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Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.
Castro, CB, Dias, CB, Hillebrandt, H, Sohrabi, HR, Chatterjee, P, Shah, TM, Fuller, SJ, Garg, ML, Martins, RN
Nutrition reviews. 2023;(9):1144-1162
Abstract
CONTEXT In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy. OBJECTIVE This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD. DATA SOURCES A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021. DATA EXTRACTION Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria. DATA ANALYSIS All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain. CONCLUSION MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42019146967.
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Multi-Domain Interventions for Dementia Prevention - A Systematic Review.
Castro, CB, Costa, LM, Dias, CB, Chen, J, Hillebrandt, H, Gardener, SL, Brown, BM, Loo, RL, Garg, ML, Rainey-Smith, SR, et al
The journal of nutrition, health & aging. 2023;(12):1271-1280
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Abstract
OBJECTIVES There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.
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Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.
Ramezani, M, Fernando, M, Eslick, S, Asih, PR, Shadfar, S, Bandara, EMS, Hillebrandt, H, Meghwar, S, Shahriari, M, Chatterjee, P, et al
Frontiers in neuroscience. 2023;:1297984
Abstract
Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.
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Antioxidant Effects of a Polyphenol-Rich Dietary Supplement Incorporating Pinus massoniana Bark Extract in Healthy Older Adults: A Two-Arm, Parallel Group, Randomized Placebo-Controlled Trial.
Ferguson, JJA, Oldmeadow, C, Bentley, D, Garg, ML
Antioxidants (Basel, Switzerland). 2022;(8)
Abstract
Oxidative stress is a key physiological phenomenon underpinning the ageing process and plays a major developmental role in age-associated chronic diseases. This study investigated the antioxidant effects of a polyphenol-rich dietary supplement containing Pinus massoniana bark extract (PMBE) in healthy older adults. In a double-blinded, placebo-controlled clinical trial, participants were randomised (in a 1:1 ratio) to receive a 50 mL/day dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) for 12 weeks. The primary outcome was fasting plasma malondialdehyde (MDA) concentrations and secondary outcomes were plasma inflammatory markers. MDA concentrations significantly reduced following PMBE for 6 weeks (−1.19 nmol/mL, 95%CI −1.62, −0.75, p < 0.001) and 12 weeks (−1.35 nmol/mL, 95%CI −1.74, −0.96, p < 0.001) compared to baseline. MDA did not significantly change after the placebo. MDA levels at 6 and 12 weeks were significantly lower following PMBE compared to placebo (p < 0.001). At 12 weeks in the PMBE group, fibrinogen concentrations significantly reduced (−0.25 g/L, 95%CI −0.39, −0.11; p < 0.0001) and interleukin-6 significantly increased compared to placebo (0.30 pg/mL, 95%CI 0.02, 0.59; p < 0.05). PMBE in a polyphenol-rich dietary supplement reduced oxidative stress in healthy older adults. Further studies are warranted to investigate the antioxidant capacity of PMBE in conditions with heightened oxidative stress, such as osteoarthritis, hypertension, type 2 diabetes, or other lifestyle related diseases.
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Effect of a polyphenol-rich dietary supplement containing Pinus massoniana bark extract on blood pressure in healthy adults: A parallel, randomized placebo-controlled trial.
Ferguson, JJA, Oldmeadow, C, Bentley, D, Eslick, S, Garg, ML
Complementary therapies in medicine. 2022;:102896
Abstract
OBJECTIVES High blood pressure (BP) is a major risk factor for cardiovascular disease and prevalence rates continue to rise with ageing populations. Polypharmacy remains a burden among the ageing, thus alternative effective strategies are warranted. This study investigated the effects of a polyphenols rich dietary supplement containing Pinus massoniana bark extract (PMBE) for modulating BP in healthy Australian adults. DESIGN This study is a secondary analysis of data from a double-blinded, placebo-controlled clinical trial. METHODS Sixty-two healthy adults aged 55-75 years were randomized to receive 50 mL dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) daily for 12 weeks. Seated systolic BP (SBP) and diastolic (DBP) were measured at baseline, 6 weeks and 12 weeks. Effects of PMBE on modulating BP was also explored in this study stratified for SBP status (optimal v high) as well as by SBP medication status. Mixed effect regression modelling was employed involving fixed categorical effects for elapsed time, treatment assignment and their interaction as well as random subject-level intercept to account for within-subject correlations resulting from repeated measurements. Significant models were further examined by addition of covariates and power calculations were performed since this study was a secondary analysis. RESULTS SBP significantly reduced (-3.29 mmHg, p = 0.028) after PMBE at 12 weeks compared to baseline. SBP in individuals with normal-high SBP (>120 mmHg) in the PMBE group reduced by - 6.46 mmHg (p = 0.001) at 12 weeks compared to baseline. No significant changes were reported for individuals with optimal (≤120 mmHg) SBP nor did DBP significantly change in either study groups. In individuals with non-medicated normal-high SBP, SBP significantly reduced by - 7.49 mmHg (p = 0.001) and DBP by - 3.06 mmHg (p = 0.011) at 12 weeks compared to baseline after PMBE. Cross-group comparisons were not statistically different. CONCLUSIONS A polyphenol-rich dietary supplement derived from PMBE led to a clinically and statistically significant reduction in SBP in adults. Future studies to investigate the effects of PMBE-polyphenol supplementation on BP are warranted to confirm and explore optimal dose and impact on hypertension.
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Bioactive Yoghurt Containing Curcumin and Chlorogenic Acid Reduces Inflammation in Postmenopausal Women.
Ahmed Nasef, N, Thota, RN, Mutukumira, AN, Rutherfurd-Markwick, K, Dickens, M, Gopal, P, Singh, H, Garg, ML
Nutrients. 2022;(21)
Abstract
Menopause is marked by a gradual and permanent decrease of estrogen from the ovaries, leading to metabolic and physiological changes in the body. Combined with increased body mass index, postmenopausal women have elevated systemic inflammation and metabolic disturbances leading to increased risk of developing chronic diseases. A bioactive coconut yoghurt containing curcumin and chlorogenic acid was developed with the potential to target inflammatory processes. In this randomized crossover study, healthy postmenopausal women with a BMI of 25-40 were recruited to consume 125 g of either the bioactive or placebo yoghurt. Blood samples were collected at baseline, 30 min, and 1, 2, 3 and 4 h postprandially. Plasma inflammatory markers (TNFα and IL6) and metabolic markers (triglycerides, insulin and glucose) were measured. Participants had significantly lower plasma TNFα Cmax after consumption of the bioactive yoghurt compared to placebo (mean difference = 0.3 pg/mL; p = 0.04). Additionally, plasma TNFα was significantly lower postprandially compared to baseline after consumption of the bioactive yogurt but not the placebo. No differences were observed in the metabolic markers measured. Conclusions: The bioactive yoghurt fortified with curcumin and chlorogenic acid has the potential to reduce inflammatory mediators; however, a larger and longer-term study is required to confirm these findings.
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Anti-inflammatory effects of oral supplementation with curcumin: a systematic review and meta-analysis of randomized controlled trials.
Ferguson, JJA, Abbott, KA, Garg, ML
Nutrition reviews. 2021;(9):1043-1066
Abstract
CONTEXT Chronic inflammation is a major contributor to the development of noncommunicable diseases. Curcumin, a bioactive polyphenol from turmeric, is a well-known anti-inflammatory agent in preclinical research. Clinical evidence remains inconclusive because of discrepancies regarding optimal dosage, duration, and formulation of curcumin. OBJECTIVE The aim of this systematic review, conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and checklist, was to evaluate the efficacy of curcumin supplementation on systemic inflammatory mediators, comparing dose, duration, and bioavailability status of interventions. DATA SOURCES The Medline, CINAHL, EMBASE, Scopus, and Cochrane literature databases were searched from 1980 to May-end 2019. Randomized controlled trials investigating effects of dietary curcumin on inflammatory mediators in humans not receiving anti-inflammatory treatment were eligible for inclusion. Two authors independently assessed titles and abstracts of identified articles for potential eligibility and respective, retrieved, full-text articles; disagreements were resolved by a third author. Evidence quality was critically appraised using the Quality Criteria Checklist for Primary Research. DATA EXTRACTION Thirty-two trials (N = 2,038 participants) were included and 28 were meta-analyzed using a random-effects model; effect sizes were expressed as Hedges' g (95%CI). DATA ANALYSIS Pooled data (reported here as weighted mean difference [WMD]; 95%CI) showed a reduction in C-reactive protein (-1.55 mg/L; -1.81 to -1.30), interleukin-6 (-1.69 pg/mL, -2.56 to -0.82), tumor necrosis factor α (-3.13 pg/mL; -4.62 to -1.64), IL-8 (-0.54 pg/mL; -0.82 to -0.28), monocyte chemoattractant protein-1 (-2.48 pg/mL; -3.96 to -1.00), and an increase in IL-10 (0.49 pg/mL; 0.10 to 0.88), with no effect on intracellular adhesion molecule-1. CONCLUSION These findings provide evidence for the anti-inflammatory effects of curcumin and support further investigation to confirm dose, duration, and formulation to optimize anti-inflammatory effects in humans with chronic inflammation. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42019148682.
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Effects of Plant-Based Diets on Weight Status in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.
Austin, G, Ferguson, JJA, Garg, ML
Nutrients. 2021;(11)
Abstract
Excessive adiposity is a major risk factor for type 2 diabetes (T2D), and dietary patterns are important determinants of weight status. Plant-based dietary patterns (PBDs) are known for their therapeutic effects on T2D. The aim is to systematically review RCTs to investigate the effects of various PBDs compared to regular meat-eating diets (RMDs), in individuals who normally consume a RMD on body weight, BMI, and waist circumference in T2D. RCTs investigating PBDs and body weight, BMI, WC for ≥6 weeks in adults with T2D since 1980 were eligible for inclusion. Seven trials (n = 269) were included in the meta-analysis using random-effects models and expressed as MD (95%Cls). Compared to RMDs, PBDs significantly lowered body weight (-2.35 kg, 95% CI: -3.51, -1.19, p < 0.001), BMI (-0.90 kg/m2, 95% CI: -1.42, -0.38, p = 0.001) and WC (-2.41 cm, 95% CI: -3.72, -1.09, p < 0.001). PBDs alone significantly reduced body weight by 5.1% (-4.95 kg, 95% CI: -7.34, -2.55, p < 0.001), BMI by 5.4% (-1.87 kg/m2, 95% CI: -2.78, -0.95, p < 0.001) and WC by 4.3%(-4.23, 95% CI: -6.38, -2.07, p < 0.001). Interventions not limiting energy intake led to a significant reduction in body weight (-2.54 kg, 95% CI: -4.16, -0.92, p < 0.005) and BMI (-0.91 kg/m2, 95% CI: -1.56, -0.25, p < 0.005). Trials ≥16 weeks had a pronounced reduction in body weight (-2.93 kg, 95% CI: -5.00, -0.87, p = 0.005) and BMI (-1.13 kg/m2, 95% CI: -1.89, -0.38, p < 0.005). These findings provide evidence for the implementation of PBDs for better management of central adiposity in individuals with T2D.
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Long-chain omega-3 polyunsaturated fatty acids and cognitive decline in non-demented adults: a systematic review and meta-analysis.
Alex, A, Abbott, KA, McEvoy, M, Schofield, PW, Garg, ML
Nutrition reviews. 2020;(7):563-578
Abstract
CONTEXT Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. OBJECTIVE The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. DATA SOURCES Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. STUDY SELECTION Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. DATA EXTRACTION A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge's g and random-effects modeling. DATA ANALYSIS Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge's g = 0.02; 95% confidence interval, -0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge's g = 0.31; P = 0.003; z = 2.945). CONCLUSION The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42017078664.
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Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3β and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer's Disease.
Thota, RN, Rosato, JI, Dias, CB, Burrows, TL, Martins, RN, Garg, ML
Nutrients. 2020;(4)
Abstract
Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer's disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 β (GSK-3β) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3β (-2.4 ± 0.4 ng/mL vs. -0.3 ± 0.6, p = 0.0068) and IAPP (-2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (-0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3β, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.