Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1: A Randomized Controlled Trial

Department of General Pediatrics, Erasmus MC University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 07/2008; 300(3):287-94. DOI: 10.1001/jama.300.3.287
Source: PubMed


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.
To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1.
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.
Simvastatin or placebo treatment once daily for 12 weeks.
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.
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.
In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration Identifier: ISRCTN14965707.

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    • "Most importantly, down regulation of the hyperactive RAS pathway by lovastatin leads to an improvement of synaptic plasticity and restores learning deficits and attention in mouse models of NF1. In humans with NF1, Krab and colleagues performed a 12-week trial with simvastatin but could not improve cognitive function in children with NF1 [13]. In contrast, an open phase 1 study revealed an improvement of verbal and non-verbal memory after three month lovastatin treatment in children [14], which could be explained by a specific function of lovastatin. "
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. In NF1 patients (n = 11; 19--44 years) and healthy controls (HC; n = 11; 19--31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.
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    • "Kinderen en volwassenen met NF1 hebben gemiddeld een lager IQ, aandachtsproblemen , forse vermindering van het visueel-ruimtelijk geheugen en motorische problematiek. Dit alles heeft een grote invloed op schoolprestaties en dagelijks leven (Krab et al., 2008; Descheemaeker et al., 2012). "
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    ABSTRACT: Eén op de vijftig kinderen wordt geboren met een verstandelijke beperking. Van oudsher wordt zo’n aangeboren verstandelijke beperking gezien als een onomkeerbaar probleem van de hersenontwikkeling. Echter, recent onderzoek laat zien dat veelal een genetisch defect ten grondslag ligt aan een ernstige verstandelijke handicap. Met het groeiende inzicht in de rol van deze genen in het functioneren van de hersenen, beginnen we ons ook te realiseren dat de visie van onomkeerbaarheid mogelijk niet altijd opgaat. Deze hypothese wordt besproken aan de hand van de genetische syndromen neurofibromatose type 1 (NF1) en tubereuze sclerose complex (TSC). Veel patiënten met NF1 hebben een lichte verstandelijke beperking, waarvoor ze bijvoorbeeld extra hulp nodig hebben op school. Bij TSC is de variatie van de verstandelijke ontwikkeling veel groter. Sommige patiënten hebben een normaal IQ, anderen hebben extra hulp nodig of zitten op speciaal onderwijs, terwijl weer anderen nooit leren praten of lopen.
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    • "Moreover, a short treatment may result in a significant improvement because of the testretest effect. For instance, in the trial of (Krab et al., 2008b), 4 out of 9 tests showed a significant improvement in the placebo group, potentially masking the effect of statins. The second challenge is determining the best outcome measure. "
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    ABSTRACT: Brain development in neurodevelopmental disorders has been considered to comprise a sequence of critical periods, and abnormalities occurring during early development have been considered irreversible in adulthood. However, findings in mouse models of neurodevelopmental disorders, including fragile X, Rett syndrome, Down syndrome, and neurofibromatosis type I suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations. Furthermore, recent studies have suggested that critical period-like plasticity can be reactivated in the adult brain by environmental manipulations or by pharmacotherapy. These studies open up a tantalizing possibility that targeted pharmacological treatments in combination with regimes of training or rehabilitation might alleviate or reverse the symptoms of neurodevelopmental disorders even after the end of critical developmental periods. Even though translation from animal experimentation to clinical practice is challenging, these results suggest a rational basis for treatment of neurodevelopmental disorders in adulthood.
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