Abstract
BackgroundNeurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes.MethodsA single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression).ResultsThirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = − 2.12, p = .055), GABA/Glx ratio (t(12) = − 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met ‘clinical responder’ criteria for behavioural outcome.ConclusionsWe show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.Trial registrationEU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu)
Highlights
Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism
Recent diffusion tensor imaging (DTI) study in human NF1 [11] demonstrated increased apparent diffusion coefficient (ADC) values localised in the caudate and other deep grey nuclei, diencephalon and frontal white matter in NF1 children compared to controls, consistent with decreased neuronal density or myelin sheath disorganisation; the extent of these effects was associated with neurological symptoms
This study demonstrates the acceptability and safety of simvastatin treatment for young children with NF1 and autism; feasibility of awake scanning, data acquisition and peripheral biomarker assay in such children given the right preparation; and the value of such a multiparametric approach in capturing the likely complexity of pathogenic mechanisms
Summary
Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/ behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Identified by neurocutaneous manifestations, morbidity in childhood NF1 usually relates to cognitive, social and behavioural difficulties, with moderate cognitive impairment and academic underachievement in about 80% [2] and attention-deficit/ hyperactivity disorder (ADHD) in 38–50% [2, 3]. Other imaging studies in human NF1 have identified reduced cortical GABA [12, 13], reduced cerebral perfusion [14], alteration in diffusion-weighted imaging [15] and abnormal network connectivity on resting state fMRI [16, 17]
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