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

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).

• Authors: 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
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 8 Issue 8 Pg. 1656-1667 (08 2021) ISSN: 2328-9503 [Electronic] United States
• PMID: 34275209 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Cholesterol
• Simvastatin

Topics

• Adult
• Aged
• Cholesterol (blood)
• Double-Blind Method
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, pharmacology)
• Longitudinal Studies
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Simvastatin (administration & dosage, pharmacology)
• White Matter (anatomy & histology, diagnostic imaging, drug effects)