A 24-hour temporal profile of in vivo brain and heart pet imaging reveals a nocturnal peak in brain 18F-fluorodeoxyglucose uptake

Abstract

Using positron emission tomography, we measured in vivo uptake of (18)F-fluorodeoxyglucose (FDG) in the brain and heart of C57Bl/6 mice at intervals across a 24-hour light-dark cycle. Our data describe a significant, high amplitude rhythm in FDG uptake throughout the whole brain, peaking at the mid-dark phase of the light-dark cycle, which is the active phase for nocturnal mice. Under these conditions, heart FDG uptake did not vary with time of day, but did show biological variation throughout the 24-hour period for measurements within the same mice. FDG uptake was scanned at different times of day within an individual mouse, and also compared to different times of day between individuals, showing both biological and technical reproducibility of the 24-hour pattern in FDG uptake. Regional analysis of brain FDG uptake revealed especially high amplitude rhythms in the olfactory bulb and cortex, while low amplitude rhythms were observed in the amygdala, brain stem and hypothalamus. Low amplitude 24-hour rhythms in regional FDG uptake may be due to multiple rhythms with different phases in a single brain structure, quenching some of the amplitude. Our data show that the whole brain exhibits significant, high amplitude daily variation in glucose uptake in living mice. Reports applying the 2-deoxy-D[(14)C]-glucose method for the quantitative determination of the rates of local cerebral glucose utilization indicate only a small number of brain regions exhibiting a day versus night variation in glucose utilization. In contrast, our data show 24-hour patterns in glucose uptake in most of the brain regions examined, including several regions that do not show a difference in glucose utilization. Our data also emphasizes a methodological requirement of controlling for the time of day of scanning FDG uptake in the brain in both clinical and pre-clinical settings, and suggests waveform normalization of FDG measurements at different times of the day.

Figure 1. Fused CT and PET images from individual representative C57Bl/6 mice.

The left panel shows a 3D reconstruction of a mouse measured in the middle of the dark phase of the light-dark cycle, where brain, heart and bladder show high FDG uptake. Both kidneys and the interscapular brown adipose tissue are also visible. Colors indicate only mid-range FDG uptake, where green is lower and red is higher uptake. On the right, representative individuals from the 4 groups measured at (from left to right) ZT6, 12, 18 and 24/0 are depicted. Images are shown for sagittal (top), coronal (middle) and transverse (bottom) planes. Scale bars belonging to the right panel for CT intensity (represented as gray-scale) and FDG uptake (in color) are shown on the bottom left.

Figure 2. Time-of-day specific analysis of FDG uptake in brain.

(A) Whole Brain FDG uptake in C57Bl/6 mice (N = 37) plotted at the time of measurement. The dashed line is a smoothed spline curve through group averages. Both group averages (B) and within individual comparisons at different times of day (C) of total brain FDG uptake showed significantly higher uptake at the middle of the active phase at ZT 18. Error bars indicate SEM. * = Proc mixed, least square means contrast: P<0.005, P<0.001 and P<0.001 with ZT 6, ZT 12 and ZT 24/0. # = Paired t-test P<0.005.

Figure 3. Time-of-day specific analysis of FDG uptake in heart.

(A) Whole heart FDG uptake in the same C57Bl/6 mice as Figure 2 (N = 37) plotted at the time of measurement. There is no statistically significant variation of total FDG uptake for grouped averages (B). The within individual comparison (C) also shows no uniform FDG uptake at different times of the day.

Figure 4. Amplitude of total FDG uptake in specific brain regions.

All brain regions, except the brain stem, show significant variations with time (Proc mixed, α = 0.05). The dashed line indicates the average and gray area indicates average ± standard deviation.