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

Castellano, Christian‐Alexandre; Nugent, Scott; Paquet, Nancy; Tremblay, Sébastien; Bocti, Christian; Lacombe, Guy; Imbeault, Hélène; Turcotte, Éric; Fülöp, Tamás; Cunnane, Stephen C.

doi:10.3233/jad-141074

Cited by 155 publications

(142 citation statements)

References 33 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…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-neurotherapeuticssupporting

confidence: 58%

“…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%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

-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 ...

show abstract

Section: Keto-neurotherapeuticssupporting

confidence: 58%

Section: Perspectivementioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Brain glucose uptake is 10-15% lower during normal aging (Nugent et al 2014), and can be up to 35% 16 lower in certain brain regions in neurodegenerative diseases such as Alzheimer's disease (AD) 17 (Castellano et al 2015). Several studies suggest that brain glucose hypometabolism potentially 18 contributes to the onset and/or progression of AD (Cunnane et al 2016;Mosconi et al 2005;Nugent et al 19 2014;Reiman et al 2004;Schöll et al 2011).…”

mentioning

confidence: 99%

Caffeine intake increases plasma ketones: an acute metabolic study in humans

Vandenberghe

St-Pierre

Courchesne-Loyer

et al. 2017

Can. J. Physiol. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

show abstract

“…Neuronal hypometabolism appears to be foundation in pathogenesis of many ND (Castellano et al, 2015): consequences of metabolic disorders set off in the preclinical stages of the disease. This is a common ground for new therapies for ND, especially in those where neuroprotection is the key (Stafstrom et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Ketogenic diet and its impact on mental processes of working population

Grom¹

2017

Zdravje Delovno Aktivne Populacije / Health of the Working-Age Population

View full text Add to dashboard Cite

Introduction: Ketogenic diet has been evaluated for wide variety of conditions, although it was initially used for treatment of epilepsy. As alternative dietary pattern it can represent means of better quality of life, improved ability to work and can prevent against cognitive decline, different dementias and more serious forms of neurodegenerative diseases. Methods: This is a systematic review of available literature. Results: As energy substrates and as signaling agents, ketones are potentially usable in mitochondriopathies that come with aging and neurodegenerative diseases, or are a consequence of stroke, trauma. It has antioxidative, antiinflammatory and antiseizure properties, improves bioenergetics of the brain, neuronal plasticity and has epigenetic function. Discussion: Expansion of current nutritional knowledge might be a paradigmatic shift in understanding what is "healthy diet" in general or in terms of segments of population.

show abstract

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

Abstract: 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.

Cited by 155 publications

References 33 publications

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

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

Caffeine intake increases plasma ketones: an acute metabolic study in humans

Ketogenic diet and its impact on mental processes of working population

Contact Info

Product

Resources

About