Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study:Rationale, Methods, and Early Data

Background: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. Methods: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. Results: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p &lt; .05) and also had more academic/educational problems. Conclusions: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.</p

Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study:Rationale, Methods, and Early Data

Background: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. Methods: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. Results: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p &lt; .05) and also had more academic/educational problems. Conclusions: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.</p

Positive association of the hepatic lipase gene polymorphism c.514C > T with estrogen replacement therapy response

<p>Abstract</p> <p>Background</p> <p>Hepatic lipase (HL), an enzyme present in the hepatic sinusoids, is responsible for the lipolysis of lipoproteins. Human HL contains four polymorphic sites: G-250A, T-710C, A-763G, and C-514T single-nucleotide polymorphism (SNPs). The last polymorphism is the focus of the current study. The genotypes associated with the C-514T polymorphism are CC (normal homozygous - W), CT (heterozygous - H), and TT (minor-allele homozygous - M). HL activity is significantly impaired in individuals of the TT and CT genotypes. A total of 58 post-menopausal women were studied. The subjects were hysterectomized women receiving hormone replacement therapy consisting of 0.625 mg of conjugated equine estrogen once a day. The inclusion criteria were menopause of up to three years and normal blood tests, radiographs, cervical-vaginal cytology, and densitometry. DNA was extracted from the buccal and blood cells of all 58 patients using a commercially available kit (GFX^®- Amersham-Pharmacia, USA).</p> <p>Results</p> <p>Statistically significant reductions in triglycerides (t = 2.16; n = 58; p = 0.03) but not in total cholesterol (t = 0.14; n = 58; p = 0.89) were found after treatment. This group of good responders were carriers of the T allele; the CT and TT genotypes were present significantly more frequently than in the group of non-responders (p = 0.02 or p = 0.07, respectively). However, no significant difference in HDL-C (t = 0.94; n = 58; p = 0.35) or LDL-C (t = -0.83; n = 58; p = 0.41) was found in these patients.</p> <p>Conclusions</p> <p>The variation in lipid profile associated with the C-514T polymorphism is significant, and the T allele is associated with the best response to ERT.</p

The Toronto Adolescent and Youth Cohort Study:Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality

BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality.METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data.RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs.CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.</p

Neuroimaging and Biosample Collection in the Toronto Adolescent and Youth Cohort Study:Rationale, Methods, and Early Data

BACKGROUND: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far.METHODS: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia.RESULTS: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%).CONCLUSIONS: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care.</p

Distinct subcortical volume alterations in pediatric and adult OCD: a worldwide meta- and mega-analysis

Objective: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful

Genomics and proteomics of vertebrate cholesterol ester lipase (LIPA) and cholesterol 25-hydroxylase (CH25H)

Cholesterol ester lipase (LIPA; EC 3.1.1.13) and cholesterol 25-hydroxylase (CH25H; EC 1.14.99.48) play essential role in cholesterol metabolism in the body by hydrolysing cholesteryl esters and triglycerides within lysosomes (LIPA) and catalysing the formation of 25-hydroxycholesterol from cholesterol (CH25H) which acts to repress cholesterol biosynthesis. Bioinformatic methods were used to predict the amino acid sequences, structures and genomic features of several vertebrate LIPA and CH25H genes and proteins, and to examine the phylogeny of vertebrate LIPA. Amino acid sequence alignments and predicted subunit structures enabled the identification of key sequences previously reported for human LIPA and CH25H and transmembrane structures for vertebrate CH25H sequences. Vertebrate LIPA and CH25H genes were located in tandem on all vertebrate genomes examined and showed several predicted transcription factor binding sites and CpG islands located within the 5′ regions of the human genes. Vertebrate LIPA genes contained nine coding exons, while all vertebrate CH25H genes were without introns. Phylogenetic analysis demonstrated the distinct nature of the vertebrate LIPA gene and protein family in comparison with other vertebrate acid lipases and has apparently evolved from an ancestral LIPA gene which predated the appearance of vertebrates

Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study

Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.DTI scans were acquired for 19 children and adolescents with ASD (∼8-18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8-18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder

Brain structural covariance networks in obsessive-compulsive disorder : a graph analysis from the ENIGMA Consortium

In the largest brain structural covariance study of OCD to date, Yun et al. show a less segregated organization of structural covariance networks and a reorganization of brain hubs, including cingulate and orbitofrontal regions, in OCD. The findings point to altered trajectories of brain development and maturation. Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z -score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Neurexin-1 and Frontal Lobe White Matter: An Overlapping Intermediate Phenotype for Schizophrenia and Autism Spectrum Disorders

Background: Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. Method/Principal Findings: 53 healthy individuals between 18–59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject’s sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 39 untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. Conclusions: Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brai