Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype.

Families comprising many individuals with Autism Spectrum Disorders (ASD) may carry a dominant predisposing mutation. We implemented rigorous phenotyping of the "Broader Autism Phenotype" (BAP) in large multiplex ASD families using a novel endophenotype approach for the identification and characterisation of distinct BAP endophenotypes. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 110 individuals, including two large multiplex families (Family A: 30; Family B: 35) and an independent sample of small families (n = 45). Our protocol identified four distinct psychological endophenotypes of the BAP that were evident across these independent samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. Patterns of inheritance of identified endophenotypes varied between the two large multiplex families, supporting their utility for identifying genes in ASD.

Estudios de agregación plaquetaria como endofenotipo de las alteraciones hereditarias de la fibra colágena / Platelet aggregation studies as an endophenotype of hereditary disorders of collagen fiber

Introducción: Las plaquetas contribuyen a la hemostasia y la interrupción heredada o adquirida; en sus procesos bioquímicos pueden alterar la función plaquetaria. Estos trastornos de agregación se han asociado a enfermedades genéticas con afectación del tejido conectivo como el síndrome Ehlers-Danlos, cuyo diagnóstico diferencial con el espectro de hipermovilidad articular resulta difícil clínica y molecularmente. Estas entidades con afectación en las fibras colágenas y diferente repercusión clínica precisan diferenciales en su diagnóstico clínico. Métodos: Se revisaron 353 historias clínicas de pacientes atendidos en el Servicio de Genética del Hospital Pediátrico William Soler desde septiembre del 2009 al 2012, con diagnóstico de hipermovilidad articular por criterios de Beighton y de Ehlers-Danlos según Villefranche (1997). Se incluyó a los pacientes de 5-18 años con resultados documentados del estudio de agregación plaquetaria, valorados por especialistas en hematología. Resultados: Se encontraron trastornos de agregación plaquetaria en 79 de 86 pacientes (92 por ciento). En 7 casos con hipermovilidad de 65 con este diagnóstico (10 por ciento), los resultados fueron negativos. Los 21 con síndrome Ehlers-Danlos tuvieron afectaciones con los fosfolípidos plaquetarios. La hipermovilidad articular estuvo asociada a la combinación difosfato de adenosina (ADP)-epinefrina y el Ehlers-Danlos a la combinación ADP-epinefrina-colágeno-fosfolípidos. Conclusiones: Los pacientes con hipermovilidad articular mostraron asociación a defectos de liberación de gránulos con agonistas como el ADP-epinefrina y los Ehlers-Danlos con la disponibilidad de los fosfolípidos, relacionados con el cambio de forma plaquetaria. Este resultado puede ser una herramienta para conocer el endofenotipo funcional plaquetario como elemento diferencial en los trastornos de la fibra colágena(AU)

Introduction: Platelets contribute to hemostasis and inherited or acquired interruption; in its biochemical processes it can alter platelet function. These aggregation disorders have been associated with genetic diseases with connective tissue involvement such as Ehlers-Danlos syndrome, whose differential diagnosis with the spectrum of joint hypermobility is clinically and molecularly difficult. These entities with involvement of the collagen fibers and different clinical repercussions require differentials in their clinical diagnosis. Methods: 353 medical records of patients attended in the Genetics service of the William Soler Pediatric Hospital from September 2009 to 2012, with a diagnosis of joint hypermobility by Beighton and Ehlers-Danlos criteria according to Villefranche (1997) were reviewed. Patients aged 5-18 years were included with documented results of the platelet aggregation study, assessed by specialists in hematology. Results: Platelet aggregation disorders were found in 79 of 86 patients (92 percent). In 7 cases with hypermobility of 65 with this diagnosis (10 percent), the results were negative. The 21 with Ehlers-Danlos syndrome had affectations with platelet phospholipids. Joint hypermobility was associated with the combination adenosine diphosphate (ADP) -epinephrine and the Ehlers-Danlos with the combination ADP-epinephrine-collagen-phospholipids. Conclusions: Patients with joint hypermobility showed an association to granule release defects with agonists such as ADP-epinephrine and Ehlers-Danlos with the availability of phospholipids, related to platelet shape change. This result can be a tool to know the platelet functional endophenotype as a differential element in collagen fiber disorders(AU)

Funcionamiento neuropsicológico en los Trastornos de la Conducta Alimentaria: un estudio comparativo / Neuropsychological functioning in Eating Disorders: a comparative study

INTRODUCCIÓN: Los trastornos de la conducta alimentaria (TCA) cursan con diversas alteraciones en tres principales rasgos o endofenotipos: coherencia central, tareas de cambio de criterio y control de impulsos según diferentes técnicas de evaluación neuropsicológicas y de neuroimagen. El objetivo de este trabajo es aportar evidencia empírica descriptiva sobre estas posibles alteraciones y su relación con variables emocionales, de funcionamiento diario y de conducta alimentaria. MÉTODO: Se compararon 38 mujeres: 19 con trastornos de la conducta alimentaria (TCA) y 19 participantes sin TCA. Se usaron diferentes técnicas para evaluar la velocidad de procesamiento, memoria, atención, impulsividad y el estado emocional. RESULTADOS: Las diferencias en el resultado de la mayoría de las pruebas neuropsicológicas empleadas fueron no significativas excepto en la Clave de Números y en el recuerdo inmediato del Test de Memoria de Rivermead. El grupo con TCA mostró síntomas depresivos moderados. CONCLUSIONES: El rendimiento similar del grupo TCA en las pruebas neuropsicológicas podría ser explicado por un estilo de procesamiento de la información basado en el detalle y sin cambio de criterio. Los síntomas depresivos parecen ser un factor de vulnerabilidad que correlaciona con la evolución del trastorno. La intervención neuropsicológica de los TCA aportaría nuevas técnicas de tratamiento de forma complementaria a las que ya se aplican; favorecería un abordaje más dimensional sacando a la luz nuevas dianas terapéuticas y también se trataría la comorbilidad de estos trastornos actuando sobre los factores comunes. En consecuencia, se sugieren nuevas líneas de investigación de neuropsicología aplicada

INTRODUCTION: Patients with eating disorders (ED) show several alterations in three main features or endophenotypes: central coherence, tasks based on changing criteria and impulse control according to different neuropsychological and neuroimaging evaluation techniques. The objective of this work is to provide descriptive empirical evidence about these possible alterations and their relationship with emotional, daily functioning and eating behavior variables. METHOD: A total of 38 women were compared: 19 with ED and 19 healthy participants. Different techniques were used to assess the speed of processing, memory, attention, impulsivity and emotional state. RESULTS: Differences in the results of the most of neuropsychological tests used were not significant except in the case of symbol search and in the immediate recall of the Rivermead Memory Test. The group with ED showed moderate depressive symptoms. CONCLUSIONS: The similar performance of the ED group respecting the neuropsychological tests could be explained by a style of information processing based on detail and without changing criteria. Depressive symptoms appear to be a vulnerability factor that correlates with the course of the disorder. Neuropsychological intervention in ED would provide new treatment techniques in a complementary way to those already applied; it would favor a more dimensional approach by bringing new therapeutic targets to light, and the comorbidity of these disorders would also be treated by acting on common factors. Consequently, new lines of applied neuropsychology research are suggested

Pre-trial and pre-response EEG microstates in schizophrenia: An endophenotypic marker.

Cognitive deficits in Schizophrenia interfere with everyday functioning and social functioning. Strong familial associations in schizophrenia might serve to establish cognitive impairments as endophenotypic markers. Therefore, visuo-spatial working memory simulating day-to-day activities at high memory load was assessed in patients with schizophrenia, their first-degree relatives and healthy controls to explore pre-trial and pre-response EEG microstates and their intracranial generators. Twenty-eight patients with schizophrenia, first-degree relatives and matched healthy controls participated in the study. Brain activity during visuo-spatial working memory task was recorded using 128-channel electroencephalography. Pre-trial and pre-response microstate maps of correct and error trials were clustered across groups according to their topography. Microstate map parameters and underlying cortical sources were compared among groups. Pre-trial (correct) microstate Map 1 was significantly different between controls and patients which could qualify it as a state marker with its intracranial generator localized to right inferior frontal gyrus (rIFG). Pre-response (correct) microstate map was significantly different between controls and first-degree relatives which could be considered an endophenotypic marker for schizophrenia. No significant differences were observed for error trials between groups. rIFG which is involved in the execution of multi-component behaviour and selective inhibitory control could distinguish patients with schizophrenia from their first-degree relatives and healthy controls. Further, microstate based biomarkers have the potential to facilitate diagnosis of schizophrenia at a preclinical stage resulting in efficient diagnosis and better prognosis.

Neurocognitive Graphs of First-Episode Schizophrenia and Major Depression Based on Cognitive Features.

Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.

Heritability of saccadic eye movements in spinocerebellar ataxia type 2: insights into an endophenotype marker

Background:Saccade slowing has been proposed as endophenotype marker in Spinocerebellar Ataxia type 2 (SCA2), nevertheless the heritability of this trait has not been properly demonstrated. Thus the present paper was aimed to assess the heritability of different saccadic parameters in SCA2.Methods:Forty-eight SCA2 patients, 25 preclinical carriers and 24 non-SCA2 mutation carriers underwent electronystagmographical assessments of saccadic eye movements as well as neurological examination and ataxia scoring. Estimates of heritability based on the intraclass correlation coefficients were calculated for saccade velocity, accuracy and latency as well as for age at disease onset from 36, 17 and 15 sibling pairs of SCA2 patients, preclinical carriers and controls, respectively.Results:Saccade velocity was significantly reduced in SCA2 patients and preclinical carriers, whereas decreased saccade accuracy and increased saccade latency were only observed in the patients cohort. Intraclass correlation coefficient for saccade velocity was highly significant in SCA2 patients, estimating a heritability around 94 percent, whereas for the age at ataxia onset this estimate was around 68 percent.Conclusions:Electronystagmographical measure of saccade velocity showed higher familial aggregation between SCA2 patients leading the suitability of this disease feature as endophenotype marker, with potential usefulness for the search of modifier genes and neurobiological underpinnings of the disease and as outcome measure in future neuroprotective clinical trials (AU)

Imaging-wide association study: Integrating imaging endophenotypes in GWAS.

A new and powerful approach, called imaging-wide association study (IWAS), is proposed to integrate imaging endophenotypes with GWAS to boost statistical power and enhance biological interpretation for GWAS discoveries. IWAS extends the promising transcriptome-wide association study (TWAS) from using gene expression endophenotypes to using imaging and other endophenotypes with a much wider range of possible applications. As illustration, we use gray-matter volumes of several brain regions of interest (ROIs) drawn from the ADNI-1 structural MRI data as imaging endophenotypes, which are then applied to the individual-level GWAS data of ADNI-GO/2 and a large meta-analyzed GWAS summary statistics dataset (based on about 74,000 individuals), uncovering some novel genes significantly associated with Alzheimer's disease (AD). We also compare the performance of IWAS with TWAS, showing much larger numbers of significant AD-associated genes discovered by IWAS, presumably due to the stronger link between brain atrophy and AD than that between gene expression of normal individuals and the risk for AD. The proposed IWAS is general and can be applied to other imaging endophenotypes, and GWAS individual-level or summary association data.

Serum phosphatidylinositol as a biomarker for bipolar disorder liability.

OBJECTIVES: Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology. METHODS: Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family size=14.79, range=2-82). We calculated a coefficient of relatedness for all family members of nine individuals with BPD in the sample (N=185); this coefficient was set to be zero in unrelated individuals (N=373). Then, under an endophenotype ranking value (ERV) approach, this scalar index was tested against 13 serum-based phospholipid concentrations in order to rank-order lipid classes by their respective overlap with BPD risk. RESULTS: The phosphatidylinositol class was significantly heritable (h2 =0.26, P=6.71 × 10-05 ). It was the top-ranked class, and was significantly associated with BPD risk after correction for multiple testing (ß=-1.18, P=2.10 × 10-03 , ERV=0.49). CONCLUSIONS: We identified a peripheral biomarker, serum-based phosphatidylinositol, which exhibits a significant association with BPD risk. Therefore, given that phosphatidylinositol and BPD risk share partially common etiology, it seems that this lipid class warrants further investigation, not only in terms of treatment, but also as a promising diagnostic and risk marker.

Un autismo, varios autismos. Variabilidad fenotípica en los trastornos del espectro autista / One autism, several autisms. Phenotypical variability in autism spectrum disorders

Introducción. Los trastornos del espectro autista comprenden un grupo heterogéneo de trastornos que se inician en los primeros meses de la vida y que siguen una evolución crónica. Su origen es biológico, con factores etiológicos complejos que implican diferentes mecanismos genéticos, epigenéticos y ambientales, que interactúan. Objetivo. Revisar los principales factores que varían la presentación del autismo considerando la evidencia científica actual. Desarrollo. Aspectos relacionados con el desarrollo de síntomas, el sexo, la comorbilidad, la edad y la etiología determinan la variabilidad en la presentación clínica de los trastornos del espectro autista. Conclusiones. El autismo es altamente heterogéneo y se relaciona fenotípicamente, en parte, con una gran heterogeneidad etiológica, que comienza a descifrarse, pero que todavía permanece desconocida en gran parte. La investigación etiológica, especialmente en el área de la genética, permitirá identificar diferentes subgrupos homogéneos con sus correspondientes fenotipos y abrir la posibilidad de alternativas terapéuticas futuras (AU)

Introduction. Autism spectrum disorders (ASD) are a heterogeneous group of disorders that begin in the early months of life and follow a chronic progression. They have a biological origin, with complex aetiological factors that involve different genetic, epigenetic and environmental mechanisms that interact with one another. Aim. To review the main factors that vary the presentation of autism taking into account the most recent scientific evidence. Development. Aspects related with the development of symptoms, gender, comorbidity, age and aetiology determine the variability in the clinical presentation of ASD. Conclusions. Autism is highly heterogeneous and is phenotypically related, at least in part, with a wide range of causations, which researchers have begun to unravel but which are still largely unknown. Aetiological research, especially in the area of genetics, will make it possible to identify different homogeneous subgroups with their corresponding phenotypes, while also opening up the way to possible therapeutic alternatives in the future (AU)

Proinflammatory genotype is associated with the frailty phenotype in the English Longitudinal Study of Ageing.

BACKGROUND: Frailty is a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes including falls, disability and death. The underlying pathophysiological pathways of frailty are not known but the hypothalamic-pituitary-adrenal axis and heightened chronic systemic inflammation appear to be major contributors. METHODS: We used the English Longitudinal Study of Ageing dataset of 3160 individuals over the age of 50 and assessed their frailty status according to the Fried-criteria. We selected single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways and performed linear association analysis using age and sex as covariates. To support the biological plausibility of any genetic associations, we selected biomarker levels for further analyses to act as potential endophenotypes of our chosen genetic loci. RESULTS: The strongest association with frailty was observed in the Tumor Necrosis Factor (TNF) (rs1800629, P = 0.001198, ß = 0.0894) and the Protein Tyrosine Phosphatase, Receptor type, J (PTPRJ) (rs1566729, P = 0.001372, ß = 0.09397) genes. Rs1800629 was significantly associated with decreased levels of high-density lipoprotein (HDL) (P = 0.00949) and cholesterol levels (P = 0.00315), whereas rs1566729 was associated with increased levels of HDL (P = 0.01943). After correcting for multiple testing none of the associations remained significant. CONCLUSIONS: We provide potential evidence for the involvement of a multifunctional proinflammatory cytokine gene (TNF) in the frailty phenotype. The implication of this gene is further supported by association with the endophenotype biomarker results.

Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

Perfil y endofenotipos neuropsicológicos en TDAH: Una revisión / Neuropsychological profile and endophenotypes in ADHD: A review

Existe un acuerdo científico generalizado acerca de que un porcentaje elevado de las personas que presentan Trastorno por Déficit de Atención con Hiperactividad (TDAH) tienen también importantes dificultades en su rendimiento psicológico. Esta afirmación cuenta con evidencias cognitivo-conductuales y neurofuncionales. Así, están ampliamente constatados los problemas en el funcionamiento ejecutivo en los pacientes con TDAH, encontrándose, en especial, tamaños de efecto robustos para la memoria de trabajo y la inhibición. En este trabajo se presenta una revisión del perfil neuropsicológico más frecuentemente encontrado en TDAH, y se discuten los distintos modelos explicativos y dificultades en el endofenotipado neuropsicológico

There is a generalized scientific agreement that a high percentage of people with attention deficit hyperactivity disorder (ADHD) also show significant difficulties in neuropsychological performance. There is evidence for both cognitive-behavioral and neurophysiological data. Deficits in executive functioning have been widely observed in ADHD and robust effect sizes for working memory and inhibition are found. In this work, we show a review of the most common neuropsychological profile found in ADHD, and discuss the explanatory models and the difficulties with neuropsychological endophenotypes

Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings.

We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.

[Endophenotypes of severe depression]. / Vakavan masennuksen endofenotyypit eli välimuotoiset ilmiasut.

Patients with the same diagnosis may present a highly different symptom picture. The concept of endophenotype has been created to facilitate the assessment of factors underlying psychiatric diseases. The concept allows the reduction of heterogenous categories of psychiatric diagnoses into less complicated components so that use is made of e.g. neuroanatomy, neurocognitive tests, biochemical factors or neuropsychology. Possible endophenotypes of severe depression include neurocognitive parameters associated with learning and memory, hippocampal volume as well as neuroticism, for example.

Ventral prefrontal executive function impairment as a potential endophenotypic marker for bipolar disorder.

BACKGROUND: Patients with remitted bipolar disorder have cognitive impairments, particularly in executive functions. However, the findings of studies that investigated cognitive functions in unaffected relatives of patients with bipolar disorder are conflicting. AIMS: The aim of this study is to investigate executive functions in healthy parents of patients with bipolar I disorder, along with bipolar I disorder patients and matched controls. It has been hypothesized that both patients with bipolar I disorder and their parents would have executive function impairments compared with controls. METHODS: 25 patients with bipolar I disorder, in full remission, 25 healthy controls that matched the patients with respect to age, gender and education, 50 healthy parents of those patients and 50 healthy controls that matched the parents for age, gender and education were included in the study. All the participants were interviewed with Structured Clinical Interview for DSM-IV-Axis I (SCID-I). Executive functions were assessed using the Verbal Fluency Test (VFT), Trail Making Test (TMT), Wisconsin Card Sorting Test (WCST) and Stroop Test. RESULTS: Patients performed significantly worse than their matched controls on the VFT, TMT and Stroop tests, but not on the WCST. Parents performed significantly worse than their matched controls on the TMT and Stroop tests, but not on the VFT and WCST. CONCLUSIONS: Our results bring more evidence that deficits in ventral, but not dorsal prefrontal executive functions are associated with familial vulnerability to bipolar disorder and ventral prefrontal executive function impairments may represent a potential endophenotype for bipolar disorder.

Phenotypes and Endotypes of Uncontrolled Severe Asthma: New Treatments

El asma grave es una enfermedad heterogénea que constituye entre un 5-10% de los sujetos asmáticos, pero representan un porcentaje significativo del consumo de los recursos sanitarios. El asma grave se caracteriza por precisar tratamiento con altas dosis de corticosteroides, e incluye diversos fenotipos tanto clínicos como fisiopatológicos. Esta heterogeneidad dificulta en gran medida la caracterización de la enfermedad, y en la mayoría de los casos también la elección del tratamiento adecuado. Por esta razón, en los últimos años se ha hecho hincapié en la mejora en el conocimiento de los distintos fenotipos del asma grave, y en la identificación de biomarcadores para cada uno de ellos. Así mismo, también ha tomado fuerza el concepto de endotipo en referencia a los distintos subtipos de la enfermedad divididos en base a su mecanismo funcional o fisiopatológico único. En esta revisión serán discutidos los aspectos más relevantes de los fenotipos clínicos e inflamatorios del asma grave, incluyendo el asma grave infantil y los diferentes endotipos del asma grave serán discutidos en este capítulo. Así mismo, se revisan las principales opciones terapéuticas disponibles en este grupo de pacientes serán revisadas (AU)

Severe asthma is a heterogeneous disease that affects only 5%-10% of asthmatic patients, although it accounts for a significant percentage of the consumption of health care resources. Severe asthma is characterized by the need for treatment with high doses of inhaled corticosteroids and includes several clinical and pathophysiological phenotypes. To a large extent, this heterogeneity restricts characterization of the disease and, in most cases, hinders the selection of appropriate treatment. In recent years, therefore, emphasis has been placed on improving our understanding of the various phenotypes of severe asthma and the identification of biomarkers for each of these phenotypes. Likewise, the concept of the endotype has been gaining acceptance with regard to the various subtypes of the disease, which are classified according to their unique functional or pathophysiological mechanism. This review discusses the most relevant aspects of the clinical and inflammatory phenotypes of severe asthma, including severe childhood asthma and the various endotypes of severe asthma. The main therapeutic options available for patients with uncontrolled severe asthma will also be reviewed (AU)

¿Son las alteraciones neuropsicológicas de los trastornos de la conducta alimentaria endofenotipos de la enfermedad? Revisión y estado actual del tema / Are the neuropsychological alterations in eating disorders endophenotypes of the disease? Review and state of the art

Introducción. Estudios recientes reflejan que las alteraciones de la función cognitiva ejecutiva pueden ser endofenotipos de trastornos de la conducta alimentaria. Objetivo. Revisar de forma crítica la bibliografía sobre alteraciones neuropsicológicas en pacientes con trastorno de la conducta alimentaria y sus familiares de primer grado. Desarrollo. Revisamos trabajos en inglés y castellano indexados en Medline y PsycINFO en los últimos 10 años. Incluimos resúmenes de artículos aún no publicados y cruzamos los términos de búsqueda. Excluidos casos clínicos aislados, obtuvimos 41 trabajos en pacientes con anorexia nerviosa (n = 17), bulimia nerviosa (n = 5), ambas (n = 13) o trastorno de la conducta alimentaria no especificado (n = 6). Conclusiones. Los estudios revisados presentan grandes limitaciones debido a su heterogénea metodología y escasa muestra, lo que genera resultados contradictorios. La mayoría se realizó en anorexia nerviosa. La rigidez cognitiva parece más frecuente en pacientes con anorexia y sus familiares, y las alteraciones en la toma de decisión o de la coherencia central en bulimia nerviosa. Existen indicios que sugieren que las alteraciones neuropsicológicas de los trastornos de la conducta alimentaria son endofenotipos de la enfermedad (AU)

Introduction. Recent studies have shown that alterations to the executive cognitive functions may be endophenotypes of eating disorders. Aim. To perform a critical review of the literature on neuropsychological alterations in patients with eating disorders and their first-degree relatives. Development. We review the papers written in English and in Spanish indexed in Medline and PsycINFO over the last 10 years. We included abstracts of papers that have still not been published and search terms were crossed. Excluding some isolated clinical cases, we obtained 41 studies on patients with anorexia nervosa (n = 17), bulimia nervosa (n = 5), both (n = 13) or a non-specific eating disorder (n = 6). Conclusions. The studies reviewed display important limitations due to their heterogeneous methodology and small samples, which give rise to contradictory results. Most of them were conducted on anorexia nervosa. Cognitive rigidity seems to be more frequent in patients with anorexia and their relatives, and alterations in decision-making or central coherence is more often found in bulimia nervosa. There is evidence suggesting that the neuropsychological alterationsfound in eating disorders are endophenotypes of the disease (AU)

Endophenotypes as a measure of suicidality.

Suicide is thought to result from the harmful interaction of multiple factors that have social, environmental, neurobiological, and genetic backgrounds. Recent studies have suggested that genetic predisposition to suicidal behavior may be independent of the risk of suicide associated to mental disorders, such as affective disorders, schizophrenia, or alcohol dependence. Given the suicidal behavior heterogeneity and its hereditary complexity, the need to find demonstrable intermediate phenotypes that may make it possible to establish links between genes and suicide behaviors (endophenotypes) seems to be necessary. The main objective of this review was to consider the candidate endophenotypes of suicidal behaviors. Due to the recent advances in neuroimaging, we also characterize brain regions implicated in vulnerability to suicide behavior that are influenced by gene polymorphisms associated with suicidal behavior.

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

BACKGROUND: Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. METHODS: Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. RESULTS: Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. CONCLUSIONS: The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research.

Mismatch Negativity (MMN) y esquizofrenia: Una revisión / Mismatch Negativity (MMN) and schizophrenia: A revision

El componente Mismatch Negativity (MMN) es un Potencial Relacionado con Eventos (PRE) de tipo auditivo, que es generado por la respuesta cerebral automática a cualquier cambio en la estimulación auditiva que excede un límite correspondiente al umbral de discriminación. Se ha reportado amplia y consistentemente menor amplitud de MMN en pacientes con esquizofrenia reciente y crónica, por lo que se ha propuesto que este componente se relaciona con alteraciones en la memoria sensorial y en las capacidades de integración del estímulo, las cuales parecen progresara lo largo de la enfermedad. Recientemente se han abierto nuevas líneas de investigación al respecto, y se han realizado estudios con familiares de pacientes con esquizofrenia para evaluar la eficacia de la MMN como endofenotipo. Asimismo, se han llevado a cabo estudios de MMN en pródromos o sujetos en riesgo clínico de desarrollar esquizofrenia, con la finalidad de conocer si existen alteraciones en el procesamiento cerebral previas al inicio de la enfermedad. Los resultados de estos trabajos han arrojado resultados prometedores, que sugieren la presencia de alteraciones sutiles en el procesamiento de estímulos auditivos en esta población, las cuales parecen aumentar con la aparición de la enfermedad. Es así como el componente MMN puede ser una herramienta electrofisiológica eficaz para proporcionar información sobre el procesamiento automático auditivo relacionado con la esquizofrenia y su cronicidad, así como para indicar la vulnerabilidad genética y riesgo clínico para desarrollarla. Sin embargo, es necesario realizar estudios futuros comparables y replicables que permitan confirmar tales hallazgos (AU)

The Mismatch Negativity (MMN) is an auditory Event-Related Potential which is generated as an automatic cerebral response to any change in the auditory stimulation that exceeds a limit corresponding to the discrimination threshold. It has been widely and consistently reported that patients with recent and chronic schizophrenia display smaller MMN amplitudes, suggesting that this component may be related with alteration in sensory memory and stimuli integration capacities, which seem to increase with the disease progression. Recently, new research areas have emerged, and studies of MMN of relatives of patients with schizophrenia have been conducted in order to assess the MMN efficacy as an endophenotype. Likewise, there have been MMN studies in schizophrenia prodromes or clinical high risk subjects, aiming to know if there are cerebral processing disturbances prior to the onset of the disease. The results of these studies have been promising, suggesting the presence of auditory stimuli processing disturbances in this population. These disturbances are subtle and seem to increase as the disease appears. The MMN component maybe a very effective electrophysiological tool that provides information about the automatic auditory processing in schizophrenia related to its chronicity. It may also be a relative reliable index of genetic vulnerability and clinical risk for developing schizophrenia. Nevertheless, it is necessary to continue performing studies to get comparable and replicable studies in the future that could confirm the information about MMN utility (AU)