We report the results of a randomized, double-blind, placebo-controlled trial to investigate the effect of simvastatin on cognitive function in children with NF1. We used a carefully selected set of outcomes, including tests resembling measurements shown to be responsive to statins in preclinical studies, tests reflecting the specific neuropsychological deficits in NF1, and objective outcomes such as prism adaptation and brain ADC values, which are insensitive to a placebo or test-retest effect. We did not find an effect of 12-weeks of simvastatin treatment on the primary and secondary outcome parameters except for higher scores on the object assembly test.
We can conclude post hoc that the power of our study was enough to reject a possible effect on most tests. For instance, for the Rey CFT (recall) (β =0.10, SE=0.23), we can reject a change larger than 0.56, and for the cancellation test (speed) (β = −0.19, SE=0.24), we can reject a change larger than 0.28. Furthermore, we chose to interpret an improvement of 1 SD as clinically significant, and none of the outcome measures showed a difference between the simvastatin and placebo group of 1 SD or larger. Thus, given the power of the study and the overall negative findings, this study does not provide support for prescribing simvastatin to treat the cognitive deficits of children with NF1.
The object assembly test was the only outcome measure that was significantly improved. Considering that we found an improvement only on this test and that we did multiple statistical comparisons without adjusting the P value, this is probably a spurious finding.
It should be noted that the improvement in object assembly was restricted to children who performed poorly at baseline. This specific improvement in the subgroup of children with poor baseline scores is not likely to be related to a practice effect because children with high baseline scores are expected to benefit most from a practice effect.25
The object assembly test measures multiple cognitive domains, but in the context of the entire neuropsychological assessment along with the clinical behavioral observations made during the assessment, visual synthesis is probably the most damaged cognitive domain. Improved visual synthesis would affect academic performance. For instance, visual synthesis needs to be mastered for children to start reading and spelling, and visual synthesis is an important part of more advanced mathematical skills.26,27
However, whether the observed improvement in object assembly is a real effect and whether simvastatin would indeed improve academic achievement remain to be confirmed.
Our study has several limitations. First, the treatment duration used in our study might have been too short to observe a clinically significant cognitive recovery in patients with NFI. We based the length of our trial on the observation that statin treatment normalized the plasticity impairment and cognitive phenotype of Nf1
mice within days13
and the observation that treatment of some cognitive problems in children can be reached within days to weeks (for instance, in the treatment of attention deficits in attention-deficit/hyperactivity disorder, reviewed by Brown et al28
). However, because precedents for translational trials of cognition are rare, we cannot exclude the possibility that the effect of simvastatin on higher cognitive functions in humans would require a longer treatment period than 12 weeks.
Second, the placebo group showed a significant improvement between baseline and 12-week scores on 4 of 9 neuropsychological outcome measures. This resulted in a performance within normal range on 3 tests. Because preclinical studies showed that statin treatment did not improve cognitive function in mice that already learned well,13
it is possible that we reached a performance ceiling that hampered detection of an effect.
Third, it is conceivable that the therapeutic effect of simvastatin on human brain function was hampered by suboptimal availability due to a first pass effect or due to inefficient crossing of the blood brain barrier. However, increasing the therapeutic dose does not seem desirable because of the lack of safety studies in children with higher doses and the increasing risk of adverse effects observed in adults.23
Furthermore, the effect of simvastatin on low-density lipoprotein cholesterol levels at 12 weeks was similar to the decrease achieved after 48 weeks of simvastatin treatment in a previous pediatric study.16
This indicates that, at least in the liver, the treatment dose was optimal with respect to inhibition of the mevalonate pathway.
Finally, there was a relatively high amount of missing data in the neuroradiological and prism adaptation results. Although this reduces the power on these outcome measures, there was no indication for a substantial bias because the distribution of observations that were missing did not significantly differ between the simvastatin and placebo groups. For the other outcome measures, the proportion of missing data was negligibly small.
The negative outcome of this trial suggests that simvastatin should not be prescribed to ameliorate the cognitive deficits associated with NF1. Further studies to evaluate a longer treatment period and whether the object assembly finding is spurious may be warranted.