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Ann Clin Transl Neurol. 2016 Feb 22;3(4):266-79. doi: 10.1002/acn3.288. eCollection 2016 Apr.

A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I.

Author information

1
Departments of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California.
2
Children's Hospital Los Angeles USC Keck School of Medicine Los Angeles California.
3
Departments of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Interdepartmental Neuroscience Program University of California Los Angeles Los Angeles California.
4
Division of Pediatric Neurology University of California Los Angeles Los Angeles California.
5
San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology Los Angeles California.
6
Departments of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Department of Biostatistics University of California Los Angeles Los Angeles California.
7
Departments of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Department of Neurobiology University of California Los Angeles Los Angeles California.

Abstract

OBJECTIVE:

Lovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.

METHOD:

Forty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.

RESULTS:

Twelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f (2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.

INTERPRETATION:

These preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

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