Regular articleBrain glucose and acetoacetate metabolism: a comparison of young and older adults
Introduction
In cognitively normal older adults, glucose uptake measured by positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has been reported to be lower in several brain regions relative to young adults, particularly in the precuneus, posterior cingulate, and parietal, temporal and frontal cortex (De Santi et al., 1995, Marano et al., 2012, Willis et al., 2002, Yanase et al., 2005). However, after correction for partial volume effects (PVE) mainly because of regional brain atrophy with age, either FDG uptake is no longer significantly different (Curiati et al., 2011, Ibanez et al., 2004, Yanase et al., 2005), or the only region in which FDG uptake remains significantly lower is in the frontal cortex (Kalpouzos et al., 2009). Lower regional glucose uptake is more pronounced in Alzheimer's disease, and may be of some use in the differential diagnosis of specific forms of aging-associated cognitive impairment (Chetelat et al., 2013, Kantarci et al., 2010, Li et al., 2008, Mosconi et al., 2009, Scheef et al., 2012). Lower regional brain glucose uptake is also present in young adults with a maternal family history of Alzheimer's disease (Mosconi et al., 2007) or with a genetic predisposition to Alzheimer's disease by virtue of carrying the apolipoprotein E ε4 allele (Reiman et al., 2004, Reiman et al., 2005).
Glucose is the brain's predominant fuel under normal conditions but it is not the brain's only fuel (Cunnane et al., 2011, Gottstein et al., 1971, Owen et al., 1967). The ketones, acetoacetate [AcAc], and β-hydroxybutyrate are the brain's main alternative fuels to glucose in adult humans and are essential brain fuels during infant development (Cremer, 1982, Nehlig, 2004, Robinson and Williamson, 1980). In adult humans, plasma ketones commonly reach 2–3 mM during 3–6 days fasting, prolonged exercise, or on a very high fat ketogenic diet (Balasse and Fery, 1989, Cahill, 2006, Mitchell et al., 1995, Owen et al., 1967). The ketogenic response to fasting is essential to preserve muscle protein, which would otherwise be depleted to produce glucose for the brain from amino acids via gluconeogenesis (Veech et al., 2001). Indeed, during starvation, ketones can provide up to 70% of the brain's fuel requirements (Cahill, 2006, Hasselbalch et al., 1995, Owen et al., 1967, Robinson and Williamson, 1980). Normal brain function can be maintained by ketone infusion during acute, controlled experimental plasma glucose depletion (Amiel et al., 1991, Page and Williamson, 1971, Veneman et al., 1994).
Ketones use a different transport system to enter the brain (monocarboxylic acid transporters) than glucose (Morris, 2005, Pierre and Pellerin, 2005), and are catabolized to acetyl CoA independently of glycolysis (Mamelak, 2012, Veech et al., 2001). Unlike glucose, ketones are taken up and metabolized by the brain in direct proportion to their arterial concentration (Blomqvist et al., 2002, Cunnane et al., 2011, Hasselbalch et al., 1996). Glucose metabolism is largely separate from ketone metabolism but some carbon from glucose can be incorporated into ketones via acetyl CoA (Laffel, 1999). However, conditions that increase plasma glucose generally also increase plasma insulin which is the main inhibitor of ketone synthesis, thereby usually insuring that acetyl CoA from glucose goes either to the Krebs' cycle or to amino acid synthesis but not to ketogenesis.
Without measuring uptake of at least one other fuel that is taken up by the brain independently of glucose, it remains unclear as to whether lower brain glucose uptake in healthy older adults or in those at risk of Alzheimer's disease can be interpreted as being a generalized marker of deteriorating brain energy metabolism or could possibly be specific to glucose. Some brain regions taking up less glucose in older adults might still be functional but cannot obtain or metabolize enough glucose because of a problem related to glucose transport or usage (Cunnane et al., 2011, Maalouf et al., 2009, Mamelak, 2012, Swerdlow, 2009). If that were the case, a fuel accessing the tricarboxylic acid cycle independently of glycolysis, that is ketones, would not necessarily display the same pattern of brain hypometabolism as glucose. Equally importantly, brain regions that apparently take up glucose normally during aging may not necessarily be able to adequately take up ketones, yet both are important for optimal brain function.
We therefore developed carbon-11 acetoacetate (11C-AcAc) as a PET ketone tracer (Tremblay et al., 2007) to use in parallel with FDG in studying brain energy metabolism during aging. Our objective was to assess the extent to which the regional pattern of brain 11C-AcAc uptake resembles that of FDG in healthy, cognitively normal young and older adults. We established a brain PET protocol in which 11C-AcAc is the first tracer injected because of its shorter half-life of 11C (20 minutes), followed by a wash-out period and then injection of FDG. PET images were co-registered to each participant's respective magnetic resonance (MR) images, and brain regions were segmented for quantitative PET tracer uptake analysis after PVE correction (Quarantelli et al., 2004).
The tracer uptake data was expressed in 3 ways: (1) cerebral metabolic rate (μmol/100 g/min) of glucose (CMRg), and AcAc (CMRa); (2) rate constants (min−1) of glucose (Kg) and AcAc (Ka), and; (3) the acetoacetate index (AI). CMR is the traditional measure for quantifying brain fuel uptake and is the product of K multiplied by the plasma concentration of the metabolite in question. Plasma ketones vary markedly even under well-controlled conditions and so directly influence CMRa variability, thereby potentially masking differences with age (Lying-Tunell et al., 1981). Reporting the Ka considerably reduces this variability and potentially reveals differences in brain AcAc uptake not otherwise detectable. The AI is based on the approach of Vaishnavi et al. (2010) in which the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake identify regions of the brain taking up higher or lower amounts of 11C-AcAc relative to FDG.
Section snippets
Participants
Ethical approval for this study was obtained from the Research Ethics Committee of the Health and Social Services Center–University of Sherbrooke Geriatrics Institute, which oversees all human research at the Research Center on Aging. All participants provided written informed consent before study entry. Participants were between either 18–30 years old (young group; n = 20), or 65–85 years old (older adult group; n = 24). They all underwent a pre-screening visit, which included blood analysis
Results
The older adults were 48 years older than the young group (p ≤ 0.001; Table 1). All anthropometric and plasma measures for both groups were within the normal range for age. However, systolic blood pressure, body mass index, and hemoglobin A1c were significantly higher whereas height and plasma albumin was significantly lower in the older adults (all p ≤ 0.05). All participants had MMSE scores ≥29/30 and there was no difference in global cognitive status between the 2 groups as assessed by the
Discussion
This is the first report of brain uptake of 11C-AcAc in humans and the first comparison of brain glucose and ketone uptake using PET in healthy older and young adults. This comparison of the uptake of the brain's two main fuels is central to the question of whether lower regional brain glucose uptake in healthy older adults is also observed with ketones, which are the brain's main alternative fuel to glucose. Our results show that there were both similarities and differences in the way the
Disclosure statement
The authors declare no actual or potential conflicts of interest.
Acknowledgements
Funding for this project was provided by the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canada Research Chairs (S.C.C.), Fonds de recherche Québec–Santé scholarship (S.N.), travel scholarships from INAF, RQRV and CFQCU (S.N.), and a University Research Chair (S.C.C.). This study was also supported by the Banner Alzheimer's Foundation, the National Institute on Aging (R01 AG031581 [E.M.R.], P30 AG19610 [E.M.R.]), and the State of Arizona [E.M.R., K.W.C.]. S.C.C.
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