Christian-Alexandre Castellano

Brain glucose and acetoacetate metabolism: a comparison of young and older adults

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brains major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.

Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease

Brain glucose uptake is impaired in Alzheimers disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β‐hydroxybutyrate and acetoacetate, are the brains main physiological alternative fuel to glucose. Three studies in mild‐to‐moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age‐matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild‐to‐moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high‐fat ketogenic diet, by supplements providing 20–70 g/day of medium‐chain triglycerides containing the eight‐ and ten‐carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed.

Lower Brain 18F-Fluorodeoxyglucose Uptake But Normal 11C-Acetoacetate Metabolism in Mild Alzheimer's Disease Dementia

BACKGROUND The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimers disease (AD). The ketones, acetoacetate and β-hydroxybutyrate, are the brains main alternative energy substrates to glucose. OBJECTIVE To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). METHODS Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. RESULTS ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 μmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. CONCLUSION Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.

Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: Estimated potential contribution to brain energy metabolism

OBJECTIVE In humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2) ¹³C-β-hydroxybutyrate and ¹³C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism. METHODS Eight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation. Using isotope ratio mass spectroscopy, ¹³C-D-β-hydroxybutyrate and ¹³C-trioctanoate β-oxidation to ¹³CO₂ was measured over 12 h on the pre- and post-MCT metabolic study days. RESULTS On the post-MCT metabolic study day, plasma ketones (β-hydroxybutyrate plus acetoacetate) peaked at 476 μM, with a mean value throughout the study day of 290 μM. Post-MCT, ¹³C-trioctanoate β-oxidation was significantly lower 1 to 8 h later but higher 10 to 12 h later. MCT supplementation did not significantly alter ¹³C-D-β-hydroxybutyrate oxidation. CONCLUSIONS This MCT supplementation protocol was mildly and safely ketogenic and had no side effects in healthy humans on their regular diet. This degree of ketonemia is estimated to contribute up to 8% to 9% of brain energy metabolism.

Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study

Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, 11C-AcAc and 18F-fluorodeoxyglucose (18F-FDG), respectively. During the KD, plasma ketones increased 8-fold (p = 0.005) while plasma glucose decreased by 24% (p = 0.005). CMRa increased 6-fold (p = 0.005), whereas CMRglc decreased by 20% (p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p < 0.0001). After four days on the KD, CMRa represented 17% of whole brain energy requirements in healthy adults with a 2-fold difference across brain regions (12–24%). The CMR of ketones (AcAc and β-hydroxybutyrate combined) while on the KD was estimated to represent about 33% of brain energy requirements or approximately double the CMRa. Whether increased ketone availability raises CMR of ketones to the same extent in older people as observed here or in conditions in which chronic brain glucose hypometabolism is present remains to be determined.

Glucose hypometabolism is highly localized, but lower cortical thickness and brain atrophy are widespread in cognitively normal older adults

Several studies have suggested that glucose hypometabolism may be present in specific brain regions in cognitively normal older adults and could contribute to the risk of subsequent cognitive decline. However, certain methodological shortcomings, including a lack of partial volume effect (PVE) correction or insufficient cognitive testing, confound the interpretation of most studies on this topic. We combined [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging to quantify cerebral metabolic rate of glucose (CMRg) as well as cortical volume and thickness in 43 anatomically defined brain regions from a group of cognitively normal younger (25 ± 3 yr old; n = 25) and older adults (71 ± 9 yr old; n = 31). After correcting for PVE, we observed 11-17% lower CMRg in three specific brain regions of the older group: the superior frontal cortex, the caudal middle frontal cortex, and the caudate (P ≤ 0.01 false discovery rate-corrected). In the older group, cortical volumes and cortical thickness were 13-33 and 7-18% lower, respectively, in multiple brain regions (P ≤ 0.01 FDR correction). There were no differences in CMRg between individuals who were or were not prescribed antihypertensive medication. There were no significant correlations between CMRg and cognitive performance or metabolic parameters measured in fasting plasma. We conclude that highly localized glucose hypometabolism and widespread cortical thinning and atrophy can be present in older adults who are cognitively normal, as assessed using age-normed neuropsychological testing measures.

Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline.

Epidemiological studies fairly convincingly suggest that higher intakes of fatty fish and n-3 fatty acids are associated with reduced risk of Alzheimers disease (AD). DHA in plasma is normally positively associated with DHA intake. However, despite being associated with lower fish and DHA intake, unexpectedly, plasma (or brain) DHA is frequently not lower in AD. This review will highlight some metabolic and physiological factors such as ageing and apoE polymorphism that influence DHA homeostasis. Compared with young adults, blood DHA is often slightly but significantly higher in older adults without any age-related cognitive decline. Higher plasma DHA in older adults could be a sign that their fish or DHA intake is higher. However, our supplementation and carbon-13 tracer studies also show that DHA metabolism, e.g. transit through the plasma, apparent retroconversion and β-oxidation, is altered in healthy older compared with healthy young adults. ApoE4 increases the risk of AD, possibly in part because it too changes DHA homeostasis. Therefore, independent of differences in fish intake, changing DHA homeostasis may tend to obscure the relationship between DHA intake and plasma DHA which, in turn, may contribute to making older adults more susceptible to cognitive decline despite older adults having similar or sometimes higher plasma DHA than in younger adults. In conclusion, recent development of new tools such as isotopically labelled DHA to study DHA metabolism in human subjects highlights some promising avenues to evaluate how and why DHA metabolism changes during ageing and AD.

Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer’s disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain’s main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain’s main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.

Fish oil diets alter the phospholipid balance, fatty acid composition, and steroid hormone concentrations in testes of adult pigs

The objective was to determine the effect of long-term dietary supplementation of two types of fish oil on lipid composition and steroidogenesis in adult pig testis. Twenty-four Duroc boars, aged 204.5 ± 9.4 d (body weight 128.1 ± 16.7 kg) received daily 2.5 kg of an iso-caloric basal diet supplemented with: 1) 62 g of hydrogenated animal fat (AF); 2) 60 g of menhaden oil (MO) containing 16% of eicosapentaenoic acid (EPA) and 18% of docosahexaenoic acid (DHA); or 3) 60 g of tuna oil (TO) containing 7% of EPA and 33% of DHA. After these diets were consumed for 7 mo, testicular hormones, phospholipid content, and fatty acid composition of individual phospholipids in testis were determined. Body and reproductive organ weights were not significantly affected by dietary treatments. Testicular tissue from boars fed a TO diet, followed by those receiving MO and AF diets, had the lowest level of phosphatidylethanolamine (TO < MO < AF; P < 0.01) but the highest sphingomyelin (TO > MO > AF; P < 0.01). For each phospholipid, boars fed either the MO or TO diet had increased total omega-3 fatty acids, particularly DHA (P < 0.01), by reciprocal replacement of total omega-6 fatty acids (20:4n-6, 22:5n-6). The MO diet increased EPA more than the other diets. Testicular concentrations of testosterone and estradiol were lower in boars fed a TO diet than a MO diet (P < 0.02). In conclusion, long-term dietary supplementation of fish oil, regardless of the EPA/DHA ratio, modified the fatty acid compositions in testis and affected steroid production of healthy adult boars, which may represent a promising models for future studies on fertility.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease

Introduction: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimers disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly &bgr;‐hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. Objective: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. Methods: 24 CTL, 20 MCI and 19 AD of similar age and metabolic phenotype underwent a dual‐tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [18F]‐fluorodeoxyglucose ([18F]‐FDG), a glucose analogue, and [11C]‐acetoacetate ([11C]‐AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1‐weighted MRI. Results: In AD compared to CTL, CMRGlu was ˜ 11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p < 0.05). KGlu was ˜ 15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ˜ 7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. Discussion: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD. HIGHLIGHTSBrain energy hypometabolism in MCI and AD is specific to glucose.Mild ketone hypermetabolism occurs in some regions in MCIKetogenic interventions may correct the brain glucose deficit in MCI or AD.