4.1. Curcumin
Baum et al. [
96] carried out a six-month randomized, double blind, placebo-controlled clinical trial on 34 Chinese patients of both sexes, ≥50 years old, with progressive decline in memory and cognitive function for 6 months, and diagnosis of probable or possible AD, to examine the curcumin safety and effects on biochemical parameters and cognitive function. Subjects received curcumin 1 g/day or 4 g/day; they were also given an additional treatment consisting in 120 mg/day of standardized gingko leaf extract. Patients treated with anticoagulant or antiplatelet agents or with bleeding risk factors were excluded. The main outcome measures were the Mini-Mental Status Examination (MMSE) score at baseline and at 6 months, plasma isoprostanes iPF2α-III and serum Aβ (at 0, 1, and 6 months); plasma levels of curcumin and its metabolites were also measured. No significant differences in MMSE score between treatments (1 g/day and 4 g/day) and placebo were observed, and neither was a reduction in serum Aβ
40 levels nor differences in plasma isoprostanes iPF2α-III found. Plasma levels of curcuminoids, measured at 1 month, did not differ significantly between 1 g/day and 4 g/day groups so they were pooled and the results were as follows (in nanomolar): 250 ± 80 curcumin, 150 ± 50 demetoxycurcumin, 90 ± 30 bisdemetoxycurcumin, 440 ± 100 tetrahydrocurcumin. No differences in adverse events between curcumin groups and placebo were reported.
Ringman et al. [
97] performed a randomized, double blind, placebo-controlled clinical trial on 36 subjects with mild-to-moderate AD. Patients were treated with Curcumin C3 Complex
® (95% curcuminoids with curcumin 70%–80%, demethoxycurcumin 15%–25%, bisdemethoxycurcumin 2.5%–6.5%) at 2 g/day or 4 g/day for 24 weeks with an open-label extension to 48 weeks. Other medications such as acetylcholinesterase inhibitors and memantine were allowed, instead antioxidant, anticoagulant or antiplatelet drugs, including
Ginkgo biloba, were not allowed. The purpose of the study was to acquire data on safety and tolerability and preliminary data on efficacy with regard to cognition, by measuring the incidence of adverse events, changes in clinical laboratory tests and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) subscale, Neuropsychiatric Inventory (NPI), Alzheimer’s Disease Co-operative Study-Activities of Daily Living (ADCS-ADL), MMSE score, plasma levels of Aβ
1-40 and Aβ
1-42, cerebrospinal fluid levels of Aβ
1-42, t-tau, p-tau181 and F
2-isoprostanes. Plasma levels of curcumin and its metabolites were also measured. No significant differences between curcumin and placebo in ADAS-Cog, NPI, ADCS-ADL or MMSE score were registered, as well as no differences between treatment groups in biomarker efficacy measures. Plasma levels of native curcumin and tetrahydrocurcumin, measured at a 24-week visit and 3 h after medication, were 7.76 ± 3.23 and 3.73 ± 2.0 ng/mL, respectively. The levels of glucuronidated curcumin and tetrahydrocurcumin were 96.05 ± 26 ng/mL and 298.2 ± 140.04 ng/mL. Levels of native curcumin were undetectable in the cerebrospinal fluid. Curcumin was generally well tolerated. On the whole, authors were unable to demonstrate clinical or biochemical evidence of curcumin efficacy against AD.
Hishikawa et al. [
98] reported three cases of patients (79, 83, and 84 years old, respectively) with AD whose behavioral symptoms were improved remarkably as a result of turmeric treatment. Patients received turmeric 764 mg/day (curcumin 100 mg/day) for more than 1 year. After 12 weeks of treatment, all three patients experienced a reduction (≥50%) of the Japanese version of Neuropsychiatric Inventory-brief Questionnaire (NPI-Q) score and the burden of caregivers was reduced (38%–86%), too. Particularly, agitation, apathy, anxiety, and irritability symptoms were relieved. One patient also increased his MMSE score from 12/30 to 17/30, improving calculation, concentration, transcription of the figure, and spontaneous writing. Of note, two patients were on donepezil treatment before starting curcumin.
Cox and colleagues [
99] performed a randomized, double-bind, placebo controlled, phase 3/4 trial in healthy older subjects using Longvida
® Optimized Curcumin, in dose of 400 mg, containing approximately 80 mg curcumin in a solid lipid formulation. Participants (aged 60–85 years) were randomly assigned to either curcumin (
n = 30) or placebo (
n = 30) treatment groups. The acute (1 and 3 h after a single dose), chronic (4 weeks) and acute-on-chronic (1 and 3 h after single dose following chronic treatment) effects of curcumin preparation on cognitive function, mood and blood biomarkers were examined. The authors reported significantly improved performance in sustained attention and working memory tasks, compared with placebo, one hour after administration of curcumin. Following chronic treatment, working memory and mood (general fatigue and change in state calmness, contentedness and fatigue induced by psychological stress) were significantly improved. A significant acute-on-chronic treatment effect on alertness and contentedness was also observed. Curcumin was associated with significant reduction of total and LDL cholesterol levels. Curcumin treatment was well tolerated and did not significantly impact any of the examined hematological safety measures.
A recent randomized, double-bind, placebo controlled trial (ACTRN12611000437965) was carried out on healthy older adults, to evaluate the potential efficacy of BCM-95
®CG (Biocurcumax™), a standardised extract of
Curcuma longa L. (88% curcuminoids and 7% volatile oil), in preventing cognitive decline [
100]. One hundred and sixty healthy subjects (40–90 years aged) were selected for the study and randomly divided into two groups: an experimental group, taking Biocurcumax™ 1500 mg/day (1 capsule 500 mg three times a day), and a control group, taking a placebo (roasted rice powder). Sixty four subjects (23 in the placebo group and 41 in the curcumin group) did not complete the study for various reasons (ineligibility to remain in the study, suspect adverse reaction, intervention non-compliance, etc.) so 96 participants were included in the final analysis. The study lasted 12 months during which subjects were evaluated at the baseline and at the 6- and 12-months follow-ups. Mood was assessed by administration of the Depression Anxiety Stress Scale (DASS) [
127]. Cognitive measures were obtained by a battery of cognitive tests for general cognitive function (MoCA) [
128], verbal fluency, percentual motor speed, psychomotor speed, working memory, executive functions and visual memory. Blood pressure and weight were checked at baseline and every 3 months. No differences were observed in all clinical measures as well as for cognitive measures except for a significant interaction between time and treatment group in the MoCA test that, however, was due to a decline in general cognitive function of the placebo group at 6 months that was not observed in curcumin treatment group.
Besides the published ones, a number of studies of curcumin supplementation in healthy older people or in patients with Mild Cognitive Impairment (MCI) or AD are still underway or completed but results are not yet available.
A clinical trial (NCT00595582) [
101] aimed at determining the efficacy of curcumin in the treatment of MCI or mild AD has been registered at the U.S. National Institutes of Health. Ten subjects (both sexes, ≥55 years old) already enrolled in another study (NCT00243451) [
129] have been included in this clinical trial. They had to receive 5.4 g/day of curcumin in combination with bioperine, to improve curcumin bioavailability, for 24 months. Primary outcome was to determine if curcumin had an effect on neuropsychological scores, while determining if curcumin impacted the metabolic lesions found in patients who had MCI or might develop MCI was the secondary outcome. Unfortunately, none of the patients terminated the study. In particular, two out of 10 interrupted the study because of adverse effects (dyspepsia).
Another randomized, double-blind, placebo-controlled phase 2 study (NCT01001637) [
102] has been designated to evaluate the efficacy and safety of the high-bioavailability curcumin formulation (Longvida
®) in AD. The study planned to enrol 26 patients (both sexes ≥50 years old) with AD, who had to be treated with placebo, 4 g/day or 6 g/day of curcumin supplementation for 2 months. The main outcomes were to determine if curcumin formulation affects cognitive function in Alzheimer’s patients, based on mental exams, and blood concentrations of Aβ. The recruitment status of this study is unknown.
A larger phase 2 clinical trial (NCT01383161) [
103] has been designed to determine the effects of the curcumin supplement on age-related cognitive impairment, after 18 months’ treatment. The investigators will study 132 subjects with MCI (aged 50–90 years), which will be randomly assigned to placebo or curcumin group (six 465 mg Theracurmin™ capsules/day, containing 30 mg of curcumin each). The main outcomes will be a change in cognitive testing results, in level of inflammatory markers in blood, and in the amount of brain amyloid protein. This study is ongoing, but is not recruiting participants.
Additionally, a randomized, double-blind, placebo-controlled phase 2 study (NCT01811381) [
104] will evaluate the clinical benefits of curcumin alone or in combination with yoga in 80 individuals with MCI, 55–90 years old. For the first 6 months of the study, subjects will take either 800 mg of curcumin (Longvida
® formulation) or placebo, before meals. Over the second 6 months of study, the curcumin and placebo groups will be further divided into groups receiving training in either aerobic or non-aerobic yoga (attendance at 2 classes of 1 h duration and 2 home practices of 30 min duration per week) to determine the synergism between curcumin supplementation and aerobic exercise. Primary outcome will be to determine if curcumin (first six month period), alone or associated to aerobic yoga (second six month period), reduces the levels of blood biomarkers for MCI. Secondary outcome will be to evaluate imaging changes in all subjects and adverse events. This study is currently recruiting participants.
Several clinical trials are also underway in Australia. The randomized, double-blind, placebo-controlled, phase 3/4 clinical trial ACTRN12616000484448 [
105] will soon start to recruit participants. This study will investigate the effects of 12 weeks of treatment with a bioavailability enhanced curcumin supplement on cognitive function, mood and wellbeing in healthy older adults (
n = 80; aged 50–85 years). Participants will receive 400 mg of Longvida
® Optimized Curcumin (containing about 80–90 mg curcumin) daily. The study will also evaluate the effects of curcumin on cardiovascular function and a range of blood markers of health, to better understand how cognitive and mood benefits might be achieved. In a subset of participants, the effects of curcumin on brain function will be explored by functional Magnetic Resonance Imaging (fMRI). Finally, the study will investigate whether genetic differences can influence the effects of curcumin.
Another randomized, double-blind, placebo-controlled, phase 2 study (ACTRN12613000681752) [
106] is in progress in Australia. This clinical trial will investigate the role of curcumin in preventing AD. Participants (
n = 100; 65–90 years old) assessed as at high risk of AD will be assigned to placebo or curcumin (Biocurcumax™) group. The latter will receive 500 mg daily of curcumin for 2 weeks, progressing to 500 mg twice daily (1000 mg/daily) for another 2 weeks, then 500 mg three times daily, (1500 mg) until the end of the study (12 months). Primarily, the ability of Biocurcumax to positively alter AD-related blood biomarker profiles compared with placebo will be investigated, secondarily the possible increase in brain glucose utilisation, as measured by FDG-PET, and the correlation with the improvement in cognitive functioning will be studied. Currently, the recruitment of participants is in progress. Present clinical trial includes also a sub study (ACTRN12614001024639) [
107], which will be performed in 48 subjects (24 healthy older people and 24 with MCI) to examine the influence of curcumin on expression of inflammatory genetic markers, by measuring associated proteins in the blood, and on existing lifestyle patterns including sleep, activity levels and nutrition.
In addition, three clinical trials have been designed to assess the possible use of curcumin in the early diagnosis of AD. It has been proposed, in fact, that beta-amyloid plaques may first appear in the retina, at the back of the eye, before they are detectable in the brain. Curcumin has molecular and optical properties that allow to image amyloid plaques using a specialized eye camera, and hence to detect Alzheimer’s disease earlier. In these open, not randomized phase 2 or phase 2/3 studies, all groups receive the same intervention, i.e., 20 g of Longvida
® (equivalent to 4 g of curcumin) along with Vitamin E supplement capsules, equivalent to 500 IU daily, for seven consecutive days; participants will be asked to have eye imaging done before and after taking curcumin for 7 days. The trial ACTRN12613000367741 [
108] includes three groups of subjects: with AD, with MCI and healthy controls. The association between retinal imaging and brain amyloid imaging will be determined in AD and in MCI in comparison with the healthy controls. The second diagnosis trial (ACTRN12615000465550) [
109] is recruiting subjects with MCI and healthy controls. Participants must have completed curcumin based fluorescence retinal imaging under the ACTRN12613000367741 study (parent study) [
108] within the previous 21 months. The primary endpoint will be to evaluate the ability to detect changes over time in retinal Aβ plaque burden, and at this aim the results from participants with MCI will be compared with the results from the healthy controls and, in addition, with the participants’ results from the parent study. Finally, ACTRN12615000677505 [
110] has been designed to investigate the presence/absence of retinal amyloid plaques in a middle-aged control cohort (40–60 years). Furthermore, the comparison between retinal Aβ protein plaque burden with brain Aβ protein plaque burden will be done. Currently, the present study is not recruiting subjects.
4.2. Resveratrol
Six studies, aimed at evaluating the effects of resveratrol on cognitive function in humans, were retrieved (see
Table 2).
In 2010, Kennedy et al. [
111] performed a randomized double-blind, placebo-controlled, crossover study to investigate the possibility that single oral doses of resveratrol modulate mental function and increase cerebral blood flow (CBF) in the frontal cortex of healthy humans. Cognitive performance was measured by a battery of tasks and the cerebral blood flow in the prefrontal cortex was detected by Near-Infrared Spectroscopy (NIRS), during the tasks. The 24 subjects enrolled (age 18–25 years) received three single dose treatments: placebo, 250 mg
trans-resveratrol, and 500 mg
trans-resveratrol. The bioavailability of resveratrol and its metabolites (resveratrol glucuronide and resveratrol sulfate) at time points relevant to the CBF/cognitive task assessment, were also evaluated in a separate cohort of 9 healthy young adults. The 500 mg resveratrol supplementation significantly increased CBF and hemoglobin status in the period of 45–81 min following administration. Also, the 250 mg resveratrol dose increased CBF compared to placebo, although in a lesser extent and at fewer time points than the higher dose, suggesting that resveratrol improves CBF in a dose-dependent manner. The peak plasma levels after treatment with 250 and 500 mg of trans-resveratrol were 5.65 ng/mL and 14.4 ng/mL respectively; at the same doses, peak plasma levels of
trans-resveratrol glucuronide were about 30 ng/mL and 200 ng/mL, respectively, while those of
trans-resveratrol sulfate were about 300 ng/mL and 750 ng/mL, respectively. Despite increased blood flow in both treatment groups, resveratrol did not enhance cognitive function.
A further randomized, double-blind, placebo controlled, crossover clinical trial has been designed to evaluate the effects of resveratrol on circulatory function and cognitive performance in obese adults [
112]. Twenty-eight subjects of both sexes (40–75 years old), obese but otherwise healthy, were enrolled. Participants were randomized to consume a capsule containing either 75 mg of resveratrol (resVida) or a color-matched placebo daily for 6 weeks. Then, participants were crossed over to an alternate dose for another 6 weeks. The assessments were done at baseline, at week 6, and at week 12. Moreover, following the assessments in week 6 and 12, participants consumed a single additional dose of the supplement and further assessments were performed 1 h after consumption. The primary outcome was to measure the degree of change in vasodilator function assessed by flow mediated dilatation (FMD) in the brachial artery. Secondary outcomes were the ability to maintain attention and concentration during the test (measured by the Stroop test), supine blood pressure, heart rate and arterial compliance. Resveratrol supplementation was found to be well tolerated and induced a 23% increase in FMD compared with placebo. Moreover, a single dose of resveratrol (75 mg) following chronic resveratrol supplementation resulted in an acute FMD response 35% greater than placebo. However, blood pressure, arterial compliance, and all components of the Stroop Color-Word Test were unaffected by chronic resveratrol supplementation.
Witte and colleagues in 2014 [
113] carried out a double-blind placebo-controlled study aimed to assess the ability of resveratrol, given over 26 weeks, to enhance the cognitive performance. Forty-six overweight older adults (50–80 years old) were recruited and randomly divided in: treatment group, receiving 200 mg/day of resveratrol in a formulation with quercetin (320 mg) to increase its bioavailability and control group, receiving placebo. Memory retention was evaluated by a battery of tasks; volume, microstructure, and functional connectivity of the hippocampus were explored by magnetic resonance imaging (MRI). Further anthropometric measures were: glucose and lipid metabolism, inflammation, neurotrophic factors, and vascular parameters. Resveratrol supplementation induced retention of memory and improved the functional connectivity between hippocampus and frontal, parietal, and occipital areas, in healthy older overweight adults compared with placebo. The changes in resting-state functional connectivity networks of the hippocampus after resveratrol intake were linked with behavioral improvements. Also, glucose metabolism was improved and this may account for some of the beneficial effects of resveratrol on neuronal function. Finally, a significant reduction of body fat and increases in leptin compared with placebo was observed.
In 2014, Wightman et al. [
114] performed a randomized, double-blind, placebo controlled, cross-over study investigating the effects of 250 mg resveratrol administered alone or co-supplemented with 20 mg piperine. The aim was to ascertain whether piperine is able to enhance the bioefficacy of resveratrol with regard to CBF and cognitive performance in a cohort of 23 healthy adults (age 19–34 years). Plasma concentrations of resveratrol were also measured in a separate cohort of 6 male adults, to investigate whether bioavailability correlated with bioefficacy. Participants were given placebo,
trans-resveratrol (250 mg) and
trans-resveratrol with 20 mg piperine on separate days, at least a week apart. Whereas 250 mg of orally administered
trans-resveratrol had no significant effects on overall CBF during the performance of cognitively demanding tasks, co-administration of the same dose of resveratrol with 20 mg piperine resulted in significantly increased CBF for the duration of the 40 min post-dose task period. Cognitive function, mood and blood pressure were not affected. In subjects treated with resveratrol alone plasma concentrations of total resveratrol metabolites ranged from 2 to 18.2 μM. Resveratrol 3-
O-sulphate was the major metabolite, contributing 59%–81% of total metabolites. The 4′-
O-glucuronide and the 3-
O-glucuronide forms made roughly equal contribution to the remaining metabolites. No significant differences were observed in the plasma concentrations of resveratrol in subjects receiving resveratrol plus piperine, so suggesting that piperine increases the efficacy of resveratrol on CBF by potentiating its vasorelaxant properties. Despite the piperine-mediated potentiation of CBF during task performance, no effects were found on cognitive performance.
Another randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild-to-moderate AD was conducted between June 2012 and March 2014 to assess the safety and efficacy of resveratrol [
115]. Participants (
n = 119, >49 years old) were recruited and randomly divided in placebo group and resveratrol group (500 mg orally once daily with dose escalation by 500 mg increments every 13 weeks, ending with 1000 mg twice daily). Pharmacokinetic studies were performed on a subset (
n = 15) at baseline and weeks 13, 26, 39, and 52. The trial showed that resveratrol, also at the higher oral dose, was safe and well-tolerated. In fact, the most common AEs were nausea and diarrhea, but their frequency was similar to placebo. In the treatment group, weight loss was also highlighted. The levels of Aβ
40 in the cerebrospinal fluid (CSF) and plasma declined more in the placebo group than the resveratrol-treated group with a significant difference at week 52 (note that Aβ
40 levels decline as dementia advances). No effects of drug treatment were found on plasma Aβ
42, CSF Aβ
42, CSF tau, CSF phospho-tau 181, hippocampal volume, entorhinal cortex thickness, MMSE score, Clinical Dementia Rating (CDR) score, ADAS-cog score, NPI score, and glucose or insulin metabolism. Plasma levels of resveratrol and its metabolites at 45 weeks were approximately: resveratrol 22 ng/mL, 3-
O-glucuronidated resveratrol 3800 ng/mL, 4-
O-glucuronidated resveratrol 5000 ng/mL, sulphated resveratrol 7400 ng/mL. The levels in CSF were approximately: resveratrol 0.45 ng/mL, 3-
O-glucuronidated resveratrol 8.5 ng/mL, 4-
O-glucuronidated resveratrol 12 ng/mL, sulphated resveratrol 13 ng/mL. The altered CSF Aβ
40 path and the pharmacokinetic data suggest that the drug penetrates the blood–brain barrier to have central effects; however, the authors concluded that this result must be interpreted with caution, because although it is suggestive of CNS effects, it does not indicate benefit.
Recently, Wong et al. [
116] carried out a randomized, double blind, placebo controlled, crossover clinical trial (registered as ACTRN12614000891628) to evaluate the effect of resveratrol supplementation on cerebrovascular function, in adults with a diagnosis of type 2 diabetes mellitus (T2DM). To manage T2DM, volunteers were using diet or exercise alone, or oral hypoglycemic agents. Enrolled participants (38 subjects of both sexes 40–80 years old) were randomly allocated to receive placebo or the resveratrol supplement Resvida™, at doses of 75 mg, 150 mg, or 300 mg, taken as a single dose during four intervention visits that took place at seven day intervals over 4 weeks. The main outcome was to determine the most effective dose of resveratrol to improve the cerebral vasodilator responsiveness (CVR) to hypercapnia in the middle cerebral artery, using Transcranial Doppler ultrasound. Effect of resveratrol on CVR in the posterior cerebral artery was the secondary outcome. Cerebral blood flow velocities were also measured. Any symptom of illness appearing during the trial was recorded. Thirty six participants concluded the study, while two withdrew their consent to participate before the first intervention visit. Resveratrol consumption significantly increased CVR in the middle cerebral artery at all tested doses with maximum improvement being observed with the lowest dose. CVR in the posterior cerebral artery was increased only at 75 mg. No adverse events occurred during the intervention.
Interestingly, several clinical trials evaluating the efficacy of resveratrol, alone or in combination with other supplements, in AD or MCI, are currently at various stages of completion. A randomized, double-blind, placebo-controlled phase three study (NCT00743743) [
117] was being designed in order to determine the effects on cognitive and global functioning in patients with mild-to-moderate AD on standard therapy. Fifty patients (50–90 years old) had to be enrolled in the study. The treatment group had to receive 1 capsule daily for 52 weeks of Longevinex brand resveratrol supplement, containing 215 mg of resveratrol active ingredient, while the control group 1 capsule of placebo. However, this study was withdrawn prior to enrolment.
Another randomized, double-blind, placebo-controlled phase 3 study (NCT00678431) [
118] recruited 27 subjects of both sexes (50–90 years old) with mild-to-moderate AD. The treatment group received liquid resveratrol (dose not reported) together with glucose and malate, using grape juice as the delivery system. The aim of this trial was to investigate the ability of resveratrol to slow the progression of AD. This endpoint was measured by the ADAS-Cog scale and Clinical Global Impression of Change (CGIC) scale at regular intervals up to 1 year after the study’s beginning. Also, the adverse effects reported by patients were examined. Although this trial was completed in June 2011, results are not available at the moment.
Additionally, a randomized, double-blind, placebo-controlled phase 1 study (NCT01126229) [
119] was aimed to assess the longer-term safety (3 months) and efficacy of resveratrol supplementation on cognitive function and physical performance in older adults. Thirty-two participants, of both sexes and aged 65–100 years, were enrolled. Subjects were randomly assigned with equal probability to receive either resveratrol (300 mg/day or 1000 mg/day) or placebo for 12 weeks. A follow-up evaluation was provided at 10 and 30 days following completion of the final post-treatment assessment. At the moment, the results on resveratrol safety have been published [
120]; conversely, those about the effects on cognitive function and physical performance are still not available.
In the NCT01794351 [
121] clinical trial (randomized, double-blind, placebo-controlled, cross-over study), the potentially cognitive enhancing effects of 500 mg
trans-resveratrol in 50 healthy young humans (both sexes, 18–35 years old) were evaluated. In this study, participants received firstly placebo and then resveratrol, on separate days, with a 7–14 day wash-out period between visits and, in the second part of the study, first resveratrol and then placebo. The main outcome was to measure the number of participants with altered cognitive function which differed from the baseline, in a time range between 40 min and 6 h post-dose. The secondary outcome was to measure the number of participants with altered mood which differed from the baseline (time range 40 min–6 h post-dose). This study was completed in December 2012, but still results are not available.
Another larger double-blind, placebo-controlled phase four clinical trial (NCT01219244) [
122] investigating whether dietary modification could provide positive effects on brain functions in elderly people with MCI is still recruiting participants. The researchers of this study planned to enrol 330 subjects (50–80 years old) with MCI. Participants will be randomly divided in 4 groups receiving placebo, or omega-3 supplementation, or resveratrol supplementation or they will undergo caloric restriction, for 6 months. The study plans also a second step in which the most effective dietary intervention will be combined with physical and cognitive training in order to highlighted the enhancing of memory functions. The effect of dietary modification on brain functions will be measured by ADAs-Cog scale. Moreover, functional and structural brain changes and plasma biomarkers will be evaluated prior to intervention and after 6 months of intervention.
The randomized double-blind placebo-controlled clinical trial NCT01766180 [
123] has been designed to determine whether the intake of resveratrol (Resvida; resveratrol 150 mg/day), alone or in combination with Fruitflow-II (tomato extract; 150 mg/day), for a period of 3 months, is effective in improving memory. A cohort of 80 subjects (both sexes aged 50–80 years) with memory impairment will be enrolled. The effects of the medications on brain blood flow and fitness will be also evaluated to find out whether the possible improvement in memory is associated with the alterations in these parameters. Memory improvement will be measured by CANTAB (Cambridge Neuropsychological Test Automated Battery), maximal oxygen uptake and blood flow to the brain. At the moment, the present clinical trial is recruiting participants.
The clinical trial NCT02621554 [
124] (randomized, double-blind, placebo-controlled phase 2/3 study) will investigate whether resveratrol could provide positive effects on memory and brain structures and functions in healthy elderly participants (both sexes ≥50 years old) with subjective memory complaints. Resveratrol (exact dose not reported) will be administered to the subjects for 6 months. Primary and secondary outcomes will be used to evaluate changes from baseline, after 6 and 12 months, with Verbal Learning Task Scores, MMSE score, structural and functional changes on the brain MRI images and plasma biomarkers. The present clinical trial is recruiting participants.
Additionally, a randomized double-blind clinical trial phase 1 (NCT02502253) [
125] will evaluate the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), a combination of three nutraceutical preparations (grape seed polyphenolic extract, resveratrol, and Concord grape juice) in patients with MCI and prediabetes. Forty-eight subjects of both sexes and aged 55–85 years will be enrolled. Participants will receive for 4 months BDPP preparation at low, moderate and high doses (the exact concentrations of BDPP are not reported in the website of clinicaltrial.gov). The main outcomes of this study will be to assess adverse events and serious adverse events, to confirm brain penetration of BDPP by measuring levels of its constituents in CBF, to evaluate the BDPP effect on mood with NPI and Cornell Scale for Depression in Dementia, and to assess the BDPP effect on cognition with a battery of memory, executive function, and attention measures. The present clinical trial is recruiting participants.
Finally, the study ACTRN12611001288910 [
126] (placebo-controlled, double-blind, randomized, phase 1/2, crossover study) is aimed at evaluating the effect of resveratrol in red wine on cognitive function in older adults. Participants (20 healthy subjects ≥65 years old) will be randomized to receive either 100 mg of grape derived resveratrol in 100 mL of red wine and 100 mL of red wine, such that at the conclusion of the study all participants will have received both treatments. The main outcomes will be to assess the effects of a moderate daily amount of resveratrol-enriched red wine on cognitive performance in older adults using the Cognitive Demand Battery (CDB) and to establish whether the dose of resveratrol (100 mg) is significant enough to reach detectable concentrations in the body. At present, the recruitment has been completed.