Evaluating longitudinal relationships between parental monitoring and substance use in a multi-year, intensive longitudinal study of 670 adolescent twins.

Introduction: Parental monitoring is a key intervention target for adolescent substance use, however this practice is largely supported by causally uninformative cross-sectional or sparse-longitudinal observational research designs. Methods: We therefore evaluated relationships between adolescent substance use (assessed weekly) and parental monitoring (assessed every two months) in 670 adolescent twins for two years. This allowed us to assess how individual-level parental monitoring and substance use trajectories were related and, via the twin design, to quantify genetic and environmental contributions to these relationships. Furthermore, we attempted to devise additional measures of parental monitoring by collecting quasi-continuous GPS locations and calculating a) time spent at home between midnight and 5am and b) time spent at school between 8am-3pm. Results: ACE-decomposed latent growth models found alcohol and cannabis use increased with age while parental monitoring, time at home, and time at school decreased. Baseline alcohol and cannabis use were correlated (r = .65) and associated with baseline parental monitoring (r = -.24 to -.29) but not with baseline GPS measures (r = -.06 to -.16). Longitudinally, changes in substance use and parental monitoring were not significantly correlated. Geospatial measures were largely unrelated to parental monitoring, though changes in cannabis use and time at home were highly correlated (r = -.53 to -.90), with genetic correlations suggesting their relationship was substantially genetically mediated. Due to power constraints, ACE estimates and biometric correlations were imprecisely estimated. Most of the substance use and parental monitoring phenotypes were substantially heritable, but genetic correlations between them were not significantly different from 0. Discussion: Overall, we found developmental changes in each phenotype, baseline correlations between substance use and parental monitoring, co-occurring changes and mutual genetic influences for time at home and cannabis use, and substantial genetic influences on many substance use and parental monitoring phenotypes. However, our geospatial variables were mostly unrelated to parental monitoring, suggesting they poorly measured this construct. Furthermore, though we did not detect evidence of genetic confounding, changes in parental monitoring and substance use were not significantly correlated, suggesting that, at least in community samples of mid-to-late adolescents, the two may not be causally related.

Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

INTRODUCTION: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. RESULTS: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aß40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo. DISCUSSION: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.