A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I.

OBJECTIVE: Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1. METHOD: Forty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures. RESULTS: Twelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f (2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects. INTERPRETATION: These preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

Prevalence and psychiatric comorbidity of attention-deficit/hyperactivity disorder in an adolescent Finnish population.

OBJECTIVE: The purpose of the study was to estimate the prevalence of attention-deficit/hyperactivity disorder (ADHD) and its clinical characteristics in the Northern Finland Birth Cohort 1986. METHOD: A general population Northern Finland Birth Cohort 1986 of 9,432 children followed prospectively from the early fetal period was surveyed at adolescence (ages 16-18) for ADHD behaviors. Among 6,622 respondents to the survey, a subset of 457 likely cases and controls were evaluated for ADHD and other psychiatric disorders. Chi-square and descriptive statistics were used to examine clinical characteristics of ADHD in the subset, and logistic regression was used to estimate prevalence by weighted extrapolation in the larger cohort. RESULTS: The estimated prevalence of ADHD among adolescents in the Northern Finland Birth Cohort 1986 is 8.5% with a male/female ratio of 5.7:1. The distribution of ADHD subtypes among the ADHD adolescents is 28% Combined, 64% Inattentive, and 8% Hyperactive-Impulsive. A lifetime diagnosis of a broadly defined ADHD (probable or definite) had a prevalence of 18.2% with a male/female odds ratio (OR) of 3.2. This lifetime diagnosis of ADHD is significantly associated with anxiety (OR 2.4), mood (OR 2.9), and disruptive behavioral disorders (OR 17.3) in the cohort. CONCLUSIONS: ADHD is a common neurobehavioral disorder among Northern Finnish adolescents and significantly associated with psychiatric comorbidity in adolescence.

Maternal smoking and hyperactivity in 8-year-old children.

OBJECTIVE: To investigate the association between maternal smoking during pregnancy and hyperactivity in 8-year-old children. METHOD: The study population consisted of children from the Northern Finland 1985/86 Birth Cohort. At 8-year follow-up 9,357 children were alive. Mothers provided information both during pregnancy and at age 8. Teachers assessed children's behavior by the Children's Behavior Questionnaire (Rutter B2). Unadjusted analyses and stratification were used to study associations and confounding variables. A multivariate logistic regression model was fitted to assess the independent association between smoking and outcome. RESULTS: Maternal smoking was associated with hyperactivity even after adjustment for sex, family structure, socioeconomic status, maternal age, and maternal alcohol use (odds ratio 1.30; 1.08-1.58). The association was particularly notable among children of young mothers with low social standing. A positive dose-response relationship was seen between maternal smoking and hyperactivity. CONCLUSION: This study, the largest population-based prospective follow-up on fetal nicotine exposure and later behavioral disorders, confirms earlier descriptions of the link between maternal smoking during gestation and childhood hyperactivity. Discontinuation or decreased use of cigarettes during pregnancy might improve behavioral outcome of children.