Objective Vitamin D deficiency is common and associated with dyslipidemia. However, it is unclear if oral vitamin D supplementation improves the lipid profile. Therefore, we conducted a randomized, placebo-controlled trial to determine the short-term effects of vitamin D repletion on the lipid profile. Methods 151 vitamin D deficient (25-hydroxyvitamin D [25(OH)D] <20ng/ml) adults with elevated risk for cardiovascular disease were randomized to receive either 50,000 IU of vitamin D3 weekly for 8 weeks or placebo. The primary outcome was the change in small LDL particle number. Secondary outcomes included changes in other NMR-based and chemical lipid fractions. Results Vitamin D failed to improve the lipid profile. Compared to placebo, vitamin D repletion did not change small LDL particle number (mean change +18 nmol/l, 95% confidence interval (CI) [−80 to +116 nmol/L], P = 0.63). There were also no changes in the chemical lipid profile: total cholesterol (+5.8 mg/dl, 95%CI [−1.4 to +13.0 mg/dl], P =0.14); LDL cholesterol (+3.8 mg/dl, 95% CI [−2.5 to +10.2 mg/dl], P = 0.13); HDL cholesterol (+0.4 mg/dl 95% CI [−1.6 to +2.6 mg/dl], P = 0.71); triglycerides (+7.9 mg/dl 95%CI [−6.5 to +22.3 mg/dl]). In the vitamin D repletion group, exploratory multivariate regression analysis demonstrates that changes in LDL cholesterol were positively correlated with changes in serum calcium (P < .001) and inversely with changes in serum PTH (P = .02). Conclusion In contrast to the association between low 25(OH)D levels and dyslipidemia, correcting vitamin D deficiency in the short-term does not improve the lipid profile. Repletion of 25(OH)D levels raised serum calcium levels and decreased serum PTH levels. These expected physiologic responses to vitamin D therapy were correlated with a significant increase in LDL cholesterol.

Design: We performed a randomized clinical trial in vitamin Ddeficient adults and compared vitamin D replenishment between subjects who received oral vitamin D 3 (n = 60) and those who received narrow-band UVB exposure (n = 58) #6 mo. Results: There was no difference in the change from baseline LDLcholesterol concentrations between oral vitamin D 3 and UVB groups (difference in median of oral vitamin D 3 minus that of UVB: 1.5 mg/dL; 95% CI: 25.0, 7.0 mg/dL). There were also no differences within groups or between groups for changes in total or HDL cholesterol or triglycerides. Transcriptional profiling of skin and blood, however, revealed significant upregulation of immune pathway signaling with oral vitamin D 3 but significant downregulation with UVB. Conclusions: Correcting vitamin D deficiency with either oral vitamin D 3 or UVB does not improve the lipid profile. Beyond cholesterol, these 2 modalities of raising 25(OH)D have disparate effects on gene transcription. This trial was registered at clinicaltrials.gov as NCT01688102.

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer’s disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA-approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of aging and Alzheimer’s disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer’s disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer’s disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, fifty subjects that met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary endpoints were baseline to 6 months changes in a) cerebral glucose metabolism as measured with fluorodeoxyglucose-positron emission tomography in pre-specified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal) and b) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer’s disease biomarker and predictor of disease progression, declined significantly less in several pre-specified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated subjects in comparison to placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group by visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole treated group than in the placebo group and investigations in future larger and longer studies to test riluzole as a potential novel therapeutic intervention for Alzheimer’s disease.

The development of translational clinical research protocols is complex. To assist investigators, we developed a structured supportive guidance process (Navigation) to expedite protocol development to the standards of good clinical practice (GCP), focusing on research ethics and integrity. Navigation consists of experienced research coordinators leading investigators through a concerted multistep protocol development process from concept initiation to submission of the final protocol. To assess the effectiveness of Navigation, we collect data on the experience of investigators, the intensity of support required for protocol development, IRB review outcomes, and protocol start and completion dates. One hundred forty-four protocols underwent Navigation and achieved IRB approval since the program began in 2007, including 37 led by trainee investigators, 26 led by MDs, 9 by MD/PhDs, 57 by PhDs, and 12 by investigators with other credentials (e.g., RN, MPH). In every year, more than 50% of Navigated protocols were approved by the IRB within 30 days. For trainees who had more than one protocol navigated, the intensity of Navigation support required decreased over time. Navigation can increase access to translational studies for basic scientists, facilitate GCP training for investigators, and accelerate development and approval of protocols of high ethical and scientific quality.