Introduction
Ageing, obesity and vascular dysfunction: the dementia risk triad
Nutrition and brain health
Caloric restriction
Reference | Population | Study design | Measurements | Intervention | Main finding |
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Witte et al. 2009 [15] | Healthy overweight elderly. n = 49 (M/F = 21/29). Age = 60.5 ± 7.6 SD. BMI = 28 ± 3.7 SD. | Parallel RCT. | Memory performance, BP, CRP, TNF- α, BDNF, glucose, insulin and lipid profile. | Duration: three months. Three groups: 1. CR (30% reduction in EI) n = 19. 2. Increase UFAs (20%) n = 20. 3. Control n = 10. | CR increases memory score significantly (20%; p < 0.001), and it has a significant inverse association with insulin, glucose and CRP among the high compliance subjects. No significant difference in UFAs and control. |
Zotova et al. 2015 [114] | Arterial hypertension (AH) and cerebral ischemia (CI) patients. n = 42 into two arms: 1. CR (M/F = 6/16), age = 54.4 ± 2.4 SD. 2. Antihypertensive drugs (M/F = 8/12), age = 55.6 ± 1 SD. | Parallel controlled clinical trial. | Cognitive function, cerebral haemodynamic (Doppler ultrasound), QoL, glucose, and lipid profile. | Duration: six months. Two groups: 1. CR n = 22. Level of CR not reported. 2. Antihypertensive therapy (ACE inhibitors, thiazide diuretics), neurometabolic drugs, drugs that improve cerebral hemodynamics) n = 20. | CR significantly improves the cognitive function, cerebral haemodynamic and QoL in both AH and CI compared to the second group and baseline. |
Prehn et al. 2017 [115] | Healthy postmenopausal obese women. n = 37. Age = 61 ± 5 SD. BMI = 34.9 ± 4 SD. | Parallel RCT. | Memory performance, cognitive function, fMRI (BOLD; oxygenation metabolism), physical activity, BP and glucose. | Duration: three months (CR) + one month of sustained weight loss (Isocaloric diet). Two groups: 1. CR (formula-diet 800 kcal/d) n = 19. 2. Control n = 18. | Improved recognition memory significantly and grey matter in the CR group compared to the control at the second time point (after the three months CR); p < 0.05, and it returned to non-significant at the endpoint, but it remained higher in CR. |
Kim et al. 2020 [116] | Healthy adults with central obesity. n = 43. Age = 52.8 ± 2 SD. BMI = 31.4 ± 5.1 SD. | Parallel RCT. | Memory performance, cognitive function, cardiometabolic, BP, glucose and lipid profile | Duration: one month. Two groups: 1. Continuous CR (500 kcal reduction), n = 22. 2. Intermittent CR (5:2 pattern; consuming 600 kcal for two consecutives days), n = 21. | Both groups enhanced the pattern separation significantly (p < 0.0005), but the intermittent CR group were significantly lower in recognition memory (p < 0.007). |
Leclerc et al. 2020 [117] | Healthy non-obese adults. n = 220. Age = 21–50 (males), 21–47 (female). BMI = 22–28. | Parallel RCT (part of CALERIE study). | Working memory, cognitive function, mood state, sleep quality and energy expenditure. | Duration: two years. Two groups: 1. CR (25% reduction). 2. Control. | CR improve working memory significantly compared to the control at second (12 months) and third (24 months) time points (p < 0.001). |
Teong et al. 2021 [118] | Healthy overweight and obese women. n = 46. Age = 50 ± 9 SD. BMI = 32.9 ± 4.4 SD. | Parallel RCT (secondary analysis). | Cognitive function, mood state, sleep quality and QoL. | Duration: two months. Two groups: 1. CR (30% reduction in EI) n = 24. 2. Intermittent fasting (IF; 30% reduction in EI) n = 22. | Both groups increase cognitive function significantly (CR; p < 0.006, IF; p < 0.03). There was no significant difference in the other measurement, except that weight loss was significant in the IF group (p < 0.001). |
Dietary nitrate
Reference | Population | Study design | Measurements | Intervention | Main finding |
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Aamand et al. 2013 [89] | Healthy young men. n = 18. Age = 25 ± 0.9 SD. Weight = 77 kg ± 1.5 SD. | Double-blind, crossover, placebo-controlled RCT. | fMRI (BOLD; oxygenation metabolism and ASL; CBF), nitrate, nitrite, BP, pulse oximetry, expired CO2, | Duration: three days for each intervention with a washout period of 9–11 days. Two groups: 1. Start with dietary nitrate (NaNO3−; saline solution), n = 9, followed by Placebo (NaCl; saline solution). 2. The opposite of the first group, n = 9. | Dietary nitrate decrease haemodynamic lag significantly (p < 0.005), which associate significantly with NO3− concentration (p < 0.05). In addition, it improves the BOLD amplitude significantly (3-way ANOVA; p < 0.05), without significant association with NO3− concentration. Moreover, a significant correlation between the lag and amplitude (p < 0.005). Furthermore, dietary nitrate increases the NO3− concentration significantly (p < 0.001) despite the intervention order, but it were not significant for the NO2− in both intervention. However, there was no significant difference in the other measurement. |
Kelly et al. 2013 [119] | Healthy old adults. n = 12 (M/F = 6/6), two were excluded. Age (M/F) = 64 ± 4 SD / 63 ± 2 SD. BMI (M/F) = 23.1/25.1. | Double-blind, crossover, placebo-controlled RCT. | Nitrite, BP, physiological and cognitive examinations. | Duration: two and half days for each intervention with a washout period of three days. Two groups: 1. Start with dietary nitrate (high-nitrate beetroot juice; 2 × 70 ml/d), n = 6, followed by placebo (depleted-nitrate beetroot juice; 2 × 70 ml/d). 2. The opposite of the first group, n = 6. | Dietary nitrate enhanced NO2− concentration significantly (p < 0.01) when compared to placebo and baseline. In addition, it significantly reduced systolic and diastolic BP when compared to baseline (p < 0.01) and placebo (p < 0.05). However, there was no significant difference in the cognitive function between nitrate intake and placebo or baseline. |
Wightman et al. 2015 [45] | Healthy adults. n = 40 (M/F = 12/28). Age = 21. BMI = 24.36 | Double-blind, parallel, placebo-control RCT. | Cognitive function (COMPASS), CBF (oxyhaemoglobin and deoxyhaemoglobin by NIRS), BP, nitrite. | Duration: single high dose, over three portions, separated by 10 min, measurements performed after one and half hours from the first portion for one hour approximately during cognitive tasks. Two groups: 1. Beetroot Juice 450 ml (nitrate-rich), n = 20. 2. Placebo (nitrate-depleted), n = 20. | Inorganic nitrate increase nitrite significantly (p < 0.01). In addition, it significantly increases CBF at the beginning of the tasks (total Hb; P < 0.05) and decreases it significantly afterwards (p < 0.01) compared to placebo. However, there was no significant difference between the groups regarding the deoxy Hb. Moreover, it improves cognitive function (p < 0.01). However, there was no significant difference on BP. |
Fan et al. 2019 [90] | Healthy young adults. n = 17 (M/F = 10/7). Age = 24.4 ± 5.7 SD. BMI = 23.2 ± 2.1 SD. | Single-blind, crossover, placebo-controlled RCT. | CBF, cerebrovascular CO2 activity, cerebral autoregulation (BP and MCAv), nitrate and nitrite. | Duration: one week for the baseline assessment plus one week for each intervention with a washout period of one week. Two groups: 1. Start with dietary nitrate (NaNO3−; 3 capsules/d), followed by placebo (microcrystalline cellulose; 3 capsules/d) 2. The opposite of the first group | Dietary nitrate enhanced NO3−and NO2−concentrations significantly compared to baseline and placebo (p < 0.002), without a significant difference between males and females. In addition, it improved the arterial stiffness significantly compared to baseline and placebo (p < 0.008). Moreover, it improved significantly cerebral autoregulation compared to placebo but not to baseline in males but not females (p < 0.025). Furthermore, it improved MCAv-CO2 only in males compared to placebo (p < 0.014). However, there was no significant difference in BP or cerebrovascular haemodynamic |
Fan et al. 2020 [91] | Transient ischemic attack overweight patients (TIA). n = 26. Age = 67.4 ± 10.2 SD. BMI = 27.9 ± 6.4 SD. | Single-blind, parallel, placebo-controlled RCT. | Cerebrovascular function (BP and CBF), cerebrovascular CO2 activity, cerebral autoregulation, nitrate and nitrite. | Duration: one week. Two groups: 1. Dietary nitrate (NaNO3−; 3 capsules/d), n = 13. 2. Placebo (microcrystalline cellulose; 3 capsules/d), n = 13. | Dietary nitrate significantly increased concentrations of NO3− (p < 0.001) and NO2− (p < 0.004) compared to placebo and baseline (p < 0.001). Additionally, placebo was not significant for both NO3−and NO2− compared to baseline. In addition, it decreased the BP significantly compared to placebo and baseline (p < 0.05). Moreover, it improves MCAv variability (p < 0.018) and cerebral autoregulation (p < 0.045) compared to placebo. However, there was no significant difference in cerebral haemodynamics compared to placebo. |
Babateen et al. 2022 [92] | Healthy overweight and obese adult. n = 62 (M/F = 24/38). Age = 66.3 ± 3.7 SD. BMI = 30.3 ± 3.7 SD. | Single-blind, parallel, placebo-controlled pilot RCT. | CBF (oxyhaemoglobin and deoxyhaemoglobin by NIRS) and cognitive function (COMPASS). | Duration: 13 weeks. Four groups: 1. High dietary nitrate (high-nitrate beetroot juice; 2 × 70 ml/d) n = 16. 2. Moderate dietary nitrate (high-nitrate beetroot juice; 70 ml/d) n = 17. 3. Low dietary nitrate (high-nitrate beetroot juice; 70 ml/alternate days) n = 14. 4. Placebo (depleted-nitrate beetroot juice; 70 ml/ alternate days) n = 15. | There was no significant difference between the groups and baseline in terms of CBF and cognitive function. |
Alharbi et al. 2023 [13] | Healthy overweight and obese adult. n = 29 (M/F = 7/22). Age = 61.3 ± 5.9. SD. BMI = 34.5 ± 5.8 SD. | Open-label, parallel, pilot RCT. | Body composition, REE, resting BP, endothelial activity, microvascular perfusion (Laser Doppler), cognitive function, hand-grip strength, physical activity, and oxidative stress biomarker. | Duration: 2 weeks. Two groups: 1. CR (40% reduction in EI) plus dietary nitrate (high-nitrate beetroot juice; 70 ml/d) n = 15. 2. CR alone (40% reduction in EI) n = 14. | There was significant improvement of systolic BP (p = 0.06), microvascular perfusion (p = 0.03), endothelial activity (p = 0.02), cognitive function (p = 0.01), and oxidative stress biomarker (p = 0.02) among CR + dietary nitrate group compared to CR alone. In addition, there was significant inversed correlation between oxidative stress biomarker and microvascular perfusion (r=-0.53, p = 0.003). |