A Dual Tracer PET-MRI Protocol for the Quantitative Measure of Regional Brain Energy Substrates Uptake in the Rat (original) (raw)
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Nutritional Neuroscience, 2011
Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, 11 C-acetoacetate ( 11 C-AcAc) for ketones and 18 F-fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD. In separate rats on the same diet conditions, expression of the transporters of glucose and ketones (glucose transporter 1 (GLUT1) and monocarboxylic acid transporter (MCT1)) was measured in brain microvessel preparations. Compared to controls, uptake of 11 C-AcAc increased more than 2-fold while on the KD or after 48 hours F (P < 0.05). Similar trends were observed for 18 FDG uptake with a 1.9-2.6 times increase on the KD and F, respectively (P < 0.05). Compared to controls, MCT1 expression increased 2-fold on the KD (P < 0.05) but did not change during F. No significant difference was observed across groups for GLUT1 expression. Significant differences across the three groups were observed for plasma beta-hydroxybutyrate (beta-HB), AcAc, glucose, triglycerides, glycerol, and cholesterol (P < 0.05), but no significant differences were observed for free fatty acids, insulin, or lactate. Although the mechanism by which mild ketonemia increases brain glucose uptake remains unclear, the KD clearly increased both the blood-brain barrier expression of MCT1 and stimulated brain 11 C-AcAc uptake. The present dual-tracer positron emission tomography approach may be particularly interesting in neurodegenerative pathologies such as Alzheimer's disease where brain energy supply appears to decline critically.
The brain relies on glucose as its primary energy substrate. However, ketone bodies, i.e. acetoacetate and hydroxybutyrate, are the main replacement fuels for brain activity during fasting or on a ketogenic (very high fat, low carbohydrate) diet. We report here a study of ketone and glucose metabolism in human brain in young (mean 26 years) and aged (mean 73 years) healthy individuals as measured with positron emission tomography (PET), using the radiotracers 11C-acetoacetate and 18F-fluorodeoxyglucose (FDG). Three blood samples were withdrawn during the two scans and were analyzed for plasma radioactivity and for concentration of acetoacetate, hydroxybutyrate and glucose. In the eighteen selected brain regions for this study, although the standard uptake values (SUV) were lower in the elderly subjects compared to the young subjects, the ratio of SUV in aged on young were almost similar in glucose and ketone metabolism. This protocol for brain fuel measurement by PET can be combined...
Brain Research, 2012
Despite decades of study, it is still unclear whether regional brain glucose uptake is lower in the cognitively healthy elderly. Whether regional brain uptake of ketones (b-hydroxybutyrate and acetoacetate [AcAc]), the main alternative brain fuel to glucose, changes with age is unknown. We used a sequential, dual tracer positron emission tomography (PET) protocol to quantify brain 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-AcAc uptake in two studies with healthy, male Sprague-Dawley rats: (i) Aged (21 months; 21M) versus young (4 months; 4M) rats, and (ii) The effect of a 14 day high-fat ketogenic diet (KD) on brain 18 F-FDG and 11 C-AcAc uptake in 24 month old rats (24M). Similar whole brain volumes assessed by magnetic resonance imaging, were observed in aged 21M versus 4M rats, but the lateral ventricles were 30% larger in the 21M rats (p ¼ 0.001). Whole brain cerebral metabolic rates of AcAc (CMR AcAc) and glucose (CMR glc) did not differ between 21M and 4M rats, but were 28% and 44% higher, respectively, in 24M-KD compared to 24M rats. The region-to-whole brain ratio of CMR glc was 37-41% lower in the cortex and 40-45% lower in the cerebellum compared to CMR AcAc in 4M and 21M rats. We conclude that a quantitative measure of uptake of the brain's two principal exogenous fuels was generally similar in healthy aged and young rats, that the % of distribution across brain regions differed between ketones and glucose, and that brain uptake of both fuels was stimulated by mild, experimental ketonemia.
2009 IEEE Nuclear Science Symposium Conference Record (NSS/MIC), 2009
The brain relies on glucose as its primary energy substrate. However, ketone bodies, i.e. acetoacetate and hydroxybutyrate, are the main replacement fuels for brain activity during fasting or on a ketogenic (very high fat, low carbohydrate) diet. We report here a study of ketone and glucose metabolism in human brain in young (mean 26 years) and aged (mean 73 years) healthy individuals as measured with positron emission tomography (PET), using the radiotracers 11 Cacetoacetate and 18 F-fluorodeoxyglucose (FDG). Three blood samples were withdrawn during the two scans and were analyzed for plasma radioactivity and for concentration of acetoacetate, hydroxybutyrate and glucose. In the eighteen selected brain regions for this study, although the standard uptake values (SUV) were lower in the elderly subjects compared to the young subjects, the ratio of SUV in aged on young were almost similar in glucose and ketone metabolism. This protocol for brain fuel measurement by PET can be combined with treatment or on ketogenic diet to further study brain metabolism in neurodegenerative pathologies.
Positron Emission Tomography of Brain Glucose Metabolism with [18F]Fluorodeoxyglucose in Humans
Brain Energy Metabolism, 2014
The practice of neuroimaging, first by SPECT and PET, and then by magnetic resonance imaging (MRI), greatly contributes to the fundamental understanding of neuroanatomical correlates of brain function. It reveals novel treatment options in disciplines such as neurology, neurosurgery, and neuropsychiatry. The new opportunities afforded by neuroimaging yield images not only of brain tissue structure of an everincreasing power of resolution but also, and perhaps more importantly, of the basic organization of brain work. Understanding brain work requires insight into the roles of regional cerebral blood flow and energy metabolism, obtained by measures of oxygen and glucose consumption rates, neuronal network and neurotransmitter system activity, and most recently the abnormal deposition of amyloid-beta in brain tissue and the resulting abnormalities of second messenger cascades that promise to reveal the origins of neurodegeneration. The quantification of the brain images, acquired by means of the different methods of neuroimaging, is vital to the improved understanding and interpretation of experimental and clinical findings that are reported at a significant and ever-increasing rate. While many brain-imaging agents, such as markers of amyloid-beta in dementia, are studied with the ultimate goal of application to clinical prognostication and differential diagnosis, other agents are fundamental research tools for understanding new drugs, such as antipsychotics, antidepressants, and anxiolytics, as well as drugs for the relief of devastating neurological disorders such as multiple sclerosis, stroke, and dementia. Some of the earliest markers were tracers of blood flow used with autoradiography, SPECT, and PET, but in 1977, Sokoloff et al. published the seminal description of the use of labeled 2-deoxyglucose to trace the rate of glucose phosphorylation in brain, initially by autoradiography but soon after also by positron emission tomography of the brain uptake of the glucose analog 2-fluoro-2-deoxyglucose, labeled with the positron emitter fluorine-18 (FDG). The basis for the use of this tracer ex as well as in vivo is a deceptively simple model of brain glucose metabolism that includes only the steps of the bidirectional transport of glucose and glucose analogs across the blood-brain barrier imposed by the tight junctions between the endothelial cells of the brain's capillaries, and the step of phosphorylation enabled by the presence of the enzyme hexokinase in the cells of the brain. This chapter provides a brief explanation of the quantitative method of PET imaging with FDG used by neuroscientists for the last 40 years to quantify the uptake and metabolism of this tracer in terms of the absolute rate of glucose phosphorylation in brain tissue during the period following the tracer administration. The chapter also highlights the issues of relative precision and accuracy of the method applied to high-resolution research tomography. It includes a description of the basic elements of quantification, and, in particular, of the necessary mathematical modeling of the dynamic brain records of the uptake of the tracer, both to justify the role of such modeling in study design and to validate some of the simplifications that are necessary in some clinical settings. As fundamental tools of neuroimaging, quantification and kinetic modeling are as important as image reconstruction and structural identification of regions of interest. The quantitative methods presented here continue to underpin the routine approaches to measures of brain glucose consumption rates in different regions of the brain and hence matter to most clinicians and clinician scientists involved in the neuroimaging practice of regional glucose phosphorylation rates.
Journal of Cerebral …, 1984
Using dynamic [ISF]fluorodeoxyglucose (FDG) positron emission tomography with a high-reso lution, seven-slice positron camera, the kinetic constants of the original three-compartment model of Sokoloff and co-workers (1977) were determined in 43 distinct topo graphic brain regions of seven healthy male volunteers aged 28-38 years. Regional averages of the cerebral met abolic rate for glucose (CMRg1u) were calculated both from individually fitted rate constants (CMRg1ukinetic) and from activity maps recorded 30-40 min after FDG injection, employing a four-parameter operational equa tion with standard rate constants from the literature (CMRg1Uautoradiographic). Metabolic rates and kinetic constants varied significantly among regions and sub jects, but not between hemispheres. kl ranged between 0.0485 ± 0.00778 min-I in the oval center and 0.0990 ± 0.01347 min-I in the primary visual cortex. k2 ranged from 0.1198 ± 0.01533 min-I in the temporal white matter to 0.1472 ± 0.01817 min-I in the cerebellar den tate nucleus. k3 was lowest (0.0386 ± 0.01482 min-I) in temporal white matter and highest (0.0823 ± 0.02552 min-I) in the caudate nucleus. Maximum likelihood cluster analysis revealed four homogeneous groups of Advanced multislice equipment for positron emission tomography (PET) with improved spatial resolution permits the determination of isotope con centrations in rather small brain regions. U sing the [ 18 F]-2-fluoro-2-deoxY-D-glucose (FDG) method, the cerebral metabolic rate for glucose (CMRg1u) can be estimated (Reivich et aI., 1979
Journal of Cerebral …, 1992
In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.
Journal of Pharmaceutical and Biomedical Analysis, 2021
Energy metabolism and neurotransmission are necessary for sustaining normal life activities. Hence, neurological or psychiatric disorders are always associated with changes in neurotransmitters and energy metabolic states in the brain. Most studies have only focused on the most important neurotransmitters, particularly GABA and Glu, however, other metabolites such as NAA and aspartate which are also very important for cerebral function are rarely investigated, ,. In this study, most of the metabolic kinetics information of different brain regions was investigated in awake rats using the [ 1 H-13 C]-NMR technique. Briefly, rats (n=8) were infused [1-13 C] glucose through the tail vein for two minutes. After 20 minutes of glucose metabolism, the animals were sacrificed and the brain tissue was extracted and treated. Utilizing the 1 H observed/ 13 C-edited nuclear magnetic resonance (POCE-NMR), the enrichment of neurochemicals was detected which reflected the metabolic changes in different brain regions and the metabolic connections between neurons and glial cells in the brain. The results suggest that the distribution of every metabolite differed from every brain region and the metabolic rate of NAA was relatively low at 8.64 ± 2.37 μmol/g/h. In addition, there were some correlations between several 13 C enriched metabolites, such as Glu4-Gln4 (p=0.062), Glu4-GABA2 (p<0.01), Glx2-Glx3 (p<0.001), Asp3-NAA3 (p<0.001). This correlativity reflects the signal transmission between astrocytes and neurons, as well as the potential interaction between energy metabolism and neurotransmission. In conclusion, the current study systematically demonstrated the metabolic kinetics in the brain which shed light on brain functions and the mechanisms of various pathophysiological states.
PET study of11C-acetoacetate kinetics in rat brain during dietary treatments affecting ketosis
American Journal of Physiology-endocrinology and Metabolism, 2009
Normally, the brain's fuel is glucose, but during fasting it increasingly relies on ketones (-hydroxybutyrate, acetoacetate, and acetone) produced in liver mitochondria from fatty acid -oxidation. Although moderately raised blood ketones produced on a very high fat ketogenic diet have important clinical effects on the brain, including reducing seizures, ketone metabolism by the brain is still poorly understood. The aim of the present work was to assess brain uptake of carbon-11-labeled acetoacetate (11 C-acetoacetate) by positron emission tomography (PET) imaging in the intact, living rat. To vary plasma ketones, we used three dietary conditions: high carbohydrate control diet (low plasma ketones), fat-rich ketogenic diet (raised plasma ketones), and 48-h fasting (raised plasma ketones). 11 C-acetoacetate metabolism was measured in the brain, heart, and tissue in the mouth area. Using 11 C-acetoacetate and small animal PET imaging, we have noninvasively quantified an approximately seven-to eightfold enhanced brain uptake of ketones on a ketogenic diet or during fasting. This opens up an opportunity to study brain ketone metabolism in humans.