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Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth.

Background: Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOGrelated phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. Methods: A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. Results: iPDFOG+ individuals presented with more motor complications (MDSUPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. Conclusion: We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding. [ABSTRACT FROM AUTHOR]

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. • Verbal fluency is an uncertain endophenotype in schizophrenia and bipolar disorder. • Family studies may be a suitable strategy for its identification. • A longitudinal five-group comparison study was performed. • Persistent fluency deficits were identified in patients and relatives. [ABSTRACT FROM AUTHOR]

• Low dose ondansetron (AD04) notably decreased heavy drinking days among individuals with alcohol use disorder and a specific genetic profile. • This genotypic profile is in the serotonin transporter and serotonin-3AB receptor complex. • AD04′s adverse events match those of a placebo. • Combining AD04 with psychological intervention will improve access to and acceptance of modern AUD treatment. • These findings are an important advance in the field of precision medicine. 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. 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions 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.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.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.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. [ABSTRACT FROM AUTHOR]

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. ASDM 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The N100, an early auditory event-related potential, has been found to be altered in patients with psychosis. However, it is unclear if the N100 is a psychosis endophenotype that is also altered in the relatives of patients. Methods: We conducted a family study using the auditory oddball paradigm to compare the N100 amplitude and latency across 243 patients with psychosis, 86 unaffected relatives, and 194 controls. We then conducted a systematic review and a random-effects meta-analysis pooling our results and 14 previously published family studies. We compared data from a total of 999 patients, 1192 relatives, and 1253 controls in order to investigate the evidence and degree of N100 differences. Results: In our family study, patients showed reduced N100 amplitudes and prolonged N100 latencies compared to controls, but no significant differences were found between unaffected relatives and controls. The meta-analysis revealed a significant reduction of the N100 amplitude and delay of the N100 latency in both patients with psychosis (standardized mean difference [s.m.d.] = −0.48 for N100 amplitude and s.m.d. = 0.43 for N100 latency) and their relatives (s.m.d. = − 0.19 for N100 amplitude and s.m.d. = 0.33 for N100 latency). However, only the N100 latency changes in relatives remained significant when excluding studies with affected relatives. Conclusions: N100 changes, especially prolonged N100 latencies, are present in both patients with psychosis and their relatives, making the N100 a promising endophenotype for psychosis. Such changes in the N100 may reflect changes in early auditory processing underlying the etiology of psychosis. [ABSTRACT FROM AUTHOR]

Background: Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods: Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. Results: GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. Conclusions: Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology. [ABSTRACT FROM AUTHOR]

BackgroundFreezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson’s disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson’s study.MethodsA cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG− (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG− (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity.ResultsiPDFOG+ individuals presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG− indicated lower scores in Benton’s Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding.ConclusionWe determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Hypotheses Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. Study Design Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study—VIA 11. Study Results We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. Conclusion FHR-SZ and FHR-BP at age 11–12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk. [ABSTRACT FROM AUTHOR]

This article explores the management of sympathetic hyperactivity in patients with traumatic brain injury (TBI). It discusses the potential benefits of interventions that restore the balance between sympathetic and parasympathetic activity, such as beta-adrenergic receptor antagonists and alpha 2-adrenergic agonists. The study focuses on the use of early dexmedetomidine administration in TBI patients and its potential association with improved outcomes. However, the study's small sample size and limited duration of dexmedetomidine exposure prevent definitive conclusions. The authors suggest that dexmedetomidine may have clinical benefits in patients with indications for intracranial pressure monitoring. The article emphasizes the need for stronger guidelines to standardize care across centers and recommends future clinical trials to evaluate the role of early sedation in improving TBI outcomes. It also acknowledges the failure of previous clinical trials for TBI and highlights the importance of defining targetable endophenotypes for personalized treatment. The article concludes by stating that dexmedetomidine could potentially improve outcomes in TBI patients, but further research is necessary to identify the appropriate patient population. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background: Drug hypersensitivity reactions (DHRs) to platinum‐based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground‐breaking procedure for their re‐introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. Methods: Seventy‐nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. Results: Oxaliplatin‐reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p <.05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL‐6 in CRR and Mx, indicating different mechanisms and endotypes. Conclusion: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin‐reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols. [ABSTRACT FROM AUTHOR]

BackgroundMacrocephaly 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.ObjectivesThe 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.MethodsHC 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.Results20,8% 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.ConclusionIn 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.

Objectives: Some studies suggest that there are deficits in neurocognitive functions in the euthymic phase of bipolar disorder and healthy relatives of patients with bipolar disorder and that these neurocognitive disorders may be the endophenotype for bipolar disorder. This study aimed to evaluate the neurocognitive functions of unaffected siblings of patients with bipolar disorder compared with the healthy controls. Methods: The study included the unaffected siblings of patients with bipolar disorder (n = 75) and healthy volunteers without a family history of bipolar disorder (n = 50). The Structured Clinical Interview for DSM-IV (SCID-I) was administered to each individual to investigate the diagnosis of Axis-I psychiatric disorders according to DSM-IV. The Judgment of Line Orientation Test, the Auditory Verbal Learning Test, the Serial Digit Learning Test, the Stroop Color Word Test, and the Trail Making Test were used to evaluate neurocognitive functions. Results: Our study found no difference between the groups regarding processing speed, set-shifting, and mental flexibility. However, unaffected siblings of patients with bipolar disorder had significantly worse performance than healthy controls in verbal learning and memory, response inhibition, and visuospatial function. Conclusions: This study suggests that visuospatial function, response inhibition, verbal learning, and memory may be endophenotypic markers for bipolar disorder.

Establishing quantifiable biological markers associated with anxiety will increase the objectivity of phenotyping and enhance genetic research of anxiety disorders. Heart rate variability (HRV) is a physiological measure reflecting the dynamic relationship between the sympathetic and parasympathetic nervous systems, and is a promising target for further investigation. This review summarizes evidence evaluating HRV as a potential physiological biomarker of anxiety disorders by highlighting literature related to anxiety and HRV combined with investigations of endophenotypes, neuroimaging, treatment response, and genetics. Deficient HRV shows promise as an endophenotype of pathological anxiety and may serve as a noninvasive index of prefrontal cortical control over the amygdala, and potentially aid with treatment outcome prediction. We propose that the genetics of HRV can be used to enhance the understanding of the genetics of pathological anxiety for etiological investigations and treatment prediction. Given the anxiety–HRV link, strategies are offered to advance genetic analytical approaches, including the use of polygenic methods, wearable devices, and pharmacogenetic study designs. Overall, HRV shows promising support as a physiological biomarker of pathological anxiety, potentially in a transdiagnostic manner, with the heart–brain entwinement providing a novel approach to advance anxiety treatment development. This review proposes that the genetics of heart rate variability (HRV) can be used to identify novel treatment targets for anxiety disorders given that impaired HRV has support as an anxiety endophenotype, reflects anxiety‐related brain activation patterns, and may predict treatment response. Advanced approaches such as use of wearables to collect large samples, polygenic risk score methods, and pharmacogenetics are suggested to develop HRV genetic research. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex‐specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female‐specific elevation in glycerophosphorylcholine and N‐acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)‐17 signaling, C‐type lectin receptor, interferon signaling, and Toll‐like receptor pathways. We pinpointed distinct microglia‐specific immunometabolism endophenotypes (i.e., lipid‐ and amino acid‐specific IL‐10 and IL‐17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate‐mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. Highlights: Sex‐specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression.Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin‐10 pathway activity.Female AD subjects showed a shift in glutamate‐mediated cell‐cell communications between excitatory neurons to microglia and astrocyte. [ABSTRACT FROM AUTHOR]

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: Despite the emphasis on sensory dysfunction phenotypes in the revised diagnostic criteria for autism spectrum disorder (ASD), there has been limited research, particularly in the field of neurobiology, investigating the concordance in sensory features between individuals with ASD and their genetic relatives. Therefore, our objective was to examine whether neurobehavioral sensory patterns could serve as endophenotypic markers for ASD. Methods: We combined questionnaire‐ and lab‐based sensory evaluations with sensory fMRI measures to examine the patterns of sensory responsivity in 30 clinically diagnosed with ASD, 26 matched controls (CON), and 48 biological parents for both groups (27 parents of individuals with ASD [P‐ASD] and 21 for individuals with CON [P‐CON]). Results: The ASD and P‐ASD groups had higher sensory responsivity and rated sensory stimuli as more unpleasant than the CON and P‐CON groups, respectively. They also exhibited greater hemodynamic responses within the sensory cortices. Overlapping activations were observed within these sensory cortices in the ASD and P‐ASD groups. Using a machine learning approach with robust prediction models across cohorts, we demonstrated that the sensory profile of biological parents accurately predicted the likelihood of their offspring having ASD, achieving a prediction accuracy of 71.4%. Conclusions: These findings provide support for the hereditary basis of sensory alterations in ASD and suggest a potential avenue to improve ASD diagnosis by utilizing the sensory signature of biological parents, especially in families with a high risk of ASD. This approach holds promising prospects for early detection, even before the birth of the offspring. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder's (BD) potential endophenotypes include neurological soft signs (NSS) and neurocognitive disorders (ND). Few research, meanwhile, has coupled NSS and ND as combined endophenotypes of BD. Object: This study intends to investigate NSS and ND and compare their differences in euthymic patients with bipolar disorder (EBP), their unaffected first‐degree relatives (FDR), and healthy controls (HC). Additionally, search for potential endophenotypic subprojects of NSS and ND and construct and verify a composite endophenotypic. Methods: The subjects were all Han Chinese and consisted of 86 EBP, 81 FDR, and 81HC. Cambridge Neurological Inventory and MATRICSTM Consensus Cognitive Battery tested NSS and ND independently. Results: All three groups displayed a trapezoidal distribution of NSS levels and cognitive abnormalities, with EBP having the most severe NSS levels and cognitive deficits, followed by FDR and HC. Among them, motor coordination in NSS and Information processing speed (IPS), Verbal learning (VL), and Working memory (WM) in neurocognitive function are consistent with the traits of the endophenotype of BD. The accuracy in differentiating EBP and HC or FDRs and HC was higher when these items were combined as predictor factors than in differentiating EBP and FDR. Conclusion: These results provide more evidence that motor coordination, IPS, VL, and WM may be internal characteristics of bipolar disease. When these characteristics are combined into a complex endophenotype, it may be possible to distinguish BD patients and high‐risk groups from normal populations. [ABSTRACT FROM AUTHOR]

Abstract 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.

ObjectivePatients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke.MethodsThe phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127).ResultsSubjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02).ConclusionNeither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer's disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.

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.

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.

IntroductionThere is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.MethodsWe included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.ResultsSingle-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.DiscussionIdentification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.

Abstract Background Bipolar disorder's (BD) potential endophenotypes include neurological soft signs (NSS) and neurocognitive disorders (ND). Few research, meanwhile, has coupled NSS and ND as combined endophenotypes of BD. Object This study intends to investigate NSS and ND and compare their differences in euthymic patients with bipolar disorder (EBP), their unaffected first‐degree relatives (FDR), and healthy controls (HC). Additionally, search for potential endophenotypic subprojects of NSS and ND and construct and verify a composite endophenotypic. Methods The subjects were all Han Chinese and consisted of 86 EBP, 81 FDR, and 81HC. Cambridge Neurological Inventory and MATRICSTM Consensus Cognitive Battery tested NSS and ND independently. Results All three groups displayed a trapezoidal distribution of NSS levels and cognitive abnormalities, with EBP having the most severe NSS levels and cognitive deficits, followed by FDR and HC. Among them, motor coordination in NSS and Information processing speed (IPS), Verbal learning (VL), and Working memory (WM) in neurocognitive function are consistent with the traits of the endophenotype of BD. The accuracy in differentiating EBP and HC or FDRs and HC was higher when these items were combined as predictor factors than in differentiating EBP and FDR. Conclusion These results provide more evidence that motor coordination, IPS, VL, and WM may be internal characteristics of bipolar disease. When these characteristics are combined into a complex endophenotype, it may be possible to distinguish BD patients and high‐risk groups from normal populations.

The underlying genetic susceptibility for Alzheimer's disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. [ABSTRACT FROM AUTHOR]

Objective: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE‐associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome‐specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. Methods: We investigated 123 participants—23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME—who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. Results: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. Significance: JAE is associated with wide‐ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Uludag University Medical Faculty / Uludağ Üniversitesi Tıp Fakültesi Dergisi is the property of Journal of Uludag University Medical Faculty and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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.

Summary: Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. Methods: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. Findings: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P

New "omic" technologies are revealing shared and distinct biological pathways within and across neurodegenerative diseases (NDDs), allowing a better understanding of endophenotypes that exceeds the boundaries of the current diagnostic criteria. Moreover, a diagnostic framework is needed that can accommodate the co‐pathology and the clinical overlap and heterogeneity of NDDs. Apart from dissecting the reasons for a revolution in how we conceive NDD, this article aims to prompt a change in how we diagnose and classify NDD, drafting a general scheme for a new nosology. As identifying a cause is the key to using the term "disease" properly, we propose using a tridimensional classification based on three axes: (1) etiology or pathogenic mechanism, (2) pathology markers and molecular biomarkers, (3) anatomic–clinical; and three hierarchical levels of etiology: (1) genetic/sporadic (2) cellular pathways and processes, and function of fluidic brain systems, and (3) risk factors. [ABSTRACT FROM AUTHOR]

The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response. • Suggestive signals were found for visuospatial processing and recall. • The top signals pointed to the involvement of genes with a neurological role. • OCD GWAS on cognitive traits rather than case/control status might be more informative. [ABSTRACT FROM AUTHOR]

Physiological systems are subject to interindividual variation encoded by genetics. Genome‐wide association studies (GWAS) operate by surveying thousands of genetic variants from a substantial number of individuals and assessing their association to a trait of interest, be it a physiological variable, a molecular phenotype (e.g. gene expression), or even a disease or condition. Through a myriad of methods, GWAS downstream analyses then explore the functional consequences of each variant and attempt to ascertain a causal relationship to the phenotype of interest, as well as to delve into its links to other traits. This type of investigation allows mechanistic insights into physiological functions, pathological disturbances and shared biological processes between traits (i.e. pleiotropy). An exciting example is the discovery of a new thyroid hormone transporter (SLC17A4) and hormone metabolising enzyme (AADAT) from a GWAS on free thyroxine levels. Therefore, GWAS have substantially contributed with insights into physiology and have been shown to be useful in unveiling the genetic control underlying complex traits and pathological conditions; they will continue to do so with global collaborations and advances in genotyping technology. Finally, the increasing number of trans‐ancestry GWAS and initiatives to include ancestry diversity in genomics will boost the power for discoveries, making them also applicable to non‐European populations. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive deficits have been reported consistently in euthymic bipolar disorder (BD) across studies. Endophenotype potential of such deficits have been reported in a few studies. However, data from the Indian subcontinent is sparse, and no studies had a sample (patients and high-risk group) aged 20-25 years, which is the actual risk period for developing BD. We studied cognitive deficits, as a potential endophenotype for BD, in recently diagnosed BD (FEM—first episode mania) in remission, young unaffected first-degree relatives (HR) of patients with BD, and healthy controls (HC). Methods: Cross-sectional study design using convenient sampling was employed. We recruited FEM (n = 25), HR (n = 25), and age-matched HC (n = 25) between 18 and 30 years. All HR subjects were <25 years of age, which is the period of vulnerability for BD. All the groups were screened using MINI Version 6. Neurocognitive assessments were done using the NIMHANS neuropsychology battery. The cognitive domains assessed were processing speed, attention, working memory, executive functions, and visual and verbal memory. Results: The three groups were comparable in age and sex (all P > 0.06). The mean (SD) age of the FEM subjects was 23.7 (3.47) years, and the mean duration of illness was 5.92 (2.94) months. Compared to the HC group, the FEM group performed poorly on multiple cognitive domains (all P < 0.05). Performance of the HR group was comparable to the FEM group, but they showed significantly poorer performance compared to HC on the verbal fluency test—controlled oral word association (COWA, F = 12.36, P = 0.001), and the visual learning and memory test—complex figure test-immediate recall (CFT-IR, F = 8.10 and p = 0.001). Conclusions: Cognition is impaired very early in the course of BD. Visual memory and executive function (verbal fluency) have endophenotypic potential. These findings are particularly important given that the HR group were still within the vulnerable period to develop BD. These findings imply a tremendous potential for early diagnosis and prevention by early interventions in BD. [ABSTRACT FROM AUTHOR]

Quantitative traits are measurable characteristics distributed along a continuous scale thought to relate to underlying biology. There is growing interest in the use of quantitative traits in behavioral and psychiatric research, particularly in research on conditions diagnosed based on reports of behaviors, including autism. This brief commentary describes quantitative traits, including defining what they are, how we can measure them, and key considerations for their use in autism research. Examples of measures include behavioral report scales like the Social Responsiveness Scale and Broader Autism Phenotype Questionnaire, as well as biological measurements, like certain neuroimaging metrics; such measures can capture quantitative traits or constructs like the broader autism phenotype, social communication, and social cognition. Quantitative trait measures align with the Research Domain Criteria (RDoC) approach and can be used in autism research to help gain a better understanding of causal pathways and biological processes. They can also be used to aid identification of genetic and environmental factors involved in such pathways, and thereby lead to an understanding of influences on traits across the entire population. Finally, in some cases, they may be used to gauge treatment response, and assist screening and clinical characterization of phenotype. In addition, practical benefits of quantitative trait measures include improved statistical power relative to categorical classifications and (for some measures) efficiency. Ultimately, research across autism fields may benefit from incorporating quantitative trait measures as a complement to categorical diagnosis to advance understanding of autism and neurodevelopment. Lay Summary: Many characteristics lie along a spectrum. Quantitative traits are measurable characteristics that lie along a continuous scale and may relate to underlying biology. This brief commentary summarizes the concept of quantitative traits, ways to measure them, and how they can be used in autism research. Examples of commonly used quantitative trait measures in autism research include questionnaires capturing social behaviors, as well as certain biological measurements. These measurements capture features or traits known to differ in autism, like social cognition. Quantitative trait measures can be used in autism research to help gain a better understanding of potential causes and pathways; to identify genetic and environmental factors involved in the development of autism; and to better understand patterns of behaviors and co‐occurring factors. Ultimately, research across autism fields may benefit from incorporating quantitative trait measures to learn more about autism and neurodevelopment. [ABSTRACT FROM AUTHOR]

BackgroundLatency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.MethodsSchizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.Results980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p

BackgroundFamily history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD.MethodsData from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes.ResultsDensity measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude.ConclusionsDensity (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.

Abstract Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case–control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Abstract Background Sleep spindles have been involved in sleep stabilization and sleep-related memory mechanisms and their deficit emerged as possible biomarker in schizophrenia. However, whether this sleep phenotype is also present in other disorders that share psychotic symptoms remains unclear. To address this gap, we assessed sleep spindles in participants of a prospective population-based cohort who underwent psychiatric assessment (CoLaus|PsyCoLaus) and polysomnographic recording (HypnoLaus). Methods Sleep was recorded using ambulatory polysomnography in participants (N = 1037) to the PsyCoLaus study. Sleep spindle parameters were measured in people with a lifelong diagnosis of schizophrenia (SZ), schizoaffective depressive (SAD), schizoaffective manic (SAM), bipolar disorder type I (BP-I) and type II (BP-II). The associations between lifetime diagnostic status (independent variables, SZ, SAD, SAM, BPD-I, BPD-II, controls) and spindle parameters (dependent variables) including density, duration, frequency and maximum amplitude, for all (slow and fast), slow- and fast-spindle were assessed using linear mixed models. Pairwise comparisons of the different spindle parameters between the SZ group and each of the other psychiatric groups was performed using a contrast testing framework from our multiple linear mixed models. Results Our results showed a deficit in the density and duration of sleep spindles in people with SZ. They also indicated that participants with a diagnosis of SAD, SAM, BP-I and BP-II exhibited different sleep spindle phenotypes. Interestingly, spindle densities and frequencies were different in people with a history of manic symptoms (SAM, BP-I, and BP-II) from those without (SZ, SAD). Conclusions Although carried out on a very small number of participants due to the low prevalence of these disorders in general population, this pilot study brought new elements that argued in favor of a deficit of sleep spindles density and duration in people with schizophrenia. In addition, while we could expect a gradual change in intensity of the same sleep spindle parameters through psychotic diagnoses, our results seem to indicate a more complex situation in which the frequency of sleep spindles might be more impacted by diagnoses including a history of mania or hypomania. Further studies with a larger number of participants are required to confirm these effects.