Microbiota and gut-brain axis dysfunction in autism spectrum disorder: Evidence for functional gastrointestinal disorders.

INTRODUCTION: The high frequency of functional gastrointestinal disorders (FGIDs) in autism spectrum disorders (ASD) has drawn attention to the composition of gut microbiota as a possible factor in ASD pathogenesis. However, characterization of a distinctive ASD microbial pattern is still unclear. OBJECTIVE: To conduct a narrative review on ASD microbial profile and diversity changes relative to NT children and FGID comorbidity and ASD pathogenesis. METHODOLOGY: First, we searched the PubMed database in peer-reviewed journals for evidence regarding the current epidemiological evidence on FGID comorbidity. For the identification of a microbial profile in ASD children, only original studies examining gut bacterial and fungal abundances and diversity in ASD children and adolescents were included. Lastly, research on the role of microbial dysbiosis as an interface between genetic and environmental risk factors in the pathogenesis of neuropsychiatric disorders, and specifically ASD, was examined. RESULTS: Prevalence and risk of FGIDs is significantly higher in ASD children and correlates with the severity of ASD. Bacterial and fungal diversity differ between ASD and NT children, indicating a difference in taxonomic abundance profiles, which have been reported at all bacterial phylogenetic levels. However, studies analyzing gut microbiota have a heterogeneous methodology and several limitations that could account for the variety of findings for each taxon. Also, covariate analysis reveals influence of demographics, diet, disease severity, GI comorbidity and allergies. Integration of these findings with changes in metabolome and genetic risk factors allowed for a better understanding of microbiota involvement in ASD pathogenesis for future research.

[Neuropsychology of generalized anxiety disorders: a systematic review]. / Neuropsicologia del trastorno de ansiedad generalizada: revision sistematica.

INTRODUCTION: Cognitive symptoms in psychiatric diseases such as schizophrenia, bipolar disorder or major depression have been widely studied and defined; however, despite the frequent subjective cognitive complaints in patients with anxiety disorders, neuropsychology of anxiety disorders has less consistent results in literature. PATIENTS AND METHODS: This study offers a systematic review of controlled studies that evaluate neuropsychological findings in adults diagnosed of generalized anxiety disorders (GAD). Finally, 40 articles were selected for this systematic review, with a total sample of 1098 patients with GAD. RESULTS: Results suggest that subjects with GAD have a worse performance than controls in the following cognitive domains: complex attention (selective attention), executive functions (working memory, cognitive inhibition, decision making), and social cognition (recognizing and processing emotions, attribution bias). Most consistent results report the influence of emotional stimuli (specifically, threatening or anxiety-provoking stimuli) on performance on cognitive task related with complex attention, working memory and cognitive inhibition. CONCLUSION: In our knowledge, there is not any previous systematic review defining the neuropsychological profile of GAD. Due to the clinical and functional consequences of cognitive symptoms in these patients, future studies that allow a better knowledge on this field are needed: including larger samples of patients; controlling variables that could eventually modify the association between cognitive symptoms and GAD, such as pharmacological treatment and comorbid depression; focusing on specific neuropsychological test for GAD; and evaluating the effect of pharmacological and psychological treatment on cognitive symptoms in GAD patients.

TITLE: Neuropsicologia del trastorno de ansiedad generalizada: revision sistematica.Introduccion. Los sintomas cognitivos en enfermedades psiquiatricas como la esquizofrenia, el trastorno bipolar o la depresion mayor se han estudiado y definido ampliamente; sin embargo, a pesar de las frecuentes quejas cognitivas en los pacientes con trastornos de ansiedad, sus hallazgos neuropsicologicos son menos consistentes en la literatura cientifica. Pacientes y metodos. Se realiza una revision sistematica de los estudios controlados que evaluan alteraciones neuropsicologicas en adultos con diagnostico clinico de trastorno de ansiedad generalizada (TAG). Finalmente se seleccionaron 40 articulos para esta revision sistematica, que en total comprendian una muestra de 1.098 pacientes con TAG. Resultados. Los estudios revisados sugieren que los sujetos con TAG tienen peor rendimiento que los controles en los siguientes dominios cognitivos: atencion compleja (atencion selectiva), funciones ejecutivas (memoria de trabajo, inhibicion cognitiva, toma de decisiones) y cognicion social (identificacion y procesamiento de las emociones, sesgo atribucional). Los resultados mas consistentes señalan la influencia de estimulos emocionales (sobre todo los estimulos de caracter amenazante o ansiogeno) en el rendimiento en tareas de atencion, memoria de trabajo e inhibicion cognitiva. Conclusiones. En nuestro conocimiento, no existen revisiones sistematicas previas que definan el perfil neuropsicologico en el TAG. Dada la repercusion clinica y funcional de los sintomas cognitivos en estos pacientes, se necesitan futuros trabajos que incluyan muestras mas amplias de pacientes y controlen posibles variables de confusion, como el tratamiento farmacologico y la comorbilidad depresiva, asi como el desarrollo de instrumentos especificos de evaluacion y el estudio del eventual efecto del tratamiento sobre estos sintomas.

[Clinically relevant late-life depression as risk factor of dementia: a systematic review and meta-analysis of prospective cohort studies]. / Depresion tardia clinicamente relevante y riesgo de demencia: revision sistematica y metaanalisis de estudios prospectivos de cohortes.

AIM: To carry out a meta-analysis of population-based prospective cohort studies to investigate the risk of dementia and Alzheimer's disease (AD) according to clinically relevant depression, assessed with Geriatric Mental State (GMS) criteria. PATIENTS AND METHODS: A systematic literature search of the studies published in PubMed and Web of Science up to January 2018 was performed to identify all longitudinal studies on the association between clinically relevant depression (diagnosed with GMS criteria) and risk of dementia in the elderly. We calculated pooled relative risks to examine depression as a possible risk factor for dementia in community studies, as well as to compute population attributable fraction (PAF). RESULTS: Six studies met inclusion criteria for the systematic review. All of them provided enough information to perform a meta-analysis. Participants with clinically relevant depression had a 54% higher risk of dementia (p = 0.026) with a PAF attributable to clinically relevant depression of 8.6%. The numbers for AD were 50% higher risk (p = 0.038) and a PAF of 10.8%. CONCLUSION: Clinically relevant depression is associated with an increased risk for dementia and AD in the community, with a potential impact higher than other known/recognized risk factors. Future studies should explore the mechanisms linking depression and dementia and AD as well as whether an effective treatment of clinically significant depression could prevent dementia and AD development.

TITLE: Depresion tardia clinicamente relevante y riesgo de demencia: revision sistematica y metaanalisis de estudios prospectivos de cohortes.Objetivo. Realizar un metaanalisis de estudios de cohortes prospectivos, con base poblacional, que investiguen el riesgo de demencia y enfermedad de Alzheimer (EA) segun la depresion clinicamente relevante, diagnosticada con criterios del Geriatric Mental State (GMS). Pacientes y metodos. Se realizo una busqueda sistematica de los estudios publicados en PubMed y Web of Science hasta enero de 2018 para identificar todos los estudios longitudinales sobre la asociacion entre la depresion clinicamente relevante (diagnosticada con criterios del GMS) y el riesgo de demencia y EA en los ancianos. Se calculo el riesgo relativo agrupado para examinar la depresion como un posible factor de riesgo para la demencia en estudios comunitarios, asi como la fraccion poblacional de demencia y EA atribuible a la depresion. Resultados. Seis estudios cumplieron los criterios de inclusion para la revision sistematica. Todos ellos proporcionaron suficiente informacion para realizar un metaanalisis. Los participantes con depresion clinicamente relevante tuvieron un riesgo un 54% mas elevado de demencia (p = 0,026) y una fraccion atribuible poblacional del 8,6%. Los pacientes con EA tuvieron un riesgo un 50% mas alto (p = 0,038) y una fraccion atribuible poblacional del 10,8%. Conclusion. La depresion clinicamente relevante se asocia con un mayor riesgo de demencia y EA en la comunidad, con un impacto potencial mayor que otros factores de riesgo conocidos. Los estudios futuros deben explorar los mecanismos que vinculan la depresion con la demencia y la EA, asi como si un tratamiento eficaz de la depresion clinicamente relevante podria prevenir la demencia y el desarrollo de la EA.

Clinically relevant anxiety and risk of Alzheimer's disease in an elderly community sample: 4.5 years of follow-up.

OBJECTIVES: To investigate whether clinically relevant anxiety increased the risk for developing Alzheimer's disease (AD) while controlling for the presence of depression and other confounders; and to report the population attributable fraction (PAF) associated with anxiety disorder. METHOD: We used data from the longitudinal, community-based Zaragoza Dementia and Depression (ZARADEMP) study. A random sample of 4057 dementia-free community dwellers aged ≥55 years were followed for 4.5 years. The Geriatric Mental State-Automated Geriatric Examination for Computer Assisted Taxonomy package was used for the diagnosis of clinically significant cases and subcases of anxiety; and AD was diagnosed by a panel of research psychiatrists according to DSM-IV criteria. Multivariate survival analysis with competing risk regression model was performed. RESULTS: We observed a significant association between anxiety cases at baseline and AD risk in the univariate analysis that persisted in the fully adjusted model (SHR: 3.90; 95% CI: 1.59-9.60; p = 0.003), with a PAF for AD of 6.11% (95% CI: 1.30%-16.17%). No significant association between 'subcases' of anxiety at baseline and AD risk was found. LIMITATIONS: Data on apolipoprotein E were not available. The hospital-based diagnosis was not completed in all cases of dementia. CONCLUSION: Late-life, clinically significant anxiety (but not subclinical anxiety) seems to increase the risk of AD, independently of the effect of several confounders, including depression. Taking into account the high prevalence of anxiety among the elderly, future studies are warranted to determine potential risk reduction of AD.

Clinically significant anxiety as a risk factor for dementia in the elderly community.

OBJECTIVE: To evaluate whether clinically significant anxiety is an independent risk factor for dementia, taking into account both depression among potentially confounding factors and the competing risk of death. METHOD: During the Zaragoza Dementia and Depression (ZARADEMP) study, a random sample of community dwellers aged 55 years or older was assessed (n = 4803), and a two-wave, 4.5-year follow-up was completed. Geriatric Mental State (GMS)-AGECAT criteria were used to diagnose anxiety and DSM-IV criteria were applied to diagnose incident dementia. The multivariate Fine and Gray regression model was implemented to calculate dementia risk. RESULTS: Compared with non-cases (GMS-AGECAT criteria), the incidence rate of dementia was significantly higher in subcases of anxiety, and particularly significant in the cases of anxiety (incidence rate ratio (IRR): 2.77; P = 0.010). Cases of anxiety, but not subcases, at baseline were significantly associated with dementia risk (adjusted subdistribution hazard ratio (SHR): 2.7; P = 0.019). CONCLUSION: Clinically significant anxiety is associated with an almost threefold increase in the risk of dementia in the population, even when controlling for depression and considering mortality in the competing risks model.

Staging cognitive impairment and incidence of dementia.

AIMS: In a background of interest in staging models in psychiatry, we tested the validity of a simple staging model of cognitive impairment to predict incident dementia. METHOD: A large community sample of adults aged ≥55 years (N = 4803) was assessed in the baseline of a longitudinal, four-wave epidemiological enquiry. A two-phase assessment was implemented in each wave, and the instruments used included the Mini-Mental Status Examination (MMSE); the History and Aetiology Schedule and the Geriatric Mental State-AGECAT. For the standardised degree of cognitive impairment Perneczky et al's MMSE criteria were applied. A panel of psychiatrists diagnosed cases of dementia according to DSM-IV criteria, and cases and sub-cases of dementia were excluded for the follow-up waves. Competing risk regression models, adjusted by potential confounders, were used to test the hypothesised association between MMSE levels and dementia risk. RESULTS: Out of the 4057 participants followed up, 607 (14.9%) were classified as 'normal' (no cognitive impairment), 2672 (65.8%) as 'questionable' cognitive impairment, 732 (18.0%) had 'mild' cognitive impairment, 38 (0.9%) had 'moderate' cognitive impairment and eight (0.2%) had 'severe' impairment. Cognitive impairment was associated with risk of dementia, the risk increasing in parallel with the level of impairment (hazard ratio: 2.72, 4.78 and 8.38 in the 'questionable', 'mild' and 'moderate' level of cognitive impairment, respectively). CONCLUSIONS: The documented gradient of increased risk of dementia associated with the severity level of cognitive impairment supports the validity of the simple staging model based on the MMSE assessment.

Conversion to dementia in mild cognitive impairment diagnosed with DSM-5 criteria and with Petersen's criteria.

OBJECTIVE: In a background of revision of criteria for states of increased risk for progression to dementia, we compare the conversion rate to dementia and Alzheimer's disease (AD) of mild cognitive impairment (MCI) as diagnosed using DSM-5 (DSM-5-MCI) and Petersen's (P-MCI) criteria. METHOD: A population representative cohort of 4057 dementia-free individuals 55+ years of age was followed up at 2.5 and 4.5 years in Zaragoza, Spain (ZARADEMP). Using the Geriatric Mental State- AGECAT for assessment, research psychiatrists diagnosed DSM-5-MCI and P-MCI following operationalized criteria. 'Conversion rate' (CR), 'annual conversion rate' (ACR), and incidence rate (IR) were calculated along with incidence rate ratio (IRR) to compare the performance of the intermediate cognitive definitions. RESULTS: At 4.5-year follow-up, in individuals aged 65+ years, ACRs for non-cases, P-MCI, and DSM-5-MCI were 0.8, 1.9 and 3.4, respectively, for global dementia. The IRRs were 2.9 and 5.3 for P-MCI and DSM5-MCI, respectively, being the non-cases the reference category. The corresponding values were slightly lower for AD. CONCLUSION: Conversion rate to dementia and AD was higher using DSM-5-MCI criteria than using Petersen's criteria. However, prediction of the construct still has some way to go, as most MCI individuals did not convert at 4.5-year follow-up.

Mild cognitive impairment diagnosed with the new DSM-5 criteria: prevalence and associations with non-cognitive psychopathology.

OBJECTIVE: To contrast the prevalence of mild cognitive impairment (MCI) as diagnosed using DSM-5 criteria (DSM5-MCI) with MCI as diagnosed using Petersen's criteria (P-MCI) and to explore the association of both with non-cognitive psychopathological symptoms (NCPS). METHOD: A two-phase epidemiological screening was implemented in a population-based sample of individuals aged 55+ (n = 4803). The Geriatric Mental State (GMS) was the main psychopathological instrument used, and AGECAT was used to make psychiatric diagnoses. Research psychiatrists diagnosed DSM5-MCI and P-MCI using operational criteria. Logistic regression models were then used to investigate the association of MCI with anxiety and depression and with NCPS. RESULTS: Weighted prevalence of DSM5-MCI and P-MCI was, respectively, 3.72% and 7.93% for the aged 65+. NCPS were common in both MCI categories, but negative-type symptoms such as 'anergia' and 'observed slowness' were considerably more frequent among persons with DSM5-MCI. Anxiety and depression diagnostic categories were associated with both P-MCI and DSM5-MCI, but affective-type symptoms were mainly associated with P-MCI. Some negative-type symptoms were inversely associated with P-MCI, and no association was observed with DSM5-MCI. CONCLUSION: The prevalence of DSM5-MCI was half that of P-MCI. Negative-type NCPS were more frequently and typically associated with DSM5-MCI.

Degree of cognitive impairment and mortality: a 17-year follow-up in a community study.

BACKGROUND: To test the hypothesis that cognitive impairment in older adults is associated with all-cause mortality risk and the risk increases when the degree of cognitive impairment augments; and then, if this association is confirmed, to report the population-attributable fraction (PAF) of mortality due to cognitive impairment. METHOD: A representative random community sample of individuals aged over 55 was interviewed, and 4557 subjects remaining alive at the end of the first year of follow-up were included in the analysis. Instruments used in the assessment included the Mini-Mental Status Examination (MMSE), the History and Aetiology Schedule (HAS) and the Geriatric Mental State (GMS)-AGECAT. For the standardised degree of cognitive impairment Perneczky et al's MMSE criteria were applied. Mortality information was obtained from the official population registry. Multivariate Cox proportional hazard models were used to test the association between MMSE degrees of cognitive impairment and mortality risk. We also estimated the PAF of mortality due to specific MMSE stages. RESULTS: Cognitive impairment was associated with mortality risk, the risk increasing in parallel with the degree of cognitive impairment (Hazard ratio, HR: 1.18 in the 'mild' degree of impairment; HR: 1.29 in the 'moderate' degree; and HR: 2.08 in the 'severe' degree). The PAF of mortality due to severe cognitive impairment was 3.49%. CONCLUSIONS: A gradient of increased mortality-risk associated with severity of cognitive impairment was observed. The results support the claim that routine assessment of cognitive function in older adults should be considered in clinical practice.