Stephen C. Cunnane

Un hypométabolisme du glucose au cerveau est retrouvé dans la maladie de Parkinson (MP). Une supplémentation en cétones, le carburant alternatif au glucose pour le cerveau, permet de contourner le déficit énergétique spécifique au glucose, mais on ignore encore si le métabolisme cérébral des cétones est affecté dans la MP. L’exercice physique améliore certaines capacités fonctionnelles dans la MP et augmente l’apport en cétones au cerveau dans la maladie d’Alzheimer. Cet essai de phase 1 (NCT04322461) visait à évaluer si la combinaison d’une supplémentation en sels de cétones avec l’exercice a un impact sur le métabolisme énergétique et la connectivité fonctionnelle au cerveau dans la MP.

Context: Alternate-day fasting (ADF) is a dietary regimen with prolonged fasting periods associated with metabolic and cardiovascular benefits. It remains unclear if ADF improves cardiac function and metabolism to explain these benefits. Objective: This study aimed to investigate the effects of a 3-week ADF intervention on myocardial efficiency, perfusion, and substrate metabolism in overweight/obese individuals. Methods: Sixteen participants with overweight (body mass index: 32 ± 1.9 kg/m2) completed this randomized crossover study comparing ADF with a standard diet. Dynamic cardiac positron emission tomography scans were performed using 5 tracers: [15O]water to assess myocardial blood flow and flow reserve (MFR), [11C]acetate to measure myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE), and [11C]β-hydroxybutyrate, [11C]palmitate, and [18F]fluorodeoxyglucose to assess metabolism of β-hydroxybutyrate (OHB), free fatty acid (FFA), and glucose, respectively. Blood samples were analyzed for OHB, FFA, glucose, lactate, and insulin. Blood pressure, heart rate, cardiac output, and left ventricular mass, ejection fraction, and volumes were assessed. Results: ADF increased circulating ketones on fasting days (peak: 0.67 ± 0.09 mmol/L), which remained elevated on eating days (0.20 ± 0.03 mmol/L). However, myocardial substrate metabolism remained unaltered following ADF. Blood pressure and cardiac output significantly decreased after ADF (systolic/diastolic: 13/9 mmHg and 0.5 L/min, respectively; P < .001). MVO2 decreased by 10% (P = .01) and total left ventricular energy use by 19% (P < .01). Resting myocardial perfusion decreased by 9% (P < .05), and MFR increased by 34% (P < .01). Conclusion: A 3-week ADF regimen reduced blood pressure and MVO2, and improved MFR, suggesting ADF may provide a nonpharmacological strategy to improve cardiovascular health in individuals with overweight.

Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) has shown potential therapeutic benefits in individuals with Alzheimer’s disease. These effects are widely presumed to be mediated by hepatic conversion of MCT into circulating ketones. However, the physiological and cellular mechanisms underlying the benefits of MCT remain understudied, particularly in the context of Alzheimer’s disease. Here, we investigated the cellular and molecular changes occurring in the brain and systemically in response to dietary supplementation with MCT versus a ketogenic diet. The experimental design consisted of comparing a 70% carbohydrate control diet to either a control diet supplemented with 10% MCT or a carbohydrate-free high-fat ketogenic diet. Diets were tested in two Alzheimer’s disease mouse models, slow-progressing 3xTg-AD mice that model pre-symptomatic/early stages and rapidly progressing 5xFAD mice that model late stages of the disease. We found that MCT supplementation and a ketogenic diet both improved hippocampal-dependent spatial learning and memory, increased dendritic spine density of hippocampal neurons and modulated hippocampal expression of genes associated with mitochondrial functions, synaptic structure and insulin signalling in Alzheimer’s disease mouse models. However, unlike the ketogenic diet, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT supplementation enhanced the peripheral insulin response of Alzheimer’s disease mice, while the ketogenic diet conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain and adiposity. The systemic metabolic disturbances of Alzheimer’s disease mice correlated with transcriptomic alterations in hepatic lipid metabolism and ketogenesis genes and increased lipid droplet accumulation. These liver metabolic abnormalities were partially reversed by both MCT supplementation and the ketogenic diet, but in distinct ways. Notably, the ketogenic diet selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression, while MCT downregulated expression of cholesterol-related genes. Collectively, these findings reveal that MCT supplementation in the context of Alzheimer’s disease improves cognition and systemic metabolism without elevating circulating ketone levels.

First episode of psychosis (FEP) has an early onset and is associated with significant functional impairment, loss of productivity and premature cardiovascular disease. Antipsychotics (AP) remain the cornerstone treatment of FEP yet they fail to improve key symptom domains and contribute to the metabolic burden of this disorder. A growing body of evidence suggests that a metabolic deficit in the brain, specifically of glucose, at the earliest stages of illness could represent an etiopathological phenotype of FEP. Correcting this metabolic deficit could improve outcomes and disease course. The acronym for this study is CAST-ATP for the collaboration between our clinical research sites in Copenhagen, Aarhus, Sherbrooke and Toronto, on the subject of Antipsychotic (AP) treatment, PET and Psychosis. The main aims of CAST-ATP are to evaluate the effect of 1) a diagnosis of FEP, and, 2) 4–6 weeks of AP treatment on brain energy metabolism measured by PET scans (uptake of ketones and glucose). The hypothesis is that (i) glucose metabolism will be impaired in AP-naïve patients as compared to healthy controls, and (ii) this defect will be worsened by AP. In contrast, across the two aims, brain ketone metabolism is predicted to not be significantly influenced by FEP or AP treatment. Participants on both sites will undergo an imaging protocol (PET scans + MRI) in addition to measures of psychopathology and related peripheral metabolic, inflammatory and hormonal markers. If our hypothesis is confirmed, it will reinforce the strategy to leverage ketone supplementation to improve symptoms, functioning and quality of life by bypassing the brain glucose deficit in FEP. As such, this should be a significant therapeutic development. To this last point, the pharmaceutical treatment of schizophrenia spectrum disorders has not progressed beyond currently available AP for over seven decades.

Context: The beneficial effects of a ketogenic diet (KD) on neurodegenerative conditions such as mild cognitive impairment (MCI) and Alzheimer disease (AD) are increasingly acknowledged, with potential implications for the general population as well. Objective: Thus, our study aimed to explore the effect of a KD on cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF) in healthy individuals. We hypothesized that a KD would increase CBF and BDNF, thereby presenting itself as an approach to prevent cognitive decline. Methods: In total, 11 cognitively healthy individuals with overweight participated in a randomized, crossover trial consisting of 2 different 3-week interventions: (i) a KD; and (ii) a standard diet (SDD). Each diet period concluded with a positron emission tomography (PET) study day, accompanied by a separate magnetic resonance imaging (MRI) scan. Blood samples were collected prior to the PET scan to measure β-hydroxybutyrate (β-OHB) and BDNF levels. CBF was assessed using a [15O]H2O PET scan co-registered with an MRI scan. Results: A KD led to increased basal plasma β-OHB levels compared to the SDD (647 [418-724] vs 50 [50-60] μmol/L, P < .05), increased CBF by 22% (P = .02), and elevated BDNF levels by 47% (P = .04). Moreover, a correlation was observed between β-OHB levels and CBF measurements across the 2 diets (R2 = 0.54, P < .001). Conclusion: Implementing a KD improved CBF and raised BDNF levels in cognitively healthy individuals, indicating that a KD should be assessed for as a potential treatment for conditions associated with reduced CBF.

Poor glucose regulation associated with gradual insulin resistance is a significant risk factor in several age-related chronic diseases. An eating plan that promotes a lower carbohydrate intake may have a beneficial effect on glucose metabolism. This study aimed to evaluate how a diet reduced in carbohydrate by 32% (RCHO) over a 2 month period would influence the metabolic profile of older individuals ( N = 24) living in a retirement home (RH). A continuous glucose monitor was used to measure blood glucose during four periods: the standard diet before (baseline) and after (washout) the intervention, during the 4 initial days of the RCHO diet (RCHO-early), and the final days of the 2 month intervention (RCHO-end). The blood metabolic profile was also measured (glucose, ketones, insulin, triglycerides, and cholesterol). RCHO intake decreased average blood glucose compared to the standard diet in hyperglycemic participants: RCHO-early 7.8 ± 1.0 vs 7.5 ± 1.1 mM ( p = 0.012) and RCHO-end 7.8 ± 1.0 vs 7.0 ± 0.9 mM ( p = 0.050). In the hyperglycemic participants, the percentage of time spent in hyperglycemia (>10.0 mM) decreased by 50% during the RCHO-early ( p = 0.012) and by 66% at RCHO-end ( p = 0.021) compared to baseline. Glycated hemoglobin was significantly lower at RCHO-end in both hyperglycemic and normoglycemic participants compared to baseline ( p < 0.008). Plasma ketones increased threefold in hyperglycemic participants at RCHO-end compared to baseline ( p < 0.028). This study shows that an RCHO diet has metabolic health benefits in an older population and confirms its safety, tolerability, and acceptability in an RH (NCT06022094).

Early detection of atypical dementia remains difficult partly because of the absence of specific cognitive screening tools. This creates undue delays in diagnosis and management. The Dépistage Cognitif de Québec (DCQ; dcqtest.org) was developed in French and later validated in participants with atypical syndromes. We report the validation of the English version. This multicentre prospective validation study was conducted in 10 centers across Canada and the United States on 260 English-speaking participants aged over 50. We translated and modified the original French DCQ to add targeted stimuli to the Visusopatial Index and social cognition vignettes to the Behavioral Index. A backward translation was performed and equivalence between languages was assessed by administering both tests to 30 bilingual participants. Mean DCQ total score (out of 100) was 95.0 (SD = 3.6). Spearman’s correlation coefficient showed a strong and significant correlation (r = 0.49, p < .001) with the Montreal Cognitive Assessment. Test–retest reliability was good (Spearman’s coefficient = 0.72, p < .001) and interrater reliability, excellent (intraclass correlation = 0.97, p < .001). Normative data shown in percentiles were stratified by age and education for a population-based sample of 260 English-speaking controls aged between 50 and 87 years old. Similar to the French version, the English DCQ proved to be a valid cognitive screening test. The original version was very sensitive to detect atypical dementias such as primary progressive aphasias, Alzheimer’s disease’ variants and syndromes along the frontotemporolobar degeneration spectrum. This 20-min test can be administered à la carte and offers an alternative to detailed comprehensive neuropsychological evaluations.

Omega-3 (n–3) PUFAs are suggested to play a role in the prevention of cognitive decline. The evidence may be inconsistent due to methodologic issues, including interrelations with other long-chain (14 or more carbons) fatty acids (LCFAs) and use of sex as a confounding factor rather than an effect modifier This study evaluated the association between serum n–3 PUFAs and performance across 4 cognitive domains, overall and by sex, while controlling for other LCFAs In total, 386 healthy older adults (aged 77.4 ± 3.8 y; 53% females) from the Quebec Longitudinal Study on Nutrition and Successful Aging underwent a cognitive evaluation and blood sampling. Verbal and nonverbal episodic memory, executive functioning, and processing speed were evaluated. Serum LCFA concentrations were measured by gas chromatography. LCFAs were grouped according to standard fatty acid classes and factor analysis using principal component analysis (FA-PCA). Multivariate linear regression models were performed, including unadjusted and adjusted models for other LCFAs Higher n–3 PUFA concentrations were associated with better nonverbal memory and processing speed in fully adjusted models not including other LCFAs (βs of 0.21 and 0.19, respectively). The magnitude of these associations varied when other LCFAs were entered in the model (βs of 0.27 and 0.32, respectively) or when FA-PCA factors were considered (βs of 0.27 and 0.21, respectively). Associations with verbal episodic memory were limited to higher concentrations of EPA, whereas there was no association between n–3 PUFAs and executive functioning. Higher n–3 PUFAs were associated with better verbal and nonverbal episodic memory in females and with better executive functioning and processing speed in males These results suggest that other LCFAs should be considered when evaluating the association between n–3 PUFAs and cognitive performance in healthy older adults. Sex differences across cognitive domains warrant further investigation.