Effects of simvastatin on white matter integrity in healthy middle-aged adults

Nicholas M Vogt, Jack F V Hunt, Yue Ma, Carol A Van Hulle, Nagesh Adluru, Richard J Chappell, Karen K Lazar, Laura E Jacobson, Benjamin P Austin, Sanjay Asthana, Sterling C Johnson, Barbara B Bendlin, Cynthia M Carlsson, Nicholas M Vogt, Jack F V Hunt, Yue Ma, Carol A Van Hulle, Nagesh Adluru, Richard J Chappell, Karen K Lazar, Laura E Jacobson, Benjamin P Austin, Sanjay Asthana, Sterling C Johnson, Barbara B Bendlin, Cynthia M Carlsson

Abstract

Background: The brain is the most cholesterol-rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol-lowing medications used by millions of adults for prevention of vascular disease, yet the effect of statins on cholesterol-rich brain white matter (WM) is largely unknown.

Methods: We used longitudinal neuroimaging data acquired from 73 healthy, cognitively unimpaired, statin-naïve, middle-aged adults during an 18-month randomized controlled trial of simvastatin 40 mg daily (n = 35) or matching placebo (n = 38). ANCOVA models (covariates: age, sex, APOE-ɛ4) tested the effect of treatment group on percent change in WM, gray matter (GM), and WM hyperintensity (WMH) neuroimaging measures at each study visit. Mediation analysis tested the indirect effects of simvastatin on WM microstructure through change in serum total cholesterol levels.

Results: At 18 months, the simvastatin group showed a significant preservation in global WM fractional anisotropy (β = 0.88%, 95% CI 0.27 to 1.50, P = 0.005), radial diffusivity (β = -1.10%, 95% CI -2.13 to -0.06, P = 0.039), and WM volume (β = 0.72%, 95% CI 0.13 to 1.32, P = 0.018) relative to the placebo group. There was no significant effect of simvastatin on GM or WMH volume. Change in serum total cholesterol mediated approximately 30% of the effect of simvastatin on WM microstructure.

Conclusions: Simvastatin treatment in healthy, middle-aged adults resulted in preserved WM microstructure and volume at 18 months. The partial mediation by serum cholesterol reduction suggests both peripheral and central mechanisms. Future studies are needed to determine whether these effects persist and translate to cognitive outcomes.

Trial registration: NCT00939822 (ClinicalTrials.gov).

Conflict of interest statement

Nothing to report.

© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Flow diagram of study trial enrollment, randomization, treatment, and exclusion criteria for neuroimaging analyses.
Figure 2
Figure 2
(A) Longitudinal trajectories of mean diffusion tensor imaging (DTI) metrics within global white matter (WM) for placebo and simvastatin groups over 18 months. At 18 months, the percent change in fractional anisotropy (FA) and radial diffusivity (RD) in global WM was significantly different between treatment groups. *P < 0.05. (B) Tract‐based spatial statistics (TBSS) results showing voxels in WM with significantly different percent change in DTI measures at 18 months for FA, mean diffusivity (MD), and RD (10,000 permutations, familywise error‐corrected P < 0.05). There were no significant voxels for axial diffusivity (AD). Dot plots to the right of axial slices show the mean percent change (± standard deviation) within significant voxels for placebo and simvastatin groups.
Figure 3
Figure 3
Longitudinal trajectories of (A) gray matter (GM) volume, white matter (WM) volume, and (B) white matter hyperintensity (WMH) lesion volume for placebo and simvastatin groups over 18 months. The simvastatin group showed significantly different percent change in total WM volume at 12 and 18 months compared to the placebo group. There were no significant differences in GM or WMH volume changes between placebo and simvastatin groups. * P < 0.05.
Figure 4
Figure 4
Models and results for mediation analyses for change in total cholesterol mediating the effect of simvastatin on change in white matter microstructure. (A) Conceptual model of mediation pathway and model parameters. For each model, the mediator variable was percent change in serum total cholesterol at 18 months, and the white matter microstructure outcome was mean percent change in DTI metrics within significant voxels (from the TBSS analyses) at 18 months. For all three DTI metrics (B‐D), the effect of simvastatin on change in white matter microstructure was partially mediated by the percent change in total cholesterol. Beta‐coefficients are shown for the mediation, direct, and total effects, along with bootstrapped 95% confidence intervals (10,000 iterations). §P = 0.06; * P < 0.05; *** P < 0.001.

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