Cognitive deficits in children with neurofibromatosis Type I: from recognition to treatment

__Abstract__ Over the past few years, mouse models have significantly contributed to our understanding of the molecular mechanisms underlying cognitive dysfunction in genetic disorders. Moreover, several preclinical studies in mouse models of for instance Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex, Down syndrome, Rett syndrome, and Fragile X syndrome have provided evidence that some of these cognitive deficits may be reversible by targeting the underlying molecular disturbances.l-5 These new findings have sparked a great interest in the search for drugs that may be used in patients to ameliorate their cognitive problems.6 A recent study described the beneficial effects of a statin, one of the most widely prescribed classes of medications, on cognitive deficits of a mouse model for NF1.7 This finding offered an exciting and unique opportunity to assess the effect of a drug that has been validated in preclinical studies and for which substantial clinical safety data is available, on cognitive problems in NF1 patients. This thesis focuses on the recognition and treatment of cognitive problems in children with NF1. It aims to provide an overview of the specific aspects of cognitive performance that affect daily life functioning in NF1 children, and tries to identify possible outcome measures that can be used to assess potential therapeutic interventions. This knowledge was used to perform the first randomized, double blind, placebo-controlled trial to assess the effect of statins on cognitive problems in children with NF1

Marked reduction of AKT1 expression and deregulation of AKT1-associated pathways in peripheral blood mononuclear cells of schizophrenia patients

Background: Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: A randomized controlled trial

Context: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. Objective: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention: Simvastatin or placebo treatment once daily for 12 weeks. Main Outcome Measures: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. Results: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β=0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (β=-0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio=2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β=0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β=0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. Conclusion: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration: isrctn.org Identifier: ISRCTN1496570