Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia: A comparison among participants between 2 and 53 years

Author´s accepted manuscript.This is the peer reviewed version of the following article: Hope, S., Nærland, T., Høyland, A. L., Torske, T., Malt, E., Abrahamsen, T. G., Nerhus, M., Wedervang-Resell, K., Lonning, V. L. H., Johannessen, J., Steen, N. E., Agartz, I., Stenberg, N., Hundhausen, T. E., Mørkrid, L. & Andreassen, O. A. (2020). Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia : A comparison among participants between 2 and 53 years. The FASEB Journal, 34(6), 8114-8124, which has been published in final form at https://doi.org/10.1096/fj.201900855RRR. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2-53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age-and gender-adjusted vitB12 z-scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z-score: 0.30) than in HC (316 pmol/L, z-score: 0.06, P < .01) and schizophrenia (306 pmol/L, z-score: −0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age-and gender-adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z-scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.acceptedVersio

The relationship between parent-rated executive dysfunction and social difficulties in children and adolescents with autism spectrum disorder

The relationship between executive function (EF) and social difficulties in children and adolescents with autism spectrum disorder (ASD) is investigated in the current thesis. Executive dysfunction is one of the cognitive theories of ASD. Even though it cannot explain all of the symptoms of ASD, executive dysfunction is a central characteristic of everyday functioning in ASD and closely related to adaptive functioning and quality of life. Few studies, however, have investigated the relationship between EF and social function in everyday life in this group. Sub-aims of this thesis were to examine how sex and comorbid attention deficit/ hyperactivity disorder (ADHD) affect the relationship between social function and EF. The role of EF by means of genetic information is also examined. We had access to polygenic scores (PGSs) for ASD, ADHD and general intelligence, and explored their association to executive dysfunction in everyday life. The first aim was to investigate the relationship between everyday EF as measured by the Behavior Rating Inventory of Executive Function (BRIEF) and social function as measured by the Social Responsiveness Scale questionnaire (SRS). In a sample of 86 children and adolescents (23 girls), we found that difficulties with the metacognitive aspects of EF were significantly related to social dysfunction (Paper I). This finding remained even after the children with comorbid ADHD were excluded from the analyses. Secondly, we wanted to examine possible sex differences in the relationship between executive dysfunction as measured by the BRIEF and autistic symptoms using the Autism Diagnostic Interview-Revised (ADI-R). The results showed a strong and significant association between BRIEF scores and ADI-R domains for social interaction and communication in girls, but not for boys. We did not find sex differences in the relationship between executive dysfunction and restricted and repetitive behaviors (Paper II). Comorbid ADHD did not have a significant impact on the association between BRIEF and ADI-R scores. The last aim was to explore if the polygenic score (PGS) for ASD was associated with executive dysfunction in everyday life in a clinical sample of children and adolescents admitted for clinical assessment of ASD. In addition, we had access to the PGSs for ADHD and general intelligence (INT) for the same participants. The sample was divided into low and high groups based on their PGSs. In a regression model, we found that ASD PGS was significantly associated with behavior regulation aspects of EF. We did not find any significant association between EF and the PGSs for ADHD or INT in our sample (Paper III). Furthermore, we found high PGS for general intelligence to be related to social difficulties in everyday life measured by the SRS. One possible clinical implication of our findings is that metacognitive aspects of EF may be of particular importance for social function in everyday life for children and adolescents with ASD. Interventions targeting metacognitive skills could therefore have a positive influence on social function for these children. Furthermore, there might be important differences between girls and boys in the relationship between executive dysfunction and reciprocal social interaction and communication. Our results indicated that the relationship for girls was stronger than for boys. This might imply that executive dysfunction and social difficulties in girls may be more closely related, and that girls with ASD may benefit more from EF interventions. Lastly, children and adolescents with high PGS for ASD might be particularly vulnerable and have more difficulties with behavior regulation aspects of EF than those with low PGS for ASD. The clinical relevance may be that preventions aimed at EF difficulties could be offered to children at risk earlier, and that the more general ASD treatment could be stratified according to PGS level

Metacognitive Aspects of Executive Function Are Highly Associated with Social Functioning on Parent-Rated Measures in Children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is characterized by social dysfunction. Even though executive dysfunction has been recognized as important in understanding ASD, the findings are inconsistent. This might be due to different definitions of executive function (EF), which part of EF that has been studied, structured vs. unstructured tasks, inclusion of different moderators (age, IQ, sex) and different diagnostic categories within the spectrum. The main finding is that people with ASD have more EF difficulties than normal controls and more difficulties on open-end tasks than on structured cognitive tasks. Since some EF difficulties may not be observable in a laboratory setting, informant measures might have higher ecological validity than neuropsychological tests. Evidence suggests that executive dysfunctions are associated with social impairments, but few studies have investigated the details of this relationship, and it remains unclear what types of EF deficits are relevant for the social problems of individuals with ASD. Here we investigated which EF domains were associated with various domains of social function on parent-rated measures. A total of 86 children and adolescents with a diagnosis of ASD were included and tested for general cognitive abilities. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Social Responsiveness Scale (SRS). Multiple regression analysis revealed significant associations between SRS scores and age, sex, total IQ and the BRIEF indexes. The Metacognition Index from the BRIEF added significantly to the prediction of the SRS total score and the subscales Social Communication, Social Motivation and Autistic Mannerisms. The findings suggest that metacognitive aspects of EF are of particular importance for social abilities in children and adolescents with ASD. Earlier research has shown that typically developing (TD) children have a different relationship between EF and social function than children with ASD. They found that in TD children the EF domain related to behavioral regulation was most important to social function. The results from the current study may have implications for understanding the cognitive components of the social problems that define ASD, and may be relevant in developing more targeted clinical EF interventions related to core ASD dysfunctions.The study is part of the BUPgen Study group and the research network NeuroDevelop. The project was supported by the National Research Council of Norway (Grant #213694) vand the South-Eastern Norway Regional Health Authority funds the Regional Research Network NeuroDevelop (Grant #39763). The corresponding author has a research grant from Vestre Viken Hospital Trust (Grant #6903002).publishedVersio

Metacognitive aspects of executive function are highly associated with social functioning on parent-rated measures in children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is characterized by social dysfunction. Even though executive dysfunction has been recognized as important in understanding ASD, the findings are inconsistent. This might be due to different definitions of executive function (EF), which part of EF that has been studied, structured vs. unstructured tasks, inclusion of different moderators (age, IQ, sex) and different diagnostic categories within the spectrum. The main finding is that people with ASD have more EF difficulties than normal controls and more difficulties on open-end tasks than on structured cognitive tasks. Since some EF difficulties may not be observable in a laboratory setting, informant measures might have higher ecological validity than neuropsychological tests. Evidence suggests that executive dysfunctions are associated with social impairments, but few studies have investigated the details of this relationship, and it remains unclear what types of EF deficits are relevant for the social problems of individuals with ASD. Here we investigated which EF domains were associated with various domains of social function on parent-rated measures. A total of 86 children and adolescents with a diagnosis of ASD were included and tested for general cognitive abilities. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Social Responsiveness Scale (SRS). Multiple regression analysis revealed significant associations between SRS scores and age, sex, total IQ and the BRIEF indexes. The Metacognition Index from the BRIEF added significantly to the prediction of the SRS total score and the subscales Social Communication, Social Motivation and Autistic Mannerisms. The findings suggest that metacognitive aspects of EF are of particular importance for social abilities in children and adolescents with ASD. Earlier research has shown that typically developing (TD) children have a different relationship between EF and social function than children with ASD. They found that in TD children the EF domain related to behavioral regulation was most important to social function. The results from the current study may have implications for understanding the cognitive components of the social problems that define ASD, and may be relevant in developing more targeted clinical EF interventions related to core ASD dysfunctions

Atypical event-related potentials revealed during the passive parts of a Go-NoGo task in autism spectrum disorder: a case-control study

Background The core features of autism spectrum disorder (ASD) are easily recognizable in non-structured clinical and real-life situations. The features are often difficult to capture in structured laboratory settings, and the results from tests do not necessarily reflect symptom severity. We investigated neurophysiological processing in the passive parts of a cued Go-NoGo task, using the active parts of the test as a comparator. Methods Forty-nine adolescents diagnosed with ASD and 49 typically developing (TD) adolescents (age 12–21 years) were included. Daily life executive function was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). We applied a visual cued Go-NoGo task and recorded event-related potentials (ERPs). We investigated occipital N1, a component related to early perception of visual stimuli, and P3a, a fronto-central component related to switching of attention, in the passive and active parts of the test. Results During the passive parts, the ASD group had statistically significantly longer N1 latency (p < 0.001, Cohens d = 0.75) and enhanced amplitude of P3a (p = 0.002, Cohens d = 0.64) compared to the TD, while no significant differences were observed in the active parts. Both components correlated significantly with the Behavioral Regulation Index of the BRIEF (partial correlation r = 0.35, p = 0.003). Conclusion Delayed N1 response, indicating altered visual perception, and enhanced P3a response, indicating increased neural activation related to attention allocation, were found during the passive parts of a Go-NoGo task in ASD participants. These abnormal ERP signals in the non-structured settings were associated with everyday executive function, suggesting that neurophysiolocal measures related to atypical control of alertness and “hyper-awareness” underlie daily life dysfunction in ASD. Assessments during passive settings have a potential to reveal core neurobiological substrates of ASD

Metacognitive Aspects of Executive Function Are Highly Associated with Social Functioning on Parent-Rated Measures in Children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is characterized by social dysfunction. Even though executive dysfunction has been recognized as important in understanding ASD, the findings are inconsistent. This might be due to different definitions of executive function (EF), which part of EF that has been studied, structured vs. unstructured tasks, inclusion of different moderators (age, IQ, sex) and different diagnostic categories within the spectrum. The main finding is that people with ASD have more EF difficulties than normal controls and more difficulties on open-end tasks than on structured cognitive tasks. Since some EF difficulties may not be observable in a laboratory setting, informant measures might have higher ecological validity than neuropsychological tests. Evidence suggests that executive dysfunctions are associated with social impairments, but few studies have investigated the details of this relationship, and it remains unclear what types of EF deficits are relevant for the social problems of individuals with ASD. Here we investigated which EF domains were associated with various domains of social function on parent-rated measures. A total of 86 children and adolescents with a diagnosis of ASD were included and tested for general cognitive abilities. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Social Responsiveness Scale (SRS). Multiple regression analysis revealed significant associations between SRS scores and age, sex, total IQ and the BRIEF indexes. The Metacognition Index from the BRIEF added significantly to the prediction of the SRS total score and the subscales Social Communication, Social Motivation and Autistic Mannerisms. The findings suggest that metacognitive aspects of EF are of particular importance for social abilities in children and adolescents with ASD. Earlier research has shown that typically developing (TD) children have a different relationship between EF and social function than children with ASD. They found that in TD children the EF domain related to behavioral regulation was most important to social function. The results from the current study may have implications for understanding the cognitive components of the social problems that define ASD, and may be relevant in developing more targeted clinical EF interventions related to core ASD dysfunctions

Event-Related Potentials in a Cued Go-NoGo Task Associated with Executive Functions in Adolescents with Autism Spectrum Disorder; A Case-Control Study

Executive functions are often affected in autism spectrum disorders (ASD). The underlying biology is however not well known. In the DSM-5, ASD is characterized by difficulties in two domains: Social Interaction and Repetitive and Restricted Behavior, RRB. Insistence of Sameness is part of RRB and has been reported related to executive functions. We aimed to identify differences between ASD and typically developing (TD) adolescents in Event Related Potentials (ERPs) associated with response preparation, conflict monitoring and response inhibition using a cued Go-NoGo paradigm. We also studied the effect of age and emotional content of paradigm related to these ERPs. We investigated 49 individuals with ASD and 49 TD aged 12–21 years, split into two groups below (young) and above (old) 16 years of age. ASD characteristics were quantified by the Social Communication Questionnaire (SCQ) and executive functions were assessed with the Behavior Rating Inventory of Executive Function (BRIEF), both parent-rated. Behavioral performance and ERPs were recorded during a cued visual Go-NoGo task which included neutral pictures (VCPT) and pictures of emotional faces (ECPT). The amplitudes of ERPs associated with response preparation, conflict monitoring, and response inhibition were analyzed. The ASD group showed markedly higher scores than TD in both SCQ and BRIEF. Behavioral data showed no case-control differences in either the VCPT or ECPT in the whole group. While there were no significant case-control differences in ERPs from the combined VCPT and ECPT in the whole sample, the Contingent Negative Variation (CNV) was significantly enhanced in the old ASD group (p = 0.017). When excluding ASD with comorbid ADHD we found a significantly increased N2 NoGo (p = 0.016) and N2-effect (p = 0.023) for the whole group. We found no case-control differences in the P3-components. Our findings suggest increased response preparation in adolescents with ASD older than 16 years and enhanced conflict monitoring in ASD without comorbid ADHD during a Go-NoGo task. The current findings may be related to Insistence of Sameness in ASD. The pathophysiological underpinnings of executive dysfunction should be further investigated to learn more about how this phenomenon is related to core characteristics of ASD

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher-order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent-reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5-22 years with full-scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full-scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2020, 13: 207-220. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often have difficulties with higher-order cognitive processes that regulate thoughts and actions during goal-directed behavior, also known as executive function (EF). We studied the association between genetics related to ASD and EF and found a relation between high polygenic score (PGS) for ASD and difficulties with behavior regulation aspects of EF in children and adolescents under assessment for ASD. Furthermore, high PGS for general intelligence was related to social problems

Attitudes among parents of persons with autism spectrum disorder towards information about genetic risk and future health

Clinical relevance of genetic testing is increasing in autism spectrum disorder (ASD). Information about genetic risk may contribute to improved diagnostics, treatment and family planning, but may also be perceived as a burden. Knowledge about the families’ preferences with regard to genetic risk information is important for both health care professionals and policy makers. We investigated attitudes towards sharing information about genetic risk of ASD and knowledge about future health among parent members of the Norwegian Autism Association (N = 1455) using a questionnaire, and the relationships with parent and child characteristics, such as age, gender and ASD severity. Most preferred autonomy in deciding whom to inform about genetic risk of ASD (74.4%) and a minority supported extensive intra-familial disclosure of the genetic risk (41.1%). The majority agreed that it is an obligation to know as much as possible relevant for future health (58.0%) and only 51.7% agreed to a principle of a ‘right not to know’. In regression models, the attitudes were associated with opinions about benefits and harms of genetic testing (e.g., treatment, family planning, understanding of ASD pathology, insurance discrimination and family conflict). In sum, the findings show that most parents want to know as much as possible relevant for their children’s future health and keep their autonomy and intra-familial confidentiality about genetic risk information. Nearly half of the parents were not concerned with a “right not to know”. These attitudes can inform development of guidelines and bioethics in the age of genomic precision medicine

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher‐order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent‐reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5–22 years with full‐scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full‐scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc