthy subjects, liver transplant patients showed areas of reduced brain density in both grey and white matter. CONCLUSIONS These results indicate that loss of brain tissue density is common in cirrhosis, progresses during the course of the disease, is greater in patients with history of hepatic encephalopathy, and persists after liver transplantation. The significance, physiopathology, and clinical relevance of this abnormality cannot be ascertained from the current study.

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.