Source analysis of spontaneous magnetoencephalograpic activity in healthy aging and mild cognitive impairment: influence of apolipoprotein E polymorphism.

The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for the development of late-onset Alzheimer's disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ε4 allele. Sources of spectral variations in these groups were calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEε4 carriers showed an increased relative power in the 4.5-6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5-6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEε4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic 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.

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 Alzheimer's 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 brain's 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.

Executive deficits: a continuum schizophrenia-bipolar disorder or specific to schizophrenia?

Executive dysfunction is a core deficit in schizophrenia (SCH). However, some controversy exists when examining such deficits in studies of bipolar disorder (BD). The aim of the present research was to investigate whether executive deficits were similar or distinct in both illnesses. 148 patients with BD, 262 patients with stable SCH and 108 healthy controls (CT) were recruited for the study. The BD patients were also differentiated according to the clinical subtype (BD subtype I, BDI, or subtype II, BDII) they exhibited and according to whether there was a previous history of psychosis. All subjects completed a broad neuropsychological battery. The influences of other clinical data were also evaluated. Both the BD and SCH patients showed widespread deficits in all executive tasks, with no differences between these two groups of patients. BDII patients only showed some selective deficits, and their scores on planning and inhibitory tasks fell on the continuum between the CT, the BDI and the SCH patients. Psychotic phenotypes did not influence the BD patients' performance on the battery. Other clinical variables related to illness severity did influence deficits in any subgroup of patients. Our results point to the existence of common executive disturbances in both diagnostic categories. Moreover, the inclusion of subclinical phenotypes in research may be helpful in cognitive assessment studies.

No effect of polymorphisms in the non-duplicated region of the CHRNA7 gene on sensory gating P50 ratios in patients with schizophrenia and bipolar disorder.

Previous research has reported that bipolar disorder and schizophrenic patients evidence sensory gating deficits. The use of intermediate phenotypes may facilitate genetic studies. Four single nucleotide polymorphisms (SNPs) located on the non-duplicated region of the alpha-7 nicotinic receptor gene (CHRNA7) were genotyped in 95 healthy subjects, 127 bipolar disorder and 153 schizophrenic patients. We evaluated the association of these polymorphisms with P50 evoked potential measures. Our results do not support a role for the candidate gene in this neurophysiological disturbance.

NR4A2: effects of an "orphan" receptor on sustained attention in a schizophrenic population.

NR4A2 (nuclear receptor subfamily 4 group A member 2) or Nurr1 is a transcription factor implied in the differentiation, maturation, and survival of dopaminergic neurons. It also has a role in the expression of several proteins that are necessary for the synthesis and regulation of dopamine (DA), such as tyrosine hidroxilase, dopamine transporter, vesicular monoamine transporter 2, and cRET. DA is an important neurotransmitter in attentional pathways. Our aim was to evaluate the influence of NR4A2 gene in the performance of schizophrenia (SZ) patients and healthy subjects on a sustained attention task. For this study, we collected 188 SZ subjects (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 100 control individuals. We genotyped 5 tag SNPs in NR4A2 gene: rs1150143 (C/G), rs1150144 (A/G), rs834830 (A/G), rs1466408 (T/A), and rs707132 (A/G). We also analyzed the influence of its haplotypes (frequency>5%). To examine sustained attention, all the individuals completed the Degraded Stimulus Continuous Performance Test. We evaluated "hits," "reaction time," "sensibility a," and "false alarms." In the schizophrenic group, recessive genotypes of rs1150143, rs1150144, rs834830, and rs707132 were associated with a worse performance. SZ subjects who carried GGGTG haplotype showed less hits (P<.004), lower sensibility a scores (P<.009), and a higher reaction time (P=.013). We observed a sex effect of the gene: genotype and haplotype associations were only present in the male group. We conclude that NR4A2 gene is involved in attentional deficits of SZ patients, modifying hits, sensibility a, and reaction time.

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 Gorp's 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.

Personality profiles between obese and control subjects assessed with five standardized personality scales.

BACKGROUND/AIM: Psychopathology may exert influence on developing and maintaining obesity. Studies of personality traits or psychopathology of personality in obesity are scarce and contradictory. The aim of this study was to compare personality profiles between obese and normal-weight subjects and to determine the most useful tool to detect differences, considering that psychological assessment and psychotherapeutical support should be included within the overall management of these patients.* METHOD: We examined 55 obese subjects (mean BMI=43kg/ m2) and 66 controls (mean BMI =21.7kg/m2). We used the personality assessment tools: MCMI-II, TCI-R, EPQ-A, BIS-111 and SSS. Factorial multivariate analysis of variance was applied; with factors BMI, Gender and Age as a covariate. RESULTS: Significant differences between groups were more marked in the clinical syndrome scales of MCMI-II, particularly in Major-Depression, Thought-Disorder, Anxiety, Somatoform and Alcohol-Dependence. Among obese, women scored higher than men in all scales but not significantly. We have found significant differences in normal personality dimensions between both groups in TCI-R. Obese showed higher scores in Harm Avoidance, and lower in Novelty Seeking, Persistence and Self-transcendence. The remaining tests have not been useful for differentiating personality traits between both groups. CONCLUSION: Obese subjects showed different personality profiles than control subjects. The most useful scales for determining these differences might be those designed to assess pathological personality such as MCMI-II. Less important would be those intended to measure normal personality traits, such as TCI-R and EPQ-A.

A study of verbal memory in a sample of euthymic patients with bipolar disorder.

BACKGROUND: Recent studies have confirmed the presence of cognitive impairment in euthymic patients with Bipolar Disorder (BD). A significant relationship between memory difficulties and poor psychosocial adjustment has also been found in these subjects. While some studies suggest that these memory deficits may be secondary to executive functioning instead of being directly related to a primary impairment of the memory systems, others suggest that these memory deficits may be secondary to clinical symptoms. Some authors reject the existence of any relationship between clinical state and neurocognitive impairments and suggest that this relationship may be mediated by other factors. The goal of this research was to replicate the findings of verbal memory impairment in euthymic patients with Bipolar Disorder and relate these impairments with neocortex structures. METHODOLOGY: We carried out a cross-sectional study. The sample was made up of 44 BDI and 9 BDII euthymic patients and 32 healthy subjects, aged 18-65 years. Both groups were evaluated with the California Verbal Learning Test. RESULTS: Both bipolar patients performed worse than healthy control subjects in most memory measures and showed difficulties in components of memory that are associated with both frontal (semantic organization) and temporal lobe function (recall and recognition). CONCLUSIONS: We have hypothesized that verbal memory could be a trait marker of bipolar disorder.

Estudio de memoria verbal en una muestra de pacientes con Trastorno Bipolar en fase eutímica / A study of verbal memory in a sample of euthymic patients with Bipolar Disorder

Introducción: Estudios recientes han demostrado la persistencia de disfunciones cognitivas en fases de remisión del trastorno bipolar (TB). Se ha encontrado una relación significativa entre los déficit de memoria y un pobre ajuste psicosocial. Mientras que algunos estudios apuntan a un déficit mnésico secundario a déficit de tipo ejecutivo, má sque a una alteración primaria de los procesos de memoria, otros estudios sugieren que los déficit mnésicos podrían ser secundarios a la sintomatología clínica. Otros autores, no encuentran relación entre el estado clínico y los déficit neurocognitivos y sugieren que esta relación debe estar mediada por otros factores. El objetivo de este trabajo fue replicarlos hallazgos de déficit en memoria verbal en pacientes con trastorno bipolar en fase eutímica y relacionar dichos déficit con estructuras del neocórtex. Metodología: Se realizó un estudio transversal. La muestra estuvo compuesta por 44 pacientes eutímicos con TBI, 9 con TBII en fase de eutimia y 32 sujetos sanos, con edades comprendidas entre los 18 y los 65 años. Se utilizócomo instrumento de evaluación de la memoria el California Verbal Learning Test. Resultados: Se observaron déficit en los dos subtipos de sujetos con TB, tanto en los componentes de memoria asociados con estructuras frontales (organización semántica)como en los relacionados con estructuras temporales(recuerdo y reconocimiento).Conclusiones La memoria verbal podrían ser una variable rasgo del TB (AU)

Background. Recent studies have confirmed the presence of cognitive impairment in euthymic patients with Bipolar Disorder (BD). A significant relationship between memory difficulties and poor psychosocial adjustment has also been found in these subjects. While some studies suggest that these memory deficits may be secondary to executive functioning instead of being directly related to a primary impairment of the memory systems, others suggest that these memory deficits may be secondary to clinical symptoms. Some authors reject the existence of any relationship between clinical state and neurocognitive impairments and suggest that this relationship may be mediated by other factors. The goal of this research was to replicate the findings of verbal memory impairment in euthymic patients with Bipolar Disorder and relate these impairments with neocortex structures. Methodology. We carried out a cross-sectional study. The sample was made up of 44 BDI and 9 BDII euthymic patients and 32 healthy subjects, aged 18-65 years. Both groups were evaluated with the California Verbal Learning Test. Results. Both bipolar patients performed worse than healthy control subjects in most memory measures andshowed difficulties in components of memory that are associated with both frontal (semantic organization) and temporal lobe function (recall and recognition) (AU)

Perfiles de personalidad en sujetos obesos y control medidos con cinco escalas estandarizadas de personalidad / Personality profiles between obese and control subjects assessed with five standardized personality scales

Introducción. La psicopatología puede ejercer influencia en el desarrollo y mantenimiento de la obesidad. Los estudios sobre los rasgos de personalidad o la psicopatología de la personalidad en obesidad son escasos y contradictorios. El objetivo de este estudio fue la comparación de los perfiles de personalidad entre sujetos obesos y normo-peso y la determinación de la herramienta más útil para la detección de diferencias, considerando que la evaluación psicológica y el apoyo psicoterapéutico deberían incluirse en el manejo de estos pacientes. Metodología. Examinamos 55 sujetos obesos (IMC=43kg/m2) y 66 controles (IMC=21,7kg/m2). Empleamos las herramientas de valoración de la personalidad: MCMI-II, TCI-R,EPQ-A, BIS-111 y SSS. Aplicamos un análisis multivariado dela varianza incluyendo los factores IMC, sexo y edad como covariables. Resultados. Se encontraron diferencias significativas más marcadas entre los grupos fueron más marcadas en las escalas clínicas del MCMI-II, especialmente en la de Depresión Mayor, Pensamiento psicótico, Ansiedad, Histeriforme y Abuso de alcohol. Entre los obesos, las mujeres puntuaron más que los hombres en todas las escalas, aunque no fue significativo. Encontramos diferencias significativas en los rasgos normales de personalidad entre ambos grupos en el TCI-R. Los obesos presentaron mayores puntuaciones en Evitación del daño y menores en Búsqueda de novedad, Persistencia y Trascendencia. El resto de los test no presentaron utilidad para la diferenciación de los rasgos de personalidad entre ambos grupos. Conclusión. Los sujetos obesos presentaron distintos perfiles de personalidad que los sujetos control. Las escalas de mayor utilidad para la determinación de estas diferencias podrían ser aquellas diseñadas para la evaluación de la personalidad patológica, tales como el MCMI-II. De menor importancia serían aquellas dirigidas a medir los rasgos de personalidad normal, tales como el TCI-R y el EPQ-A (AU)

Background/aim. Psychopathology may exert influence on developing and maintaining obesity. Studies of personality traits or psychopathology of personality in obesity are scarce and contradictory. The aim of this study was to compare personality profiles between obese and normal-weight subjects and to determine the most useful tool to detect differences, considering that psychological assessment and psychotherapeutical support should be included within the overall management of these patients. Method. We examined 55 obese subjects (mean BMI=43kg/m2) and 66 controls (mean BMI =21.7kg/m2). We used the personality assessment tools: MCMI-II, TCI-R, EPQ-A, BIS-111and SSS. Factorial multivariate analysis of variance was applied; with factors BMI, Gender and Age as a covariate. Results. Significant differences between groups were more marked in the clinical syndrome scales of MCMI-II, particularly in Major-Depression, Thought-Disorder, Anxiety, Somatoform and Alcohol-Dependence. Among obese, women scored higher than men in all scales but not significantly. We have found significant differences in normal personality dimensions between both groups in TCI-R. Obese showed higher scores in Harm Avoidance, and lower in Novelty Seeking, Persistence and Self-transcendence. The remaining tests have not been useful for differentiating personality traits between both groups. Conclusion. Obese subjects showed different personality profiles than control subjects. The most useful scales for determining these differences might be those designed to assess pathological personality such as MCMI-II. Less important would be those intended to measure normal personality traits, such as TCI-R and EPQ-A (AU)

Sensory gating deficit is associated with catechol-O-methyltransferase polymorphisms in bipolar disorder.

OBJECTIVES. Recent studies have evidenced that bipolar patients show a sensory gating deficit (P50). Among the neural systems that could be influencing this electrophysiological phenotype, dopamine seems to play an important role. We hypothesize that catechol-O-methyltransferase (COMT), the main metabolizer of dopamine in prefrontal cortex, is related to this deficit. METHODS. We selected three polymorphisms in COMT gene: rs2075507 (Promoter 2 region), Val158Met (rs4680) and rs165599 (3' region). A case-control study was performed in 784 controls and 238 bipolar patients. Besides, 122 euthymic bipolar subjects and 95 healthy subjects carried out a sensory gating task (P50). RESULTS. Polymorphism rs165599 in the COMT gene was associated with susceptibility to bipolar disorder (BD), mainly in women (AG: OR = 1.46; GG: OR = 1.84; P = 0.03). In the female group, haplotype AAG was associated with an OR = 7.6. Subjects who carried Val158 allele evidenced a deficit in suppression (P = 0.046) and rs165599 allele G carriers (mainly in homozygosis) had a bigger S2 amplitude and a higher S2/S1 ratio (1.6(e-5) < P < 0.01). Not a single association was proven in the control group. CONCLUSIONS. Our results support the association of the COMT gene with BD and with one of its potential endophenotypes, auditory sensory gating deficit, measured by the P50 paradigm.

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 Alzheimer's 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-ß and tau brain deposition.

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.