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Background  Neurofibromatosis 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.    Methods  A 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).    Results  Thirty 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.    Conclusions  We 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 registration  EU Clinical Trial Register (EudraCT) 2012-005742-38 ( www.clinicaltrialsregister.eu )    Electronic supplementary material  The online version of this article (10.1186/s13229-018-0190-z) contains supplementary material, which is available to authorized users.

Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)