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Time of the day of exercise impact on cardiovascular disease risk factors in adults: a systematic review and meta-analysis.
Sevilla-Lorente, R, Carneiro-Barrera, A, Molina-Garcia, P, Ruiz, JR, Amaro-Gahete, FJ
Journal of science and medicine in sport. 2023;26(3):169-179
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In humans, shifted sleep patterns seem to interfere with several metabolic pathways. Shift work, short sleep duration, exposure to artificial light, inadequate eating time window, and lack of physical activity, are some characteristics of the modern lifestyle that contributes to the occurrence and worsening of cardiovascular disease (CVD). The aim of this study was to analyse the time of the day of exercise-induced effects on CVD risk factors in adults. This study was a systematic review and meta-analysis of twenty-two studies. Results showed that exercise produces an acute reduction of systolic blood pressure independently of the time of the day at which it is performed. Similarly, exercise produces an acute increase in blood glucose independently of the time of the day. Authors concluded that further research is needed to establish whether there is a diurnal variation of exercise on cardiovascular health and how it is related to health status, sex, or the type of exercise.
Abstract
OBJECTIVES To compare the effect of a single bout of morning vs. evening exercise on cardiovascular risk factors in adults. DESIGN Systematic review and meta-analysis. METHODS A systematic search of studies was conducted using PubMed and Web of Science from inception to June 2022. Selected studies accomplished the following criteria: crossover design, acute effect of exercise, blood pressure, blood glucose, and/or blood lipids as the study's endpoint, a washout period of at least 24 h, and adults. Meta-analysis was performed by analyzing: 1) separated effect of morning and evening exercise (pre vs. post); and 2) comparison between morning and evening exercise. RESULTS A total of 11 studies were included for systolic and diastolic blood pressure and 10 studies for blood glucose. Meta-analysis revealed no significant difference between morning vs. evening exercise for systolic blood pressure (g ∆ = 0.02), diastolic blood pressure (g ∆ = 0.01), or blood glucose (g ∆ = 0.15). Analysis of moderator variables (age, BMI, sex, health status, intensity and duration of exercise, and hour within the morning or evening) showed no significant morning vs. evening effect. CONCLUSIONS Overall, we found no influence of the time of the day on the acute effect of exercise on blood pressure neither on blood glucose.
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The effects of time-restricted eating on sleep, cognitive decline, and Alzheimer's disease.
Ezzati, A, Pak, VM
Experimental gerontology. 2023;171:112033
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The ageing population is expected to double, with one in four people being over 65 years in Western countries by 2050. As a consequence, the presentation of age-related disorders like Alzheimer's disease (AD) and mild cognitive impairment (MCI) is likely to increase. MCI, a pre-stage of dementia, is considered reversible. However, there are no known cures for AD so far. Hence interventions such as lifestyle modifications that can delay the onset and progression of the disease are of great interest. Previous research demonstrated that calorie restriction (CR) and time-restricted eating (TRE) have beneficial effects on brain function. The authors of this article sought to summarize the current evidence of such eating patterns, as well as their underlying mechanisms and potential benefits concerning MCI and AD. The review also looked at sleep - as sleep disturbances are a risk factor and are associated with both conditions - and the effects of sleep on cognitive decline and neuroinflammatory markers. TRE presents itself as a promising intervention as it can restore the integrity of the blood-brain barrier and support healthy brain function whilst reducing oxidative stress and inflammation. Furthermore, it can be leveraged for weight and glucose management. Preliminary results also indicate a positive impact on sleep, with adequate sleep benefiting cognitive health. As this is a relatively new field, there is still much more to be understood about the underlying mechanisms, with the optimal time window for fasting needing to be determined. The authors advocate for more research on how TRE and sleep relates to neurodegenerative disease.
Expert Review
Conflicts of interest:
None
Take Home Message:
- To highlight the potential benefits of time-restricted eating (TRE) as a potential preventative approach to delay the onset and progression of neurodegenerative disease such as AD
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
- The authors highlight Alzheimer's disease (AD) is the most prevalent neurodegenerative disease affecting over 50 million aging people worldwide. While no cure is known for AD, this review proposes lifestyle interventions such as time-restricted eating (TRE) as a potential approach to delay the onset and progression of a neurodegenerative disease and could hint at autophagic mechanisms
- TRE involves strategically limiting the eating window to 8- to 12-h with fasting—drinking only water and calorie-free coffee/tea—for 12 to 16 h within a 24-h cycle.
Objectives
- To investigate the effects of TRE on sleep and cognitive decline in healthy individuals
Results
- Nine RCTs with varied length between one and sixteen weeks were examined
- A 5-week randomised controlled trial (RCT) showed no significant change in sleep quality between early TRE (fasting between 6 a.m.–3 p.m.), mid-day TRE (11 a.m.–8 p. m.) and control (ad lib intake) in 82 healthy subjects without obesity but the sleep quality improvement was greater in early TRE group (PSQI:Δ=−1.08±1.78vs.Δ=−0.22±2.19andΔ=−0.36±1.73, respectively).
- Sleep quality using the myCircadianClock app reported significant improvement in sleep quality (23 %) following a 12-week single arm intervention of 10-h TRE.
- Following a 16-week TRE intervention sleep duration was reported to be improved from a subjective score of 6 at base line to 8 after 36 weeks in eight overweight and obese subjects; however, the study used a subjective self-assessment survey for measuring sleep duration.
- The Pittsburgh Sleep Quality Index (PSQI) was carried out to assess sleep quality and disturbances in six trials but no trial reported significant improvement in sleep quality using the PSQI survey with TRE
Conclusion
- Authors highlight TRE as promising for its potential to reduce the markers of aging and neurodegenerative disease.
Clinical practice applications:
- To inform practitioners of the potential benefits of TRE that involves limiting the eating window to 8- to 12-h with fasting—drinking only water and calorie-free coffee/tea—for 12 to 16 h within a 24-h cycle.
- TRE may improve regulation of circadian rhythm and autophagy through aligning food intake with circadian rhythm, which coordinates metabolism and physiological functions including glucose, insulin sensitivity, lipid levels, energy expenditure, inflammation, sleep and cognitive function.
- TRE activates a metabolic switch which occurs 12–36 h after fasting is initiated and free fatty acids are released into the blood.
- TRE improved sleep quality and sleep duration, where a longer fasting period in TRE approach (≥12 h fasting) was associated with significantly higher sleep duration.
Considerations for future research:
- The potential benefits of TRE in neurodegenerative diseases such as AD should be further investigated clinically.
- The optimal time to initiate fasting needs to be identified in future trials.
- The potential benefits of TRE in neurodegenerative diseases such as AD in the context of sleep should be further investigated.
Abstract
According to the United Nations, by 2050, one in six individuals will be over age 65 globally, and one in four people would be aged 65 and older in western countries. The unprecedented growth of the aging population is associated with increased age-related disorders like Alzheimer's disease (AD) and Mild cognitive impairment (MCI). To date, no cure is known for AD, thus lifestyle interventions including calorie restriction (CR) and time-restricted eating (TRE) are proposed as potential approach to delay the onset and progression of the disease. Sleep disturbances are common in people with MCI and AD. Moreover, accumulating data indicates that pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-10 increase in individuals with AD and MCI versus healthy subjects. Thus, the purpose of the present review is to describe the potential effects of TRE on sleep, cognition decline, and neuroinflammatory markers in humans. Preliminary evidence suggests that TRE may produce neuroprotective effects on cognition and reduce neuroinflammatory markers related to AD in humans. To date, no studies investigated the effects of TRE on sleep disturbances and patients with AD. Thereby, the impact of TRE on cognition in individuals with cognitive decline and AD needs to be investigated further in randomized controlled trials (RCTs).
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Sleep-Opt-In: A Randomized Controlled Pilot Study to Improve Sleep and Glycemic Variability in Adults With Type 1 Diabetes.
Martyn-Nemeth, P, Duffecy, J, Quinn, L, Steffen, A, Baron, K, Chapagai, S, Burke, L, Reutrakul, S
The science of diabetes self-management and care. 2023;49(1):11-22
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Insufficient sleep (insufficient total sleep time) and irregular sleep timing (variability in the occurrence of sleep within a 24-hour period) are increasingly recognized as important contributors to glycaemic control and variability in type 1 diabetes (T1D). The aims of this study were to evaluate the feasibility and acceptability of a sleep intervention (Sleep-Opt-In) targeted for adults with type 1 diabetes with short or irregular sleep and to examine the effects of Sleep-Opt-In on sleep duration and regularity, glucose indices, and patient-reported outcomes. This study was a randomised controlled parallel trial design. Participants (n=14) were randomly assigned to either the Sleep-Opt-In intervention or a Healthy Living attention control group. Results showed that: - Sleep-Opt-In was feasible and acceptable to the target population. - participants with objectively confirmed short or irregular sleep, sleep irregularity improved by 25 minutes on average, whereas sleep duration improved only negligibly (8 minutes). - the control group experienced an increase in sleep duration but no change in sleep regularity. Authors conclude that Sleep-Opt-In is feasible, acceptable, and promising for further evaluation to improve sleep duration or regularity, glucose parameters and important patient reported outcomes of diabetes distress, daytime sleepiness, fatigue and depressive mood in the T1D population.
Abstract
PURPOSE The purpose of this study was to evaluate the feasibility and acceptability of a technology-assisted behavioral sleep intervention (Sleep-Opt-In) and to examine the effects of Sleep-Opt-In on sleep duration and regularity, glucose indices, and patient-reported outcomes. Short sleep duration and irregular sleep schedules are associated with reduced glycemic control and greater glycemic variability. METHODS A randomized controlled parallel-arm pilot study was employed. Adults with type 1 diabetes (n = 14) were recruited from the Midwest and randomized 3:2 to the sleep-optimization (Sleep-Opt-In) or Healthy Living attention control group. Sleep-Opt-In was an 8-week, remotely delivered intervention consisting of digital lessons, sleep tracker, and weekly coaching phone calls by a trained sleep coach. Assessments of sleep (actigraphy), glucose (A1C, continuous glucose monitoring), and patient-reported outcomes (questionnaires for daytime sleepiness, fatigue, diabetes distress, and depressive mood) were completed at baseline and at completion of the intervention. RESULTS Sleep-Opt-In was feasible and acceptable. Those in Sleep-Opt-In with objectively confirmed short or irregular sleep demonstrated an improvement in sleep regularity (25 minutes), reduced glycemic variability (3.2%), and improved time in range (6.9%) compared to the Healthy Living attention control group. Patient-reported outcomes improved only for the Sleep-Opt-In group. Fatigue and depressive mood improved compared to the control. CONCLUSIONS Sleep-Opt-In is feasible, acceptable, and promising for further evaluation as a means to improve sleep duration or regularity in the population of people with type 1 diabetes.
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Polyphenol Intake in Pregnant Women on Gestational Diabetes Risk and Neurodevelopmental Disorders in Offspring: A Systematic Review.
Salinas-Roca, B, Rubió-Piqué, L, Montull-López, A
Nutrients. 2022;14(18)
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In Europe, gestational diabetes affects approximately 10.9% of pregnant women. According to previous research, the cardiometabolic health of the mother and the mother's dietary habits during pregnancy may affect the foetus' neurodevelopment. Taking polyphenol supplements and eating foods rich in polyphenols is beneficial for promoting health across generations. In this systematic review, fourteen studies were included in order to evaluate the effects of polyphenols on gestational diabetes and mental health in the offspring. A higher prevalence of neurodevelopmental diseases in offspring is associated with gestational diabetes. The results of this systematic review revealed that polyphenol intake during pregnancy might have a beneficial effect on improving cardiometabolic health, reducing inflammation, DNA methylation and oxidative stress, thus reducing the risk of developing fetal neurodevelopmental disorders, such as attention deficit hyperactivity disorder, autism spectrum disorder and learning disorders. There is a need for further robust research, as the existing evidence regarding the safety of long-term polyphenol supplementation and its effects on gestational diabetes and fetal neurodevelopment is very limited. In spite of this, healthcare professionals can use the findings of this systematic review to learn more about the positive health benefits of polyphenols in pregnant women.
Abstract
The intake of foods containing polyphenols can have a protective role to avoid comorbidities during pregnancy and, at the same time, promote transgenerational health. This review aims to describe the effect of polyphenol intake through supplements or polyphenol-rich foods during pregnancy on the incidence and evolution of gestational diabetes mellitus (GDM), as well as the link with the neurodevelopment of the fetus. Using PRISMA procedures, a systematic review was conducted by searching in biomedical databases (PubMed, Cinahl and Scopus) from January to June 2022. Full articles were screened (n = 419) and critically appraised. Fourteen studies were selected and were divided into two different thematic blocks considering (i) the effect of polyphenols in GDM and (ii) the effect of GDM to mental disorders in the offspring. A positive relationship was observed between the intake of polyphenols and the prevention and control of cardiometabolic complications during pregnancy, such as GDM, which could be related to thwarted inflammatory and oxidative processes, as well as neuronal factors. GDM is related to a greater risk of suffering from diseases related to neurodevelopment, such as attention deficit hyperactivity disorder, autism spectrum disorder and learning disorder. Further clinical research on the molecule protective mechanism of polyphenols on pregnant women is required to understand the transgenerational impact on fetal neurodevelopment.
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The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
Brakedal, B, Dölle, C, Riemer, F, Ma, Y, Nido, GS, Skeie, GO, Craven, AR, Schwarzlmüller, T, Brekke, N, Diab, J, et al
Cell metabolism. 2022;34(3):396-407.e6
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Parkinson’s disease (PD) is a major cause of death and disability, and current treatments can provide partial symptomatic relief, mainly for motor symptoms but make no substantial impact on disease progression. A growing body of evidence supports that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) may confer neuroprotective effects in both healthy aging and neurodegeneration. The primary aim of this study was to assess penetration and metabolic responses of the brain to nicotinamide riboside (NR) supplementation in patients with PD. This study is a double-blinded, randomised, placebo-controlled phase I study of NR in newly diagnosed PD patients, naïve to dopaminergic therapy. Participants (n=30) where randomly assigned (1:1) to one of the two groups: NR group or placebo group. Results show that: - oral NR therapy increases brain NAD levels and impacts cerebral metabolism in PD. - supplementation with NR may target multiple processes implicated in the pathophysiology of the disease by upregulating the expression of genes involved in mitochondrial respiration, oxidative damage response, lysosomal and proteasomal function and downregulating inflammatory cytokines in the central nervous system. Authors conclude that NR can be a potential neuroprotective agent against PD. However, further investigation in a larger trial is required to warrant these findings.
Abstract
We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.
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Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial.
Lehtisalo, J, Rusanen, M, Solomon, A, Antikainen, R, Laatikainen, T, Peltonen, M, Strandberg, T, Tuomilehto, J, Soininen, H, Kivipelto, M, et al
European heart journal. 2022;43(21):2054-2061
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Older people are at high risk of cardiovascular disease, and 90% of the risk factors can be modified, including an unhealthy diet, poor physical activity, obesity, smoking, and obesity-related comorbidities. This randomised controlled trial examined a multifactorial approach combining several lifestyle modifications in 1259 older adults between 60 and 77 years of age to reduce the risk of cardiovascular disease. Participants were randomly assigned to intensive multi-domain lifestyle intervention or regular health advice control groups. The multifactorial lifestyle intervention incorporated dietary counselling, exercise training, cognitive training, and managing CVD and metabolic risk factors. Dietary interventions included tailored strategies that considered increased consumption of fruits, berries, vegetables, whole grains, margarine, oil, and fish. Physical exercise interventions included strength training, balance exercises, and aerobic exercises. Cognitive interventions and intensive strategies to manage metabolic factors were also implemented. In the multifactorial lifestyle intervention group, cerebrovascular events were lower after two years than in the control group. In addition, cardiovascular disease and stroke incidence were lower in the elderly with a history of cardiovascular disease. Healthcare professionals can use the results from this study to understand the benefits of multifactorial lifestyle interventions on cardiovascular disease. However, there is a need for longer-term robust studies since the evidence is sparse.
Abstract
AIMS: Joint prevention of cardiovascular disease (CVD) and dementia could reduce the burden of both conditions. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated a beneficial effect on cognition (primary outcome) and we assessed the effect of this lifestyle intervention on incident CVD (pre-specified secondary outcome). METHODS AND RESULTS FINGER enrolled 1259 individuals aged 60-77 years (ClinicalTrials.gov NCT01041989). They were randomized (1:1) to a 2-year multi-domain intervention with diet, physical and cognitive activity, and vascular monitoring (n = 631), or general health advice (n = 628). National registries provided data on CVD including stroke, transient ischaemic attack (TIA), or coronary heart event. During an average of 7.4 years, 229 participants (18%) had at least one CVD diagnosis: 107 in the intervention group and 122 in the control group. The incidence of cerebrovascular events was lower in the intervention than the control group: hazard ratio (HR) for combined stroke/TIA was 0.71 [95% confidence interval (CI): 0.51-0.99] after adjusting for background characteristics. Hazard ratio for coronary events was 0.84 (CI: 0.56-1.26) and total CVD events 0.80 (95% CI: 0.61-1.04). Among those with history of CVD (n = 145), the incidence of both total CVD events (HR: 0.50, 95% CI: 0.28-0.90) and stroke/TIA (HR: 0.40, 95% CI: 0.20-0.81) was lower in the intervention than the control group. CONCLUSION A 2-year multi-domain lifestyle intervention among older adults was effective in preventing cerebrovascular events and also total CVD events among those who had history of CVD.
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The relationship between diabetes mellitus and attention deficit hyperactivity disorder: A systematic review and meta-analysis.
Ai, Y, Zhao, J, Liu, H, Li, J, Zhu, T
Frontiers in pediatrics. 2022;10:936813
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Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder characterised by inattention and/or hyperactivity/impulsivity. Several studies have found bidirectional associations between ADHD and diabetes mellitus (DM). The aims of this study were to assess the prevalence of ADHD in DM patients as well as the prevalence of DM in ADHD patients compared with those without ADHD, and to explore the impacts of ADHD on glycaemic control in patients with DM. This study is a systematic review and meta-analysis of 17 articles; five were cohort studies, three were case-control studies, and nine were cross-sectional studies. Results through the pooled analyses suggest an important comorbid relationship between diabetes and ADHD. Overall, there was an increase in T2DM of 166% and 51% in children and adults with ADHD, respectively, relative to those without ADHD. Furthermore, there was an overall 37% increase in T1DM in children with ADHD. Authors conclude that further studies are needed to better understand the relationship between ADHD and DM. Additionally, it is important to take into consideration the type of DM if this association is different in various age groups (children and adults).
Abstract
BACKGROUND This study aims to investigate the prevalence estimate of diabetes mellitus (DM) among people with attention deficit hyperactivity disorder (ADHD) as well as the prevalence of ADHD among those with DM. In addition, the impact of ADHD on glycemic control in patients with DM was also assessed using a systematic review and meta-analysis of currently available published data. MATERIALS AND METHODS The PubMed, Embase, Web of Science, and PsycInfo databases were searched for potential studies. Two reviewers independently selected studies according to the inclusion and exclusion criteria. All pooled analyses were conducted using the random-effects models on Review Manager 5.3. RESULTS Seventeen observational studies were included. The pooled results showed an increase in the prevalence of DM among patients with ADHD versus those without ADHD [type 1 DM OR 1.37 (95% CI: 1.17-1.61); type 2 DM OR 2.05 (95% CI: 1.37-3.07)]. There was an overall 35% increase in the prevalence of ADHD among patients with type 1 DM [OR: 1.35 (95% CI: 1.08-1.73)]. Children with type 1 DM and ADHD had higher levels of hemoglobin A1c [standardized mean of differences: 0.67 (95% CI: 0.48-0.86)], and prevalence of hypoglycemic and ketoacidosis index compared with those without ADHD. CONCLUSION Our study revealed the bidirectional associations between ADHD and DM. Patients with ADHD and type 1 DM comorbidities were more likely to have poorer diabetes control. More studies are needed to confirm this association and elucidate the underlying mechanism.
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Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease.
Phillips, MCL, Deprez, LM, Mortimer, GMN, Murtagh, DKJ, McCoy, S, Mylchreest, R, Gilbertson, LJ, Clark, KM, Simpson, PV, McManus, EJ, et al
Alzheimer's research & therapy. 2021;13(1):51
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Most people with dementia have Alzheimer’s disease (AD), a disorder that characteristically results in progressive cognitive and functional decline. Brain energy metabolism is impaired in AD. Ketogenic diets can theoretically mitigate impaired brain energy metabolism in AD, leading to improved cognition, daily function, or quality of life. Ketogenic diets are high-fat, low-carbohydrate diets that shift the body towards fat metabolism. The aim of this study was to determine whether a 12-week modified ketogenic diet was well-tolerated and improved cognition, daily function, or quality of life in a hospital clinic of AD patients. This study is a single-phase, assessor-blinded, two-period randomised crossover trial. Participants (n=26) were randomised (1:1 allocation) to a modified ketogenic diet (intervention diet) or their usual diet supplemented with low-fat healthy-eating guidelines and optional recipes (control diet). Results show that high rates of retention and adherence are achievable by following a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life. Furthermore, changes in cardiovascular risk factors were mostly favourable and adverse effects were mild. Authors conclude that ketogenic diets may hold promise as viable and effective treatment strategies in AD, but larger and longer studies are needed in order to draw definitive conclusions.
Abstract
BACKGROUND Brain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients. METHODS We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects. RESULTS We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild. CONCLUSIONS This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia. TRIAL REGISTRATION This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202 . The trial was registered on August 28, 2018.
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A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.
Fortier, M, Castellano, CA, St-Pierre, V, Myette-Côté, É, Langlois, F, Roy, M, Morin, MC, Bocti, C, Fulop, T, Godin, JP, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021;17(3):543-552
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Brain energy rescue is emerging as a potential strategy to reduce cognitive decline in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The main aim of this study was to report the complete cognitive outcomes of the BENEFIC (Brain Energy, Functional Imaging, and Cognition) trial. The secondary objectives are to report plasma ketones (free caprylic and capric acids) levels; as well as the metabolic response, safety, and tolerability after the 6-month intervention. This study is a 6-month randomised, placebo-controlled trial. A total of 122 participants were enrolled and randomised into one of the two arms: ketogenic medium chain triglyceride (kMCT) or placebo arm. Results show that performance on widely used tests of episodic memory, executive function, and language improved over 6 months in MCI when consuming 30g/day of a kMCT drink relative to a matching placebo. Moderate to large effect sizes were observed on four cognitive tests in the kMCT group. Furthermore, it is safe and feasible for an MCI population to consume a 15g kMCT supplement twice daily for 6 months. Authors conclude that formulation of a kMCT drink improved four cognitive outcomes in MCI by increasing blood ketone levels.
Expert Review
Conflicts of interest:
None
Take Home Message:
- MCT supplementation is a promising strategy to rescue energy metabolism in the brain for those with MCIs by providing an alternative energy source
- Improvements in cognition were associated with increased blood ketone levels from MCT supplementation
- Practitioners should be mindful that higher intakes of MCTs (>30g/d) may lead to negative GI effects in some individuals.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
This randomized controlled trial demonstrates that supplementation of a ketogenic drink containing medium-chain triglycerides (MCTs) is both safe and effective in improving cognitive outcomes in individuals with mild cognitive impairments (MCI), and does so through supporting energy metabolism in the brain.
Clinical practice applications:
These findings might be useful for Nutritional Therapists and Clinical Practitioners as follows:
- The results of this randomised controlled trial demonstrate that MCT supplementation (at 30g per day, split between two doses) is a viable strategy to support brain metabolism in individuals experiencing MCIs
- There was a dose-dependant response on elevated ketones and selected cognitive improvements which may have pertinent applications to therapeutic practice (either dietary or supplemental)
- The paper highlighted the involvement of energy metabolism in cognitive decline; this has potential therapeutic applications in terms of targeted nutritional support for mitochondrial function or energy signalling
- Some individuals experienced negative gastrointestinal effects when consuming MCTs at 30g/d for prolonged periods; practitioners should be mindful of this.
Considerations for future research:
Future research should consider:
- Whether dietary-induced ketosis can therapeutically impact MCI and support patient well-being
- Use of MCTs in those with severe cognitive impairments or those taking medication such as cholinesterase inhibitors
the role of glucose hypometabolism to determine alternative strategies for those who have GI issues with MCTs
- Whether APOE4 status has any impact on therapeutic outcomes to MCT supplementation
- Whether adjunct nutritional support for mitochondrial function alongside MCT could further impact on MCIs.
Abstract
INTRODUCTION Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.
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PROFAST: A Randomized Trial Assessing the Effects of Intermittent Fasting and Lacticaseibacillus rhamnosus Probiotic among People with Prediabetes.
Tay, A, Pringle, H, Penning, E, Plank, LD, Murphy, R
Nutrients. 2020;12(11)
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The prevalence of diabetes is increasing worldwide, and with it, the risk of cardiovascular disease is also increasing. Intermittent fasting has been shown to reduce weight and improve glycaemic control. Weight control and glycaemic control were also improved with probiotic Lacticaseibacillus rhamnosus HN001 supplementation. This pilot, 12-week, double-blinded, two-armed, randomized 1:1 study aimed to investigate the combined effects of intermittent fasting with daily probiotic Lacticaseibacillus rhamnosus HN001 supplementation on glycaemic management in participants with prediabetes. For two days, participants restricted their calorie intake to 600-650 kcal, followed by five days of ad libitum consumption (5:2). Intermittent fasting for 12 weeks improved glycaemic control (reduced HbA1c) and reduced body weight by 5%. The supplementation with Lacticaseibacillus rhamnosus HN001 did not significantly improve these outcomes. Probiotic supplementation significantly improved mental health and social functioning in participants. There is a need for further large, robust studies to assess the effects of intermittent fasting alone and when it is combined with different exercise forms and different prebiotic and probiotic supplements on cardiometabolic markers and mental health. The findings of this study may be useful to healthcare professionals in understanding the effects of fasting on metabolism as well as the psychological benefits of Lacticaseibacillus rhamnosus HN001 supplementation.
Abstract
Both intermittent fasting and specific probiotics have shown promise in improving glucose tolerance with a potential for synergistic effects through alterations to gut microbiota. In this randomized, double-blinded, two-arm feasibility study, we investigated whether intermittent fasting, supplemented with Lacticaseibacillus rhamnosus HN001 probiotic, reduces HbA1c in individuals with prediabetes. All participants with HbA1c 40-50 mmol/mol commenced intermittent fasting (2 days per week of calorie restriction to 600-650 kcal/day) and were randomized 1:1 to either daily probiotic (Lacticaseibacillus rhamnosus HN001) or placebo for 12 weeks. The primary outcome was a change in HbA1c. Secondary outcomes included changes in anthropometry, body composition, glucoregulatory markers, lipids, hunger hormones, liver enzymes, inflammatory markers, gut hormones, calorie and macronutrient intake, quality of life, hunger, mood and eating behavior. Of 33 participants who commenced the trial, 26 participants (mean age 52 years, body mass index (BMI) 34.7 kg/m2) completed the intervention (n = 11 placebo, n = 15 probiotic). HbA1c decreased from 43 ± 2.7 mmol/mol to 41 ± 2.3 mmol/mol, p < 0.001, with average of 5% weight loss. No significant between-group differences were seen in primary or secondary outcomes except for social functioning (p = 0.050) and mental health (p = 0.007) scores as improvements were seen in the probiotic group, but not in the placebo group. This study shows additional psychological benefits of probiotic supplementation during intermittent fasting to achieve weight loss and glycemic improvement in prediabetes.