Background: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC gene. Patients with FAP have multiple extraintestinal manifestations that follow a genotype-phenotype pattern; however, few data exist characterizing their cognitive abilities. Given the role of the APC protein in development of the central nervous system, we hypothesized that patients with FAP would show differences in cognitive functioning compared to controls. Methods: Matched case-control study designed to evaluate cognitive function using the Test of Nonverbal Intelligence-4, the Bateria III Woodcock-Munoz, and the Behavior Rating Inventory of Executive Functions-Adult. Twenty-six individuals with FAP (mean age = 34.2 +/- 15.0 years) and 25 age-gender and educational level matched controls (mean age = 32.7 +/- 13.8 years) were evaluated. Results: FAP-cases had significantly lower IQ (p = 0.005). Across all tasks of the Bateria III Woodcock-Munoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls (p < 0.0001). Patients with FAP scored within the deficient range for Long-Term Retrieval and Cognitive Fluency. Conclusion: APC protein has an important role in neurocognitive function. The pervasive nature of the observed cognitive dysfunction suggests that loss or dysfunction of the APC protein impacts processes in cortical and subcortical brain regions. Additional studies examining larger ethnically diverse cohorts with FAP are warranted.

OBJECTIVE: To evaluate the percentage of children born extremely preterm (EP) who screen positive for > /=1 DSM-IV psychiatric disorders, the co-occurrence of and sex-related differences in these classifications, and the functional correlates of psychiatric symptoms. METHODS: The Extremely Low Gestational Age Newborn (ELGAN) Study is a prospective cohort follow-up of children born < 28 weeks' gestation. For 871 10-year-old children, parents completed the Child Symptom Inventory-4 (CSI-4), a child educational/medical history questionnaire, and the Pediatric Quality of Life Inventory (PedsQL). RESULTS: At age 10 years, ELGANs were more likely to screen positive for a number of psychiatric disorders when compared with normative expectations on the CSI-4, with a few sex-related differences. Fifteen percent of participants screened positive for 1 disorder, 7% for 2, 3% for 3, and 4% for > /=4 psychiatric disorders. Compared with children who did not screen positive for psychiatric disorders, children who screened positive for > /=3 psychiatric disorders were approximately twice as likely to have repeated a grade, have an individualized educational program, have an individual school aide, and to require special remediation classes. Children who screened positive for any psychiatric disorder were 4 times more likely to use 1 or more psychotropic medication, and those who screened positive for > /=2 psychiatric disorders had lower PedsQL scores. CONCLUSION: Among 10-year-old children born EP, rates of psychiatric symptoms exceeded normative expectation, and children who screened positive for more than 1 psychiatric disorder were at increased risk of having multiple functional impairments.

This study evaluated the hypothesis that prenatal maternal socioeconomic status (SES) adversity is associated with DNA methylation in the placenta. SES adversity was defined by the presence of, as well as a summative count of, four factors: less than college education, single marital status, food and nutritional service assistance, and public health insurance. Epigenome-wide DNA methylation was assessed using the Illumina EPIC array in 426 placentas from a sample of infants born < 28 weeks of gestation from the Extremely Low Gestational Age Newborn cohort. Associations between SES adversity and DNA methylation were assessed with robust linear regressions adjusted for covariates and controlled the false discovery rate at < 10%. We also examined whether such associations were sex specific. Indicators of SES adversity were associated with differential methylation at 33 CpG sites. Of the 33 identified CpG sites, 19 (57.6%) displayed increased methylation, and 14 (42.4%) displayed decreased methylation in association with at least one of the SES adversity factors. Sex differences were observed in DNA methylation associated with summative SES score; in which placentas derived from female pregnancies showed more robust differential CpG methylation than placentas from male pregnancies. Maternal SES adversity was associated with differential methylation of genes with key role in gene transcription and placental function, potentially altering immunity and stress response. Further investigation is needed to evaluate the role of epigenetic differences in mediating the association between maternal socioeconomic status during pregnancy and later life health outcomes in children.

BACKGROUND: To identify modifiable antecedents during pre-pregnancy and pregnancy windows associated with a positive child health at 10 years of age. METHODS: Data on 889 children enrolled in the Extremely Low Gestational Age Newborn (ELGAN) study in 2002-2004 were analyzed for associations between potentially modifiable maternal antecedents during pre-pregnancy and pregnancy time windows and a previously described positive child health index (PCHI) score at 10 years of age. Stratification by race was also investigated for associations with investigated antecedents. RESULTS: Factors associated with higher PCHI (more positive health) included greater gestational age, birth weight, multiple gestation, and medical interventions, including assisted reproduction and cervical cerclage. Factors associated with lower PCHI included correlates of lower socioeconomic status, pre-pregnancy chronic medical disorders in the mother such as pre-pregnancy body mass index (BMI), and maternal asthma. When stratified by race, variation in significant results was observed. CONCLUSIONS: Among children born extremely preterm, medical interventions and higher socioeconomic status were associated with improved PCHI, while chronic illness and high BMI in the mother is associated with lower PCHI at 10 years of age. Knowledge of such antecedent factors could inform efforts to develop interventions that promote positive child health outcomes in future pregnancies.

Introduction – Neuroplasticity based auditory and visual training programs appear to improve neurocognitive function in adults with schizophrenia, but use in younger individuals has not been determined. We hypothesized that adolescents might play more often and respond better than adults to training using a game-like laptop in their home environment. Methods -- Youth 10-19 years with Early Onset Psychosis (EOP) were provided a laptop and randomly assigned to play games to enhance basic auditory, visual and social processing neuroplasticity games (NPG) or assigned to control games with cognitive components, such as Sudoku or hangman or (CG). All received neurocognitive assessments at baseline, intervention completion and 4 months post treatment. Results — 12 youth (15.5 +3.2 yrs) were assigned to NPG and 10 participants (16.2 +2.1 years) were assigned to CG. More NPG than CG participants completed the prescribed hours of game play (block 1 - 92% vs. 70% over the first 40 hours), with both groups engaged less over time. Although most neurocognitive functions did not change, the NPG group did show improvements in WRAML Visual Learning, WISC Digit Span Forward, Spatial Span Backwards and CPT omission errors. Surprisingly, satisfaction was lower for NPG than CG. Conclusions — Groups were well matched for baseline illness characteristics. On the global measures of cognition, both EOP groups showed improvement over time but those improvements were generally greater in the CG than in the NPG group, with potentially significant differences favoring the CG evident in the neurocognitive composite score (p=0.072) and BRIEF metacognition (p=.117). Youth did not play as frequently or as long as requested despite providing a laptop for their home use and stipends for playing.

OBJECTIVE: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). METHOD: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. RESULTS: Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. CONCLUSIONS: Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703.

OBJECTIVE: We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship of different variables of illness severity and adaptive behavior to neuropsychological functioning. METHOD: Participants ranged in age from 8 to 19 years. Diagnostic status was confirmed via structured interview over multiple time points. Domains of neuropsychological functioning included fine-motor, attention, working memory, problem-solving efficiency, inhibitory control, and social cognition. Other variables included intelligence (IQ), academic achievement skills, adaptive behavior, and different measures of illness severity. RESULTS: The two groups did not differ on IQ or on any of the neuropsychological domains. The SZ group performed significantly lower in spelling. A high proportion of individuals in both groups reflected significant intellectual and academic achievement skill deficits. Significant correlations were found between the neurocognitive domains and both illness severity and adaptive behavior variables. CONCLUSIONS: There were few differences between the SZ and SA groups on IQ, achievement, or neuropsychological functioning; however, both groups showed significantly high rates of deficits in IQ and basic academic skills. Correlations of the neurocognitive functions with illness severity and adaptive behavior were small to moderate in magnitude. These findings continue to implicate the importance of neurocognitive functioning as a key area of vulnerability in the study of youth with schizophrenia spectrum disorders.

BACKGROUND: Lithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity. METHODS: Under the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies. RESULTS: The Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites. CONCLUSION: These innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness. TRIAL REGISTRATION: NCT00442039.