Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

Abstract

In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as “continuous resting-state data” for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model.

Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I

“…A limitation of the current study is the modest size of the patient group, although similar group sizes have been used in other fMRI studies in NF1 (Chabernaud et al, 2012;Violante et al, 2012). Behavioral data were available for only a subset of control subjects, although group differences were very much in line with those observed in earlier studies with larger control samples.…”

“…A number of task-based functional imaging studies showed abnormal activation of brain regions associated with phonological and visual processing, as well as the effect of medication on the DMN (Billingsley et al, 2004;Chabernaud et al, 2012;Clements-Stephens et al, 2008;Violante et al, 2012), all reporting on task-related functional network changes.…”

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

“…While lovastatin is lipophilic and crosses the bloodbrain barrier, it is possible that our dose was not sufficient to produce a therapeutic effect on human brain function. Although indirect evidence of improved memory and functional connectivity from a 12-week phase I study suggests that our dose may have been sufficient to inhibit RAS-mitogen-activated protein kinase activity, 7,8 this small open-label study was not powered for efficacy. Increasing the dose, especially in a pediatric population, would likely increase the risk of AEs, and the effect of statins on hormones critical in sexual development is unknown.…”

“…While 2 randomized controlled trials of simvastatin reported no treatment effect on cognitive outcomes, 5,6 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 network 7 with accompanying improvements in memory and attention. 8 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 selecting our treatment duration, we relied on preclinical data suggesting that lovastatin normalized plasticity and behavioral impairments in Nf1 mice within days and findings from a phase I lovastatin trial suggesting improvements in functional connectivity 12 weeks after treatment. 7,8 Finally, while many of the cognitive outcomes used in our study have a long history of successfully detecting change in clinical trials, it is possible that some were not sufficiently sensitive within a pediatric NF1 context. Future studies should establish NF1-specific normative data and test-retest reliability to guide future selection of cognitive endpoints.…”