Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer's disease: a pilot study

Abstract

Background/aims: Hypercholesterolemia in midlife increases risk for Alzheimer's disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD.

Methods: In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound.

Results: At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p < 0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo.

Conclusion: In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD.

Clinical trial registration: http://clinicaltrials.gov Identifier: NCT00751907.

Figure 1

A. Baseline age correlated inversely with baseline CBF in the posterior cingulate (shown, r=−0.530, p=0.051), hippocampus (shown, r=−0.541, p=0.046), parahippocampus (r=−0.577, p=0.031), thalamus (−0.546, p=0.043), and the cingulate gyrus (r=−0.566, p=0.035). B. Baseline HDL-C correlated directly with baseline CBF in the posterior cingulate (shown, r=0.629, p=0.016), hippocampus (shown, r=0.737, p=0.003), parahippocampus (r=0.722, p=0.004), and thalamus (r=0.607, p=0.021), as well as with global perfusion (r=0.651, p=0.012). C. Higher baseline Framingham 10-year CVD risk correlated with worse baseline CBF in the posterior cingulate (shown, r=−0.756, p=0.002), hippocampus (shown, r=−0.676, p=0.008), parahippocampus (r=−0.712, p=0.004), parietal lobe (r=−0.751, p=0.002), thalamus (r=−0.770, p=0.001), cingulate gyrus (r=−0.712, p=0.004), superior parietal lobe (r=−0.551, p=0.041), and inferior parietal lobe (r=−0.616, p=0.019), as well as with global perfusion (r=−0.719, p=0.004). D. At baseline, FMD at 60 seconds was directly correlated with baseline CBF in the posterior cingulate (shown, r=0.609, p=0.021), thalamus (r=0.701, p=0.005) and cingulate gyrus (r=0.675, p=0.008) and showed a trend toward a positive correlation in the parahippocamus (r=0.512, p=0.061), parietal lobe (r=0.512, p=0.061) and on global perfusion (r=0.516, p=0.059). FMD at baseline did not correlate with baseline CBF in the hippocampus (shown, r=0.429, p=0.126).

Figure 2

Participants randomized to atorvastatin treatment showed greater increase in regional CBF in bilateral hippocampus, fusiform gyrus, putamen and insular cortices compared to participants on placebo (p_voxel <0.05 with extent threshold for cluster size > 1200 voxels).