Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2018 Feb 22:9:12.
doi: 10.1186/s13229-018-0190-z. eCollection 2018.

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

Stavros Stivaros #  1   2 , Shruti Garg #  3 , Maria Tziraki  4 , Ying Cai  5 , Owen Thomas  6 , Joseph Mellor  7 , Andrew A Morris  8 , Carly Jim  9 , Karolina Szumanska-Ryt  4 , Laura M Parkes  4 , Hamied A Haroon  4 , Daniela Montaldi  4 , Nicholas Webb  10 , John Keane  7 , Francisco X Castellanos  11 , Alcino J Silva  5 , Sue Huson  12 , Stephen Williams  2 , D Gareth Evans  12 , Richard Emsley  13 , Jonathan Green #  3 ; SANTA Consortium
Collaborators, Affiliations
Randomized Controlled Trial

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

Stavros Stivaros et al. Mol Autism. .

Abstract

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).

Keywords: Autism; Neurofibromatosis type 1; Neuroimaging; Randomised controlled trial; Simvastatin; Statin.

PubMed Disclaimer

Conflict of interest statement

The study was approved by the National Research Ethics Service Committee North West-Great Manchester Central (reference 13/NW/0111).All data generated or analysed during the study are included in this published article (and its Additional files).D. Gareth Evans had a travel for a trial meeting paid for by the Amgen and declared no other conflicts of interest. All other authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Representative Western blot showing p MAPK (top) and total MAPK (bottom) levels in peripheral blood mononuclear cells from NF1 patient treated either with placebo or simvastatin
Fig. 2
Fig. 2
Distribution of MAP Kinase Assay levels at baseline and endpoint
Fig. 3
Fig. 3
MR spectroscopy; change in a frontal white matter (FWM) GABA and b deep grey nuclei (DGN) Glx
Fig. 4
Fig. 4
a Change in perfusion measured from ASL in the ventral diencephalon and b changes in ADC value in the cingulate cortex
Fig. 5
Fig. 5
rsfMRI a default mode network (DMN) demonstrated by probabilistic group ICA of week 12 acquisitions (axial, coronal, sagittal). b At week 12, foci of decreased DMN co-activation were identified at the 10% level within the right occipital and left perirolandic regions. No significant differences in the DMN were identified at the 5% level, corrected
Fig. 6
Fig. 6
Three-dimensional plot of the ADC values in the occipital cortex, parietal and occipital white matter; right vs. left
See this image and copyright information in PMC

References

    1. Evans D, Howard E, Giblin C, Clancy T, Spencer H, Huson S, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet. 2010;152A:327–332. doi: 10.1002/ajmg.a.33139. - DOI - PubMed
    1. Hyman S, Shores A, North K. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Dev Med Child Neurol. 2007;4812:973–977. doi: 10.1111/j.1469-8749.2006.tb01268.x. - DOI - PubMed
    1. Mautner V, Kluwe L, Thakker S, Leark R. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol. 2002;44(3):164–170. doi: 10.1017/S0012162201001876. - DOI - PubMed
    1. Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG, et al. Neurofibromatosis type 1 and autism spectrum disorder. Pediatrics. 2013;132(6):e1642–e1648. doi: 10.1542/peds.2013-1868. - DOI - PubMed
    1. Plasschaert E, Descheemaeker MJ, Van Eylen L, Noens I, Steyaert J, Legius E. Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet. 2014; - PubMed

Publication types

MeSH terms

Associated data