Abstract
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Objectives Caprylidene is a medical food that, when metabolized, produces beta-hydroxybutyrate and acetoacetate, or ketone bodies, which can cross the blood brain barrier. It has been hypothesized that ketone bodies can be used as an alternate energy source by neurons with impaired glucose utilization. There is evidence that suggests caprylidene delays cognitive decline in patients with mild to moderate Alzheimer’s disease (AD) due to the production of ketone bodies. Here we examine the neurobiological effects of caprylidene on regional cerebral blood flow (rCBF) in patients with mild to moderate AD.
Methods Sixteen subjects with mild to moderate AD, based on NINCDS-ARDRDA criteria, were enrolled in a double-blind, placebo-controlled, randomized, clinical trial. Fourteen subjects received treatment with caprylidene, and 2 subjects were given placebo. Subjects received 4 15O-water PET scans over the course of the study to assess rCBF. Each subject was scanned before receiving a standard caprylidene or placebo dose and 90 minutes after the dose, on both the first day (“Day 1”) and after 45 days of daily caprylidene or placebo consumption. The scans were examined by both voxel-based statistical parametric mapping software and standardized volumes of interest methods of analysis. Comparisons were performed within subjects (e.g., 90 min vs baseline), as well as between groups (i.e., treatment vs placebo).
Results 90 minutes after the first dose of caprylidene on Day 1, there was increased rCBF of the bilateral anterior cingulate cortex (p < 0.0005 at peak voxel), and there was a concomitant decrease in rCBF in the bilateral anterior cerebella peak-voxel (p<0.0005; cluster size p=0.035 after correction for multiple comparisons) and the left parietotemporal cortex (p < 0.0005). After 45 days of daily caprylidene consumption, there was an increase in rCBF of the bilateral primary visual cortex (p<0.0005; cluster size p=0.001 after multiple comparison correction) when compared to baseline, pre-treatment. On day 45 and 90 minutes after the dose, there was an increase in rCBF in the bilateral precuneus (p < 0.0005), and a decrease in the left parieto-occipital region (p < 0.0005). Compared to the placebo arm, there was a significant decrease in rCBF in the anterior cerebellum 90 minutes after the first dose of caprylidene was administered (p < 0.0005). Within the treatment group, there was also significant increase in rCBF of the left inferior temporal cortex (p<0.0005) and right posterior cingulate cortex (p < 0.0005), compared to the placebo group. There was a positive correlation in rCBF between the initial response, 0 minutes to 90 minutes on Day 1, and long-term response, Day 1 to Day 45, of the right posterior cingulate gyrus after consumption of caprylidene (r = 0.88, p=0.0008).
Conclusions Ingestion of a ketogenic agent was associated with regionally specific effects on cerebral blood flow in subjects randomized to undergo a 45 day course of therapy with caprylidene. These were notable for significant increases in precuneus, posterior cingulate, and left temporal cortical areas, all brain regions that have diminished activity in patients with Alzheimer’s disease at baseline. Moreover, the long-term effect on posterior cingulate activity was predicted by the magnitude of initial response of this region to caprylidene.