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

Croteau, Étienne; Castellano, Christian‐Alexandre; Fortier, Mélanie; Bocti, Christian; Fülöp, Tamás; Paquet, Nancy; Cunnane, Stephen C.

doi:10.1016/j.exger.2017.07.004

Cited by 209 publications

(157 citation statements)

References 31 publications

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“…That IF may be another approach for subjects at risk of or with AD is suggested by a study using 11 C-acetoacetate positron emission tomography (PET) imaging that showed that within 48 hours of the onset of fasting, there is a sevenfold to eightfold increase in brain uptake of ketones 4,145 . Moreover, whereas brain cell uptake of glucose is severely impaired in patients with AD, the cells remain capable of utilizing ketones 146 .…”

Section: Ims and Neurological Disordersmentioning

confidence: 99%

Intermittent metabolic switching, neuroplasticity and brain health

et al. 2018

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During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

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Section: Ims and Neurological Disordersmentioning

confidence: 99%

Intermittent metabolic switching, neuroplasticity and brain health

et al. 2018

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“…Specifically, ketogenic diets provide therapeutic benefit in animal models of dementia [47]. Additionally, quantitative kinetic positron emission tomography–magnetic resonance imaging of human brain glucose and acetoacetate metabolism confirms that the brain has lower brain energy metabolism in dementias (mild cognitive impairment and AD) [48]. Thus, Croteau et al [48] conclude that during dementia, the deterioration in brain energy metabolism is specific to glucose; further their results suggest that a ketogenic intervention would increase energy availability for the brain [48].…”

Section: Discussionmentioning

confidence: 99%

Chronic vitamin E deficiency impairs cognitive function in adult zebrafish via dysregulation of brain lipids and energy metabolism

McDougall

Choi

Magnusson

et al. 2017

Free Radical Biology and Medicine

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Zebrafish (Danio rerio) are a recognized model for studying the pathogenesis of cognitive deficits and the mechanisms underlying behavioral impairments, including the consequences of increased oxidative stress within the brain. The lipophilic antioxidant vitamin E (α-tocopherol; VitE) has an established role in neurological health and cognitive function, but the biological rationale for this action remains unknown. In the present study, we investigated behavioral perturbations due to chronic VitE deficiency in adult zebrafish fed from 45 days to 18-months of age diets that were either VitE-deficient (E−) or sufficient (E+). We hypothesized that E− zebrafish would display cognitive impairments associated with elevated lipid peroxidation and metabolic disruptions in the brain. Quantified VitE levels at 18-months in E− brains (5.7 ± 0.1 nmol/g tissue) were ~22-times lower than in E+ (122.8 ± 1.1; n= 10/group). Using assays of both associative (avoidance conditioning) and non-associative (habituation) learning, we found E− vs E+ fish were learning impaired. These functional deficits occurred concomitantly with the following observations in adult E− brains: decreased concentrations of and increased peroxidation of polyunsaturated fatty acids (especially docosahexaenoic acid, DHA), altered brain phospholipid and lysophospholipid composition, as well as perturbed energy (glucose/ketone), phosphatidylcholine and choline/methyl-donor metabolism. Collectively, these data suggest that chronic VitE deficiency leads to neurological dysfunction through multiple mechanisms that become dysregulated secondary to VitE deficiency. Apparently, the E− animals alter their metabolism to compensate for the VitE deficiency, but these compensatory mechanisms are insufficient to maintain cognitive function.

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“…Our studies also show that brain ketone uptake is entirely normal in exactly the same Alzheimer or MCI cases that have lower brain glucose uptake (Castellano et al, 2015Croteau et al, 2017). So, the good news is that the brain's energy problem in Alzheimer's disease is specific to glucose and does not affect brain ketone uptake.…”

Section: Keto-neurotherapeuticsmentioning

confidence: 52%

“…Our PET protocol involves sequentially assessing brain ketone uptake first (because 11 C is a short-lived radiotracer) followed by assessing brain glucose uptake with the tracer -18 F-flurodeoxyglucose. This provides a measure of brain uptake of both fuels within a three hour period in the same person on the same day, which is as comparable an assessment of both brain glucose and ketone metabolism as possible (Roy et al, 2012(Roy et al, , 2013Castellano et al, 2017;Courchesne-Loyer et al, 2017;Croteau et al, 2017).…”

Section: Keto-neurotherapeuticsmentioning

confidence: 99%

“…Much later, we quantified the brain glucose deficit (mmol/100 g/min) in cognitively healthy older people, MCI and Alzheimer's disease compared to healthy young adults. Without having done so, we could not have estimated the therapeutic target for ketones to bypass the energy deficit (Nugent et al, 2014;Castellano et al, 2015;Cunnane et al, 2016a, b;Croteau et al, 2017). It is laborious and it is more expensive but, in the development of keto-neurotherapeutics, quantification was essential at several levels.…”

Section: Perspectivementioning

confidence: 99%

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Ketones, omega-3 fatty acids and the Yin-Yang balance in the brain: insights from infant development and Alzheimer’s disease, and implications for human brain evolution

Cunnane

2018

OCL

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-Optimal brain performance is intimately linked to the brain's Yin and the Yang À the balance between its structure and its energy metabolism. This relationship is clearly exemplified in infant brain development and in Alzheimer's disease, and probably also applies to human brain evolution. In these examples, redundant pathways help achieve this important balance. For instance, the key structural lipid for the brain, docosahexaenoic acid (DHA), is supplied to the infant brain from at last three overlapping sources: (i) milk; (ii) infant's own fat stores and (iii) by some endogenous synthesis from a-linolenic acid (ALA) or eicosapentaenoic acid (EPA). On the energy side, glucose is normally the brain's main fuel but under conditions of prolonged starvation, it can be almost totally replaced by the ketone bodies, acetoacetate and b-hydroxybutyrate. When ketones are present in the blood they spare glucose uptake by the brain because they are actually the brain's preferred fuel and are essential for normal infant brain development. The redundant sources of ketones are long chain fatty acids (including the relatively ketogenic ALA) in infant stores, and medium chain triglycerides (MCT) in milk. Besides infancy, nowhere is the strain on the brain's balance between yin and yang more apparent than in Alzheimer's disease (AD). One of the reasons why attempts to treat AD have largely failed could well be because chronically inadequate glucose supply to some areas of the brain on the order of 10% is present in people at risk of AD long before cognitive decline begins. However, brain ketone uptake is still normal even in moderately advanced AD. Hence, treatments that ignore the brain energy (glucose) deficit in AD would be predicted to fail, but treatments that attempt to rescue brain fuel availability via ketones would be predicted to have a better chance of succeeding. By analogy to ketones sparing glucose for brain energy metabolism, perhaps ALA or EPA entering the brain can help spare (conserve) DHA for its structural role. If so, it would not necessarily be futile to transport ALA and EPA into the brain just to b-oxidize the majority afterwards; DHA sparing as well as ketone production could be important beneficiaries.Keywords: brain / brain development / Alzheimer's disease / glucose / ketones / beta-hydroxybutyrate / aging / omega-3 fatty acids / alpha-linolenic acid / eicosapentaenoic acid / docosahexaneoic acid Résumé -Cétones et acides gras omega-3, la balance du Yin et du Yang au niveau cérébral : apport des données acquises sur le développement de l'enfant à la maladie d'Alzheimer et implications dans l'évolution du cerveau humain. Les performances optimales du cerveau sont intimement liées au Yin/Yang cérébral : l'équilibre entre sa structure et son métabolisme énergétique. Ce phénomène s'applique spécifiquement au cours du développement cérébral du jeune enfant et de la maladie d'Alzheimer et très probablement tout au long de l'évolution du cerveau humain. Dans le cas des exemples précités, des voies ...

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

Cited by 209 publications

References 31 publications

Intermittent metabolic switching, neuroplasticity and brain health

Intermittent metabolic switching, neuroplasticity and brain health

Chronic vitamin E deficiency impairs cognitive function in adult zebrafish via dysregulation of brain lipids and energy metabolism

Ketones, omega-3 fatty acids and the Yin-Yang balance in the brain: insights from infant development and Alzheimer’s disease, and implications for human brain evolution

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