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

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 (ß = 0.88%, 95% CI 0.27 to 1.50, P = 0.005), radial diffusivity (ß = -1.10%, 95% CI -2.13 to -0.06, P = 0.039), and WM volume (ß = 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).

Measurement batch differences and between-batch conversion of Alzheimer's disease cerebrospinal fluid biomarker values.

INTRODUCTION: Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods. METHODS: A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches. RESULTS: We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R 2 except for converting P-tau between batches 1 and 3. DISCUSSION: Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers.

Factors Associated with Lumbar Puncture Participation in Alzheimer's Disease Research.

BACKGROUND: Cerebrospinal fluid (CSF) provides insight into the spectrum of Alzheimer's disease (AD) pathology. While lumbar punctures (LPs) for CSF collection are generally considered safe procedures, many participants remain hesitant to participate in research involving LPs. OBJECTIVE: To explore factors associated with participant willingness to undergo a research LP at baseline and follow-up research study visit. METHODS: We analyzed data from 700 participants with varying cognition (unimpaired, mild cognitive impairment, and dementia) in the Wisconsin Alzheimer's Disease Research Center. We evaluated the relationship of demographic variables (age, sex, race, ethnicity, and years of education) and clinical variables (waist-to-hip ratio, body mass index, AD parental history, cognitive diagnosis) on decision to undergo baseline LP1. We evaluated the relationship of prior LP1 experience (procedure success and adverse events) with the decision to undergo follow-up LP2. The strongest predictors were incorporated into regression models. RESULTS: Over half of eligible participants opted into both baseline and follow-up LP. Participants who underwent LP1 had higher mean education than those who declined (p = 0.020). White participants were more likely to choose to undergo LP1 (p < 0.001); 33% of African American participants opted in compared to 65% of white participants. Controlling for age, education, and AD parental history, race was the only significant predictor for LP1 participation. Controlling for LP1 mild adverse events, successful LP1 predicted LP2 participation. CONCLUSION: Race was the most important predictor of baseline LP participation, and successful prior LP was the most important predictor of follow-up LP participation.

Effects of Simvastatin on Augmentation Index Are Transient: Outcomes From a Randomized Controlled Trial.

Background Statins improve endothelial function, but their effects on arterial stiffness and aortic blood pressure in middle-aged adults are uncertain. Methods and Results This was a prospective, randomized, double-blind, placebo-controlled trial of middle-aged (40-72 years old) adults who were randomly assigned to receive simvastatin 40 mg (n=44) or placebo (n=44) daily for 18 months to evaluate impact on dementia-related biomarkers (primary end points) and measures of vascular health (secondary end points). This analysis focuses on the predetermined secondary end points of changes in central aortic blood pressure, aortic augmentation index, and brachial artery flow-mediated dilation. Measurements were performed at baseline and after 6, 12, and 18 months. Multivariable models were used to identify predictors of these prespecified vascular end points. Study groups were similar at baseline; low-density lipoprotein cholesterol declined in the statin group but not in the placebo group (P<0.01). There were no significant differences in changes in central blood pressure parameters or flow-mediated dilation (all P>0.2). After 12 months, augmentation index decreased from baseline in the statin group compared with the placebo group (-2.3% [5.5%] versus 1.2% [5.7%], P=0.007), but by 18 months the response in both groups trend toward baseline (-1.1% [5.8%] versus 0.2% [4.8%], P=0.3). Low-density lipoprotein cholesterol was not associated with changes in augmentation index at any time point. Conclusions Statin therapy led to a short-term reduction in augmentation index after 12 months, but this effect did not persist after 18 months despite continued reduction in low-density lipoprotein cholesterol levels. These findings suggest that statins may have a transient effect on aortic stiffness. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00939822.