No significant alteration in white matter microstructure in first-degree relatives of patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by structural alteration within white matter tissues of cortico-striato-thalamo-cortical, temporal and occipital circuits. However, the presence of microstructural changes in the white matter tracts of unaffected first-degree relatives of patients with OCD as a vulnerability marker remains unclear. Therefore, here, diffusion-tensor magnetic resonance imaging (DTI) data were obtained from 29 first-degree relatives of patients with OCD and 59 healthy controls. We investigated the group differences in FA using whole-brain analysis (DTI analysis). For additional regions of interest (ROI) analysis, we focused on the posterior thalamic radiation and sagittal stratum, shown in recent meta-analysis of patients with OCD. In both whole-brain and ROI analyses, using a strict statistical threshold (family-wise error rate [FWE] corrected p<.05 for whole-brain analyses, and p<.0125 (0.05/4) with Bonferroni correction for ROI analyses), we found no significant group differences in FA. Subtle reductions were observed in the anterior corona radiata, forceps minor, cingulum bundle, and corpus callosum only when a lenient statistical was applied (FWE corrected p<.20). These findings suggest that alterations in the white matter microstructure of first-degree relatives, as potential vulnerability markers for OCD, are likely subtle.

A Systematic Review to Explore a Neuropsychological Profile that Predates Anorexia Nervosa.

OBJECTIVE: Research demonstrates reduced cognitive flexibility and weak central coherence during acute illness and following recovery from anorexia nervosa (AN). This systematic review investigated if these impairments are present in first-degree relatives of individuals with AN, representing a possible neuropsychological risk profile. METHODS: A systematic review of electronic databases was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search ended on July 14, 2023. Established search terms and inclusion criteria identified relevant research. Risk of bias was assessed using the Critical Appraisal Skills Program. The review was registered with Prospero international prospective register of systematic reviews (No. CRD42023401268). Study selection, descriptive data, critical appraisal, and risk of bias are presented in tables and figures. RESULTS: The search yielded 10 studies. The included studies conducted neuropsychological assessments of discordant AN relatives and lifetime longitudinal study participants. Most studies found cognitive flexibility and central coherence to be significantly reduced in participants with AN and their relatives compared with controls. One study found decision making to be significantly impaired in AN participants and relatives. Effect sizes were moderate to large. DISCUSSION: Reduced cognitive flexibility and weak central coherence appear to be endophenotypes of AN. Further research is required with relatives concordant for AN to establish whether these biomarkers co-segregate with AN within families. These findings suggest a possibility of developing screeners to identify individuals at risk of AN allowing for early intervention.

Verbal fluency in schizophrenia and bipolar disorder - A longitudinal, family study.

Verbal fluency (VF) has been proposed as a putative neurocognitive endophenotype in schizophrenia (SZ) and bipolar disorder (BD). However, this hypothesis has not been examined using a longitudinal family approach. We conducted a five-group, comparative study. The sample comprised 323 adult participants, including 81 BD patients, 47 unaffected relatives of BD BD-Rel), 76 SZ patients, 40 unaffected relatives of SZ (SZ-Rel), and 79 genetically unrelated healthy controls (HC). All subjects were assessed twice with semantic VF (sem-VF) and phonological VF (ph-VF) tests over a 2-year follow-up period. ANCOVAs controlling for age and years of education were used to compare performance across groups. Patients with SZ and BD and their unaffected relatives showed sem-VF and ph-VF deficits at baseline, which persisted over time (all, p < 0.05). Moreover, BD-Rel showed an intermediate performance between SZ and HC. A repeated-measures ANOVA revealed no significant differences in the between-group trajectories comparison (p > 0.05). Our findings support that VF may represent a neurocognitive endophenotype for SZ and BD. Further longitudinal, family studies are warranted to confirm this preliminary evidence.

Head circumference growth in children with Autism Spectrum Disorder: trend and clinical correlates in the first five years of life.

Background: Macrocephaly is described in almost 15% of children with Autism Spectrum Disorder (ASD). Relationships between head growth trajectories and clinical findings in ASD children show a high degree of variability, highlighting the complex heterogeneity of the disorder. Objectives: The aim of this study was to measure differences of the early growth trajectory of head circumference (HC) in children with ASD and macrocephaly compared to ASD normocephalic children, examining clinical correlates in the two groups of patients. Methods: HC data were collected from birth to 5 years of age in a sample of children with a confirmed diagnosis of ASD. Participants were classified into two groups: ASD macrocephaly (ASD-M, Z-scores ≥1.88 in at least two consecutive HC measurements), and ASD non-macrocephaly (ASD-N). Based on the distribution of HC measurements (Z-scores), five age groups were identified for the longitudinal study. Developmental and behavioral characteristics of the ASD-M children compared to the ASD-N group were compared by using standardized scores. Results: 20,8% of the children sample met criteria for macrocephaly. HC values became indicative of macrocephaly in the ASD-M group at the age range from 1 to 6 months, and persisted thereafter throughout the first five years of age. ASD-M children showed significantly higher developmental quotients of Griffiths III B and D subscales compared to ASD-N group. No significant differences in the severity of ASD symptoms assessed by ADOS-2 were observed between ASD-M and ASD-N groups. Conclusion: In this study HC size from birth to 5 years links to accelerated HC growth rate as early as the first 6 months of age in children with ASD and macrocephaly, preceding the onset and diagnosis of ASD. We found that in early childhood, children with ASD-M may exhibit some advantages in language and social communication and emotional skills without differences in autism severity, when compared with age-matched normocephalic ASD children. Longitudinal analyses are required to catch-up prospectively possible relationships between head size as proxy measure of brain development and neuro-developmental and behavioral features in children with ASD.

Basophil activation test is a complementary tool in the diagnosis of immediate reactions to platinum salts and taxanes.

BACKGROUND: Delabelling pathways offer confirmatory diagnosis and can prevent unnecessary second-line therapies or drug desensitization procedures after chemotherapeutic hypersensitivity reactions (CHT-HSRs). However, these pathways rely on risky in vivo tests. Data on whether in vitro tests could be helpful are scarce. We assessed the role of basophil activation test (BAT) in the diagnosis of HSRs to platin salts (PSs) and taxanes (TXs) in a well-defined population featuring varied endophenotypes and severities of HSRs. METHODS: We conducted a 3-year-long multicentric, prospective study with 121 suspected-immediate CHT-HSR patients. The allergy workup included clinical history (initial reaction based on Type I, cytokine release syndrome, and mixed phenotype's symptoms and if unable to fit in any of these, as "indeterminate"), skin testing (ST), and drug provocation testing (DPT), provided risk assessment was favorable. Final diagnosis classified patients as "hypersensitive," "non-hypersensitive," or "inconclusive." We performed BAT using CD63 and CD203c as activation markers in patients and controls. Patients underwent DPT regardless of BAT results to prevent bias. RESULTS: ST positivity significantly correlated with skin involvement, Type I phenotype, cancer recurrence, and lifetime exposures before reactions. DPTs were negative in all indeterminate phenotype patients (p = .02) and those considered low-risk, whereas they were negative in 62% moderate-risk patients. 55% were confirmed as hypersensitive (mainly Type I reactions, p < .0001), 24% as non-hypersensitive (mainly TXs and indeterminate phenotypes), and 21% as inconclusive. BAT showed 79% sensitivity in Type I IgE-mediated reactions to PSs with a high correlation to ST. CONCLUSIONS: BAT is a promising tool for delabelling and endotyping CHT-HSRs, especially Type I reactions to PSs, possibly identifying patients at risk of positive DPT. ST seems useful in confirming CHT-HSRs, especially PS-induced reactions, and DPT remains the gold standard, being essential even in moderate-risk patients.

Multimorbidity in Severe Mental Illness as Part of the Neurodevelopmental Continuum: Physical Health-Related Endophenotypes of Schizophrenia-A Narrative Review.

BACKGROUND: The majority of deaths in patients with schizophrenia and other severe mental illnesses (SMIs) are caused by natural causes, such as cardiovascular diseases (CVDs). The increased risk of CVD and other somatic diseases in SMIs cannot be fully explained by the contribution of traditional risk factors, behavioral risk factors, patients' lifestyle peculiarities, and the influence of antipsychotics. The present review has the following main objectives: (1) to aggregate evidence that neurodevelopmental disorders are the basis of SMIs; (2) to provide a review of studies that have addressed the shared genetic architecture of SMI and cardiovascular disease; and (3) to propose and substantiate the consideration of somatic diseases as independent endophenotypes of SMIs, which will make it possible to place the research of somatic diseases in SMIs within the framework of the concepts of the "neurodevelopmental continuum and gradient" and "endophenotype". METHODS: A comprehensive literature search was performed on 1 July 2024. The search was performed using PubMed and Google Scholar databases up to June 2024. RESULTS: The current literature reveals considerable overlap between the genetic susceptibility loci for SMIs and CVDs. We propose that somatic diseases observed in SMIs that have a shared genetic architecture with SMIs can be considered distinct physical health-related endophenotypes. CONCLUSIONS: In this narrative review, the results of recent studies of CVDs in SMIs are summarized. Reframing schizophrenia as a multisystem disease should contribute to the activation of new research on somatic diseases in SMIs.

No Evidence for Cross-Sectional or Longitudinal Associations between Cognitive Flexibility Performances and Nutritional Status in a Cohort of Inpatients with Anorexia Nervosa.

BACKGROUND: According to the Cognitive-Interpersonal model of anorexia nervosa (AN), the combined influence of cognitive and socio-emotional difficulties would constitute vulnerability and maintaining factors. Poor cognitive flexibility is one of the endophenotypic candidates (i.e., a trait marker) of the disorder, but few studies have examined its association with illness symptom variations, notably weight status. The study aimed to evaluate the relationships between cognitive flexibility performances and nutritional status indices (BMI; body composition) at different times of the disorder. METHODS: Cross-sectional and longitudinal associations between cognitive flexibility (TAP 2.1) and nutritional status indices, along with anxious and depressive (HAD) and eating disorder (EDE-Q) symptomatology were investigated using univariate and multivariate analyses in a cohort of AN inpatients evaluated at hospital admission (N = 167) and discharge (N = 94). RESULTS: We found no or negligible associations between nutritional status and HAD or EDE-Q scores or cognitive flexibility performances, either cross-sectionally or longitudinally. Cognitive performances did not significantly differ between the AN subtypes. CONCLUSIONS: In agreement with the Cognitive-Interpersonal model of AN, cognitive flexibility is independent of nutritional status, as well as the AN subtype. It is also independent of the levels of anxious, depressive, or ED symptomatology. A new therapeutic approach targeting cognitive flexibility and intolerance to change could benefit severely emaciated people with AN, regardless of disease subtype and level of dysphoria.

Toward an endophenotype for ADHD: Exploring the duration mismatch negativity in drug-free children with ADHD.

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent disorders in children that is considered to affect early stages of information processes. Inefficient processing of temporal information, which is a vital auditory processing skill suggests itself as a potential candidate for investigating ADHD deficits. The Research Domain Criteria (RDoC), a neuroscience-based research framework, has been introduced to study mental illness without relying on pre-established diagnostic categories. In this regard, Mismatch Negativity (MMN) has been considered an ideal electrophysiological marker for investigating ADHD deficits. This study investigates alterations in the amplitude and latency of the MMN component in response to changes in the duration and Inter-Stimulus Interval (ISI) of basic sound stimuli within an oddball task. The MMN paradigm was employed to examine duration deviations in ADHD (n = 25, 84% male, mean age: 7.3 years, SD = 2.01) compared to Control group of typically developing (TD) children (n = 25, 72% male, mean age: 7.2 years, SD = 1.92). Participants with ADHD were introduced from an accredited psychiatrist. TD children were recruited from social media and online forms. Both groups were matched in terms of gender, age and IQ. The psychological tests conducted in this study included Conners' Parent Rating Scale (CPRS), Gilliam Autism Rating Scale|Third Edition (Gars3), Sensory profile questionnaire and Edinburgh Handedness inventory. Our findings revealed reduced MMN amplitudes in response to two blocks of duration and ISI-based deviations in ADHD children. To elaborate in greater detail, at Fz, in Duration and ISI block, respectively, the ADHD group showed an amplitude of -1.2097 ± 0.2938 and -0.8553 ± 0.4423, while the normal group showed an amplitude of -1.8325 ± 0.3689 and -2.0855 ± 0.3802. Additionally, at Cz, the ADHD group exhibited a shorter amplitude (-1.2515 ± 0.3261 and -0.9367 ± 0.3432) compared to the normal group (-2.1319 ± 0.4445 and -2.7561 ± 0.4883), in the duration and ISI blocks, respectively. Furthermore, children with ADHD display longer MMN latencies in both experimental blocks, suggesting atypical responses. To provide more detail, at Fz, the ADHD group displayed MMN latencies of 239.68 ± 5.059 and 226.88 ± 4.885 in the Duration and ISI blocks, respectively, whereas the normal group showed MMN latencies of 228.56 ± 6.584 and 213.56 ± 4.153. Similarly, at Cz, the ADHD group exhibited longer MMN latencies (234.40 ± 5.741 and 231.44 ± 5.464) compared to the normal group (227.52 ± 6.710 and 218.00 ± 5.261) in the Duration and ISI blocks, respectively. Our findings were interpreted in the context of the internal clock model, which involves the pace of an internal pacemaker regulated by dopamine (DA) levels. The convergence of MMN and auditory timing abnormalities within the RDoC framework suggests their potential as endophenotypes for ADHD, highlighting the significance of sensory processing in understanding the disorder.

Genetic and polygenic investigation of heart rate variability to identify biomarkers associated with Anxiety disorders.

Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.

Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Funcionamiento ejecutivo y metacognición en la alta capacidad intelectual / Executive functioning and metacognition in high intel lectual capacity

Resumen Introducción : Las funciones ejecutivas y la meta cognición se integran para la gestión de recursos inte lectuales, en estrecha relación con la inteligencia, su funcionamiento y resultados, especialmente interesan te para comprender la expresión y desarrollo, más o menos óptimos, de la alta capacidad intelectual (ACI). El Objetivo del trabajo es conocer la relación entre las funciones ejecutivas (y componentes) y la metacognición (y componentes) en escolares con ACI. Materiales y Métodos : Las medidas de funcionamien to y ejecutivo, metacognitivo y de perfeccionismo ex traídas en una muestra de n= 147 escolares con ACI son analizadas estadísticamente mediante el Path análisis. Resultados : Se obtiene un modelo ajustado en el que se relacionan los distintos componentes ejecutivos con los metacognitivos. Discusión : Se concluye y discute el modelo integrador entre función ejecutiva y metacognición y su papel me diador, como endofenotipo entre la dotación genética y la expresión de rendimiento de los recursos, sugiriendo la transferencia de resultados a la educación de la alta capacidad intelectual para la óptima y ética expresión del alto potencial.

Abstract Introduction : Executive functions and Metacogni tion are integrated for the management of intellectual resources in close relation to intelligence its function ing and results; they are specially interesting for un derstanding the expression and development of high intellectual abilility (HIA). The aim of the study is to find out the relationship between executive functions (and components) and metacognition (and components) in schoolchildren with HIA. Materials and Method : Measures of executive and metacognitive functioning and perfectionism were ex tracted from a sample of n= 147 schoolchildren with HIA. Results : statistical analyses using Path analysis, of fered an adjusted model in which the different ex ecutive components are related to the metacognitive components. Discussion : We conclude and discuss the integrative model between executive function and metacognition and its mediating role as an endophenotype between genetic endowment and the expression of resource performance, suggesting the transfer of results to the education of high intellectual ability for the optimal and ethical expression of high potential.

A Systematic Review on Autism and Hyperserotonemia: State-of-the-Art, Limitations, and Future Directions.

Hyperserotonemia is one of the most studied endophenotypes in autism spectrum disorder (ASD), but there are still no unequivocal results about its causes or biological and behavioral outcomes. This systematic review summarizes the studies investigating the relationship between blood serotonin (5-HT) levels and ASD, comparing diagnostic tools, analytical methods, and clinical outcomes. A literature search on peripheral 5-HT levels and ASD was conducted. In total, 1104 publications were screened, of which 113 entered the present systematic review. Of these, 59 articles reported hyperserotonemia in subjects with ASD, and 26 presented correlations between 5-HT levels and ASD-core clinical outcomes. The 5-HT levels are increased in about half, and correlations between hyperserotonemia and clinical outcomes are detected in a quarter of the studies. The present research highlights a large amount of heterogeneity in this field, ranging from the characterization of ASD and control groups to diagnostic and clinical assessments, from blood sampling procedures to analytical methods, allowing us to delineate critical topics for future studies.

Investigational applications of transcranial magnetic stimulation (TMS) in Mood Disorders: Studies from a tertiary care center in India.

The investigational potential of TMS in psychiatry is largely underutilized. In the current article, we present the results of five studies with similar TMS protocols that looked at the investigative applications of TMS via measuring cortical reactivity as potential biomarkers in mood disorders. The first two studies, evaluate potential of TMS parameters and Motor neuron system (MNS) as state or trait markers of BD. Third and fourth studies evaluate these as endophenotypic markers of BD. The fifth study which is an RCT evaluating add-on yoga in UD, evaluates if markers of CI can index the therapeutic response of yoga. In study one MT1 was significantly greater in the SM (symptomatic-mania) group compared to HC (healthy-control) (P=0.032). The cortical inhibition measures SICI was reduced in SM(P=0.021) and BD (remitted Bipolar) (P=0.023) groups compared to HC. LICI was increased in the SM(0.021) and BD(P=0.06) groups compared to HC. In study two, a significant group x time interaction effect was observed indicating higher putative MNS-activity mediation in patients compared to HC on SlCl(P=0.024), LlCl(P=0.033). There were no significant group differences noted in the endophenotype studies. The fifth study showed a significant time X group interaction for CSP, favoring improvement in YG (yoga-group) (p<0.01).No significant change was observed for LICI(p=0.2), SICI(p=0.5). Limitations of these studies notwithstanding, we conclude that cortical reactivity measured using TMS is a potential biomarker across the course of mood disorders, starting from state and trait markers to understanding the therapeutic mechanism of a particular treatment modality in these disorders.

Neurocognitive Impairment in Patients With Ataxia Telangiectasia and Their Unaffected Parents: Is It Similar?

BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystemic disorder affecting the nervous system. Data on neurocognitive functioning in AT are limited and focused on patients at various stages of disease. Because of the genetic nature of the disorder, parents of patients may also display subtle neurological problems. This study aimed to evaluate neurocognitive functioning in patients with AT and their unaffected parents. METHODS: The study included 26 patients with AT and 41 parents among which 13 patients and 18 parents were evaluated with neurocognitive tests. Clinical and radiological data were reviewed retrospectively. Data were analyzed with descriptive statistics. RESULTS: The median ages of patients and parents were 12.5 years (interquartile range [IQR] = 9.5) and 38.0 years (IQR = 12.0), respectively. Median intelligence quotients were 62.0 (IQR = 21.3) and 82.5 (IQR = 16.8), respectively, for patients and parents. Rates of intellectual disability for patients and parents were 100.0% and 83.3%, respectively. Areas of impairment in patients in decreasing order of frequency were motor skills, visual perception/memory, visual-manual coordination, spontaneous/focused and sustained attention (100.0% for each), social judgment, as well as vocabulary and arithmetic skills (75.0% for each). Areas of impairment in unaffected parents in decreasing order of frequency were visual-manual coordination (77.8%), working memory (76.5%), and visual perception and motor skills (66.7% for each). CONCLUSION: Intellectual disabilities, visual-spatial disabilities, and reduced visual-motor coordination seem to be similar in patients with AT and their parents. These results should be replicated with larger samples from multiple centers and may form putative cognitive endophenotypes for the disorder.

Biomarkers for phenotype-endotype relationship in atopic dermatitis: a critical review.

Atopic dermatitis (AD) is the most common form of chronic skin inflammation with diverse clinical variants. Historically, various AD phenotypes have been grouped together without considering their heterogeneity. This approach has resulted in a lack of phenotype- and endotype-adapted therapeutic strategies. Comprehensive insights into AD pathogenesis have enabled precise medicinal approach for AD. These efforts aimed to redefine the endophenotype of AD and develop various biomarkers for diverse purposes. Among these endeavours, efforts are underway to elucidate the mechanisms (and related biomarkers) that lead to the emergence and progression of atopic diseases originating from AD (e.g., atopic march). This review focuses on diverse AD phenotypes and calls for a definition of endophenotypes. While awaiting scientific validation, these biomarkers ensure predicting disease onset and trajectory and tailoring therapeutic strategies for the future.

Genetic and multi-omic risk assessment of Alzheimer's disease implicates core associated biological domains.

INTRODUCTION: Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. METHODS: Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system-level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank-and-organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. RESULTS: The top AD-risk-associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. DISCUSSION: This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.

Chronotype and subjective sleep quality predict white matter integrity in young people with emerging mental disorders.

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Novel genetic loci of inhibitory control in ADHD and healthy children and genetic correlations with ADHD.

Cumulative evidence has showed the deficits of inhibitory control in patients with attention deficit hyperactivity disorder (ADHD), which is considered as an endophenotype of ADHD. Genetic study of inhibitory control could advance gene discovery and further facilitate the understanding of ADHD genetic basis, but the studies were limited in both the general population and ADHD patients. To reveal genetic risk variants of inhibitory control and its potential genetic relationship with ADHD, we conducted genome-wide association studies (GWAS) on inhibitory control using three datasets, which included 783 and 957 ADHD patients and 1350 healthy children. Subsequently, we employed polygenic risk scores (PRS) to explore the association of inhibitory control with ADHD and related psychiatric disorders. Firstly, we identified three significant loci for inhibitory control in the healthy dataset, two loci in the case dataset, and one locus in the meta-analysis of three datasets. Besides, we found more risk genes and variants by applying transcriptome-wide association study (TWAS) and conditional FDR method. Then, we constructed a network by connecting the genes identified in our study, leading to the identification of several vital genes. Lastly, we identified a potential relationship between inhibitory control and ADHD and autism by PRS analysis and found the direct and mediated contribution of the identified genetic loci on ADHD symptoms by mediation analysis. In conclusion, we revealed some genetic risk variants associated with inhibitory control and elucidated the benefit of inhibitory control as an endophenotype, providing valuable insights into the mechanisms underlying ADHD.

The importance of improving cognitive flexibility in adolescents with anorexia nervosa: The case for cognitive remediation therapy.

OBJECTIVE: Inefficiencies in executive functioning (EF), more specifically cognitive flexibility and an overly detailed processing style, are frequently observed in individuals with Anorexia Nervosa (AN) and have been identified as potential targets in treatment. Cognitive Remediation Therapy (CRT) is an adjunctive treatment approach specifically designed to have a positive impact on EF. Mainly evaluated in adults, CRT has been criticized for its perceived ineffectiveness in promoting weight restoration or directly reducing eating disorder symptoms. METHOD: We argue that we need to refocus our conceptual framework for using CRT as an adjunctive treatment and specifically explore its potential benefit in adolescents. RESULTS: Adolescence is a critical window for EF development during which CRT has the potential to have the most impact. While it may not specifically ameliorate eating disorder symptoms and directly improve weight gain, CRT may mitigate the impact of malnutrition on adolescent brain development, reduce attrition rates in treatment, and improve cognitive flexibility and (indirectly) other maintaining factors, thereby improving global functioning. DISCUSSION: More research needs to be done to understand the development of EF in adolescents with AN and how best to employ CRT as an adjunctive treatment to support development and target maintaining factors. The current article broadly reviews findings on executive functioning inefficiencies in adolescents with AN and discusses the purpose and role of CRT in treating AN. Finally, we highlight key critiques of using CRT and pose questions for future research. PUBLIC SIGNIFICANCE: Treatments targeting executive functioning in adolescents with AN are limited. We need to better understand how CRT can benefit adolescents in treatment. Increasing treatment options, including adjunctive treatments, is necessary to reduce the long-term impact of AN.

[Executive functioning and metacognition in high intellectual capacity]. / Funcionamiento ejecutivo y metacognición en la alta capacidad intelectual.

INTRODUCTION: Executive functions and Metacognition are integrated for the management of intellectual resources in close relation to intelligence its functioning and results; they are specially interesting for understanding the expression and development of high intellectual abilility (HIA). The aim of the study is to find out the relationship between executive functions (and components) and metacognition (and components) in schoolchildren with HIA. MATERIALS AND METHOD: Measures of executive and metacognitive functioning and perfectionism were extracted from a sample of n= 147 schoolchildren with HIA. RESULTS: statistical analyses using Path analysis, offered an adjusted model in which the different executive components are related to the metacognitive components. DISCUSSION: We conclude and discuss the integrative model between executive function and metacognition and its mediating role as an endophenotype between genetic endowment and the expression of resource performance, suggesting the transfer of results to the education of high intellectual ability for the optimal and ethical expression of high potential.

Introducción: Las funciones ejecutivas y la metacognición se integran para la gestión de recursos intelectuales, en estrecha relación con la inteligencia, su funcionamiento y resultados, especialmente interesante para comprender la expresión y desarrollo, más o menos óptimos, de la alta capacidad intelectual (ACI). El Objetivo del trabajo es conocer la relación entre las funciones ejecutivas (y componentes) y la metacognición (y componentes) en escolares con ACI. Materiales y Métodos: Las medidas de funcionamiento y ejecutivo, metacognitivo y de perfeccionismo extraídas en una muestra de n= 147 escolares con ACI son analizadas estadísticamente mediante el Path análisis. Resultados: Se obtiene un modelo ajustado en el que se relacionan los distintos componentes ejecutivos con los metacognitivos. Discusión: Se concluye y discute el modelo integrador entre función ejecutiva y metacognición y su papel mediador, como endofenotipo entre la dotación genética y la expresión de rendimiento de los recursos, sugiriendo la transferencia de resultados a la educación de la alta capacidad intelectual para la óptima y ética expresión del alto potencial.