Ana Barabash

Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

Comparative study of neurocognitive function in euthymic bipolar patients and stabilized schizophrenic patients

Few studies have compared neurocognitive performance in euthymic patients with bipolar disorder (BD), stabilized patients with schizophrenia (SC) and normal controls (NC) using a comprehensive neuropsychological battery, and those that have been conducted have yielded discrepant results. We evaluated the neurocognitive profile shown by 73 euthymic patients with BD, 89 stabilized patients with SC and 67 NC. All participants completed a cognitive battery in which the domains evaluated were executive functioning, sustained attention, and verbal and visual memory. Individuals with BD were administered the Quality of Life Scale (QLS). Patients with BD manifested dysfunction in executive functioning (moderate-to-large effect size), sustained attention (moderate effect size) and verbal/visual memory (large effect size) compared with NC. Verbal memory deficit in patients with BD was related to poor functional outcome on the QLS and Global Assessment of Functioning (GAF). Patients with BD performed significantly better than patients with SC on the Trail Making Test (TMT) part B, backward digit span, and California Verbal Learning Test (CVLT) learning trials. Other neuropsychological measures showed no significant differences between the two patient groups. These findings support the notion that euthymic BD patients suffer from an extensive neurocognitive deficit that affects all cognitive domains and is qualitatively similar to that in SC patients. Persistent verbal memory impairment in BD has clinical relevance because it is associated with poor psychosocial function.

Regional cerebral blood flow assessed with 99mTc-ECD SPET as a marker of progression of mild cognitive impairment to Alzheimer's disease

Patients diagnosed with mild cognitive impairment (MCI) have a higher risk of developing Alzheimers disease (AD). However, not all such patients develop this kind of dementia. The purpose of this prospective study was to assess whether regional cerebral blood flow (rCBF) patterns measured with technetium-99m ethyl cysteinate dimer single-photon emission tomography (99mTc-ECD SPET) in patients suffering from MCI are useful in predicting progression to AD. The study group comprised 42 patients who fulfilled MCI criteria according to the International Psychogeriatric Association and the Alzheimers Disease Cooperative Study. rCBF was calculated in 16 regions of interest (ROIs). All patients were clinically assessed for 1–3 years. Twenty-one developed AD (group I) while the initial diagnosis of MCI was retained in the other 21 (group II). ROC curves were designed, and sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were determined for each ROI. Compared with group II (MCI), group I (AD) showed a significant reduction of relative blood flow (RBF), ranging from 7% to 10%, in the following areas: right and left prefrontal, right and left frontal, right and left parietal, right and left temporal, right and left frontoparietotemporal and left posterior lateral temporal. Left prefrontal, left frontal and left parietal areas showed sensitivities and specificities higher than 75% and areas below the ROC curve close to 80%. This study shows that RBF patterns in the right and left prefrontal, right and left frontal and left parietal areas are sensitive early markers of progression towards AD. Reduction of rCBF in the medial temporal and anterior lateral temporal cortex has no value as a predictor since it also occurs in patients with MCI who remain stable.

Single-anastomosis duodenoileal bypass with sleeve gastrectomy: metabolic improvement and weight loss in first 100 patients

BACKGROUND Single-anastomosis duodenoileal bypass with sleeve gastrectomy is a simplified 1-loop duodenal switch with a 200-250 common channel. Our objective was to analyze the weight loss and metabolic results of the technique on a series of 100 consecutively operated patients at a tertiary center university hospital. METHODS A total of 100 patients consecutively underwent surgery. The criteria of inclusion were morbid obesity or metabolic disease. In the first 50 cases, the common/efferent limb measured 200 cm. The length was changed to 250 cm to reduce the hypoproteinemia rate. RESULTS No mortality and no severe complications developed. The mean excess weight loss was >95% maintained during the follow-up period. More than 90% of the patients experimented complete remission of type 2 diabetes mellitus. Two conversions to a standard duodenal switch with a longer alimentary channel were required because of recurrent hypoproteinemia. Hypertension was controlled in 98% of the patients, with a 58% remission rate. The mean number of bowel movements was 2.5/d. CONCLUSION Single-anastomosis duodenoileal bypass with sleeve gastrectomy is a simplified duodenal switch procedure that is safe and quicker to perform and offers good results for the treatment of both morbid obesity and its metabolic complications.

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimers disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.

Neuropsychological Markers of Progression From Mild Cognitive Impairment to Alzheimer’s Disease

To find early clinical markers that may predict a likely progression to Alzheimer’s disease (AD), the authors performed neuropsychological tests on 82 mild cognitive impairment (MCI) subjects. After 3 years, 38 patients developed AD while 44 retained the diagnosis of MCI. The cognitive differences between the groups were studied. Patients who developed AD showed significantly lower values than did MCI subjects in some neuropsychological scores (P = .02-.001), with sensitivities and specificities higher than 84% and 64%, respectively, for detecting early-onset AD, with a 7.9-fold increased risk of converting to AD (P < .001). Regarding the logistic regression model, the CAMCOG Memory and Perception cognitive screening items were the optimum independent tools to classify the patients who will progress to AD, showing a relative risk of progression of 10.5 (P = .002), 5.5 (P = .008), and 3.9 times (P = .05), respectively, with a sensibility of of 92.1% and a specificity 72.7%.

Evidence for association of the non-duplicated region of CHRNA7 gene with bipolar disorder but not with Schizophrenia.

Objective Biological evidence in both human and animal studies suggests α7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) as a suitable functional candidate for genetic studies in psychiatric populations. This gene maps to chromosome 15q13-14, a major linkage hotspot for schizophrenia (SCH) and bipolar disorder (BD). In this study we examine the role of CHRNA7 in influencing the risk of SCH and BD. Methods In the present investigation four SNPs of the non-duplicated region of CHRNA7 were genotyped: -86C/T variant, located in the 5′-upstream regulatory region; and three intronic polymorphisms (rs883473, rs6494223 and rs904952). Genetic analysis was performed on 510 patients diagnosed with SCH, 245 with BD and on 793 unrelated healthy controls. Results SNP analysis suggested a significant difference in -86C/T allele (P=0.025) and genotype (P=0.03) frequencies between BD and control groups, although significance was lost after correction for multiple testing. Besides, the nucleotide change (T) in rs6494223 had a protective effect against BD [odds ratio (OR)=0.70 (0.57–0.87); P=0.001]. Genotype frequencies also showed significant association (P=0.001) [CT genotype OR=0.71 (0.5–0.96); TT genotype OR=0.47 (0.29–0.77)]. Haplotypic analysis revealed a positive association of the gene with BD (global-stat=24.18, P value=0.007) with a maximum effect in the region that covered introns 3 and 4. In contrast, no evidence of risk variants was found in the analysis of the SCH sample. Conclusion Our data support the non-duplicated region of CHRNA7 gene as a susceptibility region for BD but not for SCH. Further genotyping of this region may help to delimit the causal polymorphism.

Influence of the APOE ε4 Allele and Mild Cognitive Impairment Diagnosis in the Disruption of the MEG Resting State Functional Connectivity in Sources Space

The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimers disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brains functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

The Effect of MAPT H1 and APOE ε4 on Transition from Mild Cognitive Impairment to Dementia

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimers disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition.

P50 sensory gating is a trait marker of the bipolar spectrum

UNLABELLED Sensory gating deficit, assessed by a paired auditory stimulus paradigm (P50), has been reported as a stable marker of schizophrenia. The aim of this study was to explore if this neurophysiological disturbance also fulfilled stability criteria in the bipolar disorder (BD) spectrum bipolar, as state independence is one of the main points to be considered as a potential endophenotype of the illness. The P50 evoked potential was studied in 95 healthy controls and 126 bipolar euthymic patients. Euthymia was established according to Van Gorps criteria. Bipolar I and II subtypes were analyzed separately. The influence of a lifetime history of psychoses was also evaluated in the clinical sample. P50 gating was deficitary in all the subsamples of patients relative to healthy comparison subjects. Bipolar I patients with and without a history of psychosis showed higher P50 ratios than the other subgroups of patients, although these differences were not significant. P50 alterations were mainly due to a deficit in the inhibition of the second wave (test wave or S2) amplitude. CONCLUSIONS The findings suggest that this inhibitory deficit can be considered characteristic of the illness and that the intensity of the gating abnormality varies according to the severity of BD.