Monday, November 21, 2016

Lovastatin does not ameliorate cognitive deficits in neurofibromatosis type 1

Payne, Jonathan M. DPsych; Barton, Belinda PhD; Ullrich, Nicole J. MD, PhD; Cantor, Alan PhD; Hearps, Stephen J.C. PGDip; Cutter, Gary PhD; Rosser, Tena MD; Walsh, Karin S. PsyD; Gioia, Gerard A. PhD; Wolters, Pamela L. PhD; Tonsgard, James MD; Schorry, Elizabeth MD; Viskochil, David PhD; Klesse, Laura PhD, MD; Fisher, Michael MD; Gutmann, David H. MD, PhD; Silva, Alcino J. PhD; Hunter, Scott J. PhD; Rey-Casserly, Celiane PhD; Cantor, Nancy L. PhD; Byars, Anna W. PhD; Stavinoha, Peter L. PhD; Ackerson, Joseph D. PhD; Armstrong, Carol L. PhD; Isenberg, Jill PhD; O'Neil, Sharon H. PhD; Packer, Roger J. MD; Korf, Bruce PhD; Acosta, Maria T. MD; North, Kathryn N. MD; For the NF Clinical Trials Consortium.  Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.  Neurology.  Article in press.

ABSTRACT

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).

Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8–15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.

Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = −0.15, 95% confidence interval −0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval −0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo.

Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.

ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493).

Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Courtesy of:  https://www.mdlinx.com/neurology/medical-news-article/2016/11/21/neurofibromatosis-type-1-lovastatin-children/6940707/?category=latest&page_id=1
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From the article

Mice with a heterozygous inactivating mutation in the Nf1 gene (Nf11/2) have been used to model the pathology underlying the human cognitive phenotype. Spatial learning and attention impairments have been associated with elevated RAS activity, increased activity-dependent g-aminobutyric acid (GABA) release, and reduced synaptic plasticity. Pharmacologic reduction of RAS activity with lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, normalized synaptic plasticity and rescued the behavioral phenotype in Nf11/2 mice, providing a rationale for human clinical trials.

Initial trials using statin medications in children with NF1 have been inconclusive. While 2 randomized controlled trials of simvastatin reported no treatment effect on cognitive outcomes,  studies evaluating lovastatin have been more promising. An initial open-label phase I trial of lovastatin demonstrated normalization of functional connectivity within the default mode network7 with accompanying improvements in memory and attention. More recently, results from a small randomized controlled trial in children and adults with NF1 reported beneficial effects of lovastatin on learning and memory.


In the current study, we tested the hypothesis that 16 weeks of lovastatin will result in cognitive, behavioral, and quality-of-life improvements for children with NF1. The safety profile of lovastatin was also evaluated. This is the largest statin trial in NF1 and the first to limit participation to patients with a learning or attention impairment at baseline.

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