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

Abstract

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 (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -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 (beta = 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 (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 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: ISRCTN14965707.

Figure 1. Flowchart of Patient Inclusion

Figure 2. Interaction Between Baseline Score and Effect of Simvastatin on Object Assembly Test Results

For each subgroup, individual z scores and uncorrected group mean z scores are provided. For each subgroup, the left range shows scores at baseline and the right range, scores at 12 weeks. For the simvastatin group, n=16 for the low baseline score at baseline but n=15 for the low baseline score at 12 weeks; n=15 for the high baseline score. For the placebo group, n=22 for the low baseline score, and n=9 for the high baseline score. The difference between the simvastatin and placebo groups after 12 weeks is significant in the groups with low baseline performance (β=0.80; 95% confidence interval, 0.29 to 1.30; P=.003), but not in the groups with high baseline performance (β=0.47; 95% confidence interval, −0.64 to 1.59). Error bars represent 95% confidence intervals.