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| Date: 06-30-2017 | HC# 111655-571 |
Mazzanti G, Di Giacomo S. Curcumin and resveratrol in the management of cognitive disorders: what is the clinical evidence? Molecules. 2016;21(9):1243. doi: 10.3390/molecules21091243.
Alzheimer's disease (AD) is a complex cognitive disorder that affects over 30 million people worldwide and no disease-modifying treatments are available. Evidence from in vitro and in vivo studies suggests that the polyphenols curcumin from turmeric (Curcuma longa, Zingiberaceae) rhizome and resveratrol from red grape (Vitis spp., Vitaceae) berry skin have neuroprotective effects and may improve cognitive function via several mechanisms. In addition, epidemiological studies indicate curcumin and resveratrol reduce the risk of developing AD. The purpose of this review was to provide an overview of the clinical studies completed or in progress that evaluate the effect of curcumin and resveratrol on cognitive function.
To identify published clinical trials, the PubMed, MedlinePlus, and Google Scholar databases were searched with the following sets of key words: (1) curcumin, curcuminoids, turmeric, Curcuma longa, resveratrol, grapes, stilbenes, wine; and (2) neurodegenerative disorders, cognitive impairment, cognitive disorders, cognitive function, memory, learning, brain disease, dementia, Alzheimer, neuroprotection, and clinical trials. To identify ongoing clinical studies, the National Institutes of Health Clinical Trials.gov and Australian New Zealand Clinical Trials Registry were searched using the aforementioned search terms. No time or language restrictions were used. Included were studies evaluating curcumin or resveratrol in the prevention or treatment of cognitive disorders, as well as studies evaluating the effect of curcumin or resveratrol on cerebral blood flow (a parameter associated with improved cognitive performance).
A total of 11 published studies (n=5, curcumin and n=6, resveratrol) and 19 ongoing studies were included (n=10, curcumin and n=9, resveratrol) in this review.
Curcumin
It should be noted that the term curcumin is used throughout this article to refer to turmeric extracts with varying concentrations of curcuminoids.
Of the five included curcumin studies, four were randomized, double-blind, placebo-controlled studies, and one was a case report study of three patients. The randomized, controlled trials (RCTs) included a total of 70 patients with AD (n=2 studies) and 220 healthy subjects (n=2 studies). Each trial evaluated a different curcumin product, and doses ranged from 400 mg/day to 4 g/day (80 mg to 3.8 g curcuminoids/day). Treatment duration was four weeks, six months (n=2), or 12 months. Three out of four of the RCTs concluded that curcumin did not significantly improve cognition compared to placebo. One RCT in 60 healthy subjects (aged 60-85 years) reported that 400 mg/day Longvida® Optimized Curcumin (Verdure Sciences; Noblesville, Indiana) significantly improved sustained attention and working memory tasks compared with placebo one hour after acute treatment with curcumin, and significantly improved working memory and mood after four weeks of treatment. The case study of three patients with progressive dementia (aged 79, 83, and 84 years) taking 764 mg/day turmeric (curcumin 100 mg/day) for > 12 months concluded that treatment improved some behavioral symptoms and quality of life. In terms of adverse events, the largest (n=160) and longest-duration (12 months) RCT reported gastrointestinal complaints in 23 subjects (treatment group not specified); this study also had the highest dropout rate (64/160).
Of the ten ongoing curcumin studies, six are randomized, double-blind, placebo-controlled studies, and four are open-label, non-randomized studies. The RCTs are planned to include a total of 466 patients with probable AD, patients with mild cognitive impairment (MCI), or healthy subjects, and will have a duration of two months to 12 months. Each trial will evaluate a different curcumin product, and doses will range from 400 mg/day to 6 g/day. One small (n=10), open-label study has already been terminated due to patient dropouts. Of particular interest, the three remaining open-label studies are designed to evaluate the potential role of curcumin (20 g/day with 500 IU vitamin E) in the early detection of AD by using the optical properties of curcumin to image amyloid plaques with special retinal cameras. They are planned to include a total of 180 patients with probable AD, patients with MCI, or healthy subjects. Each will have a duration of seven days.
Resveratrol
All six included resveratrol studies were randomized, double-blind, placebo-controlled studies; four RCTs included healthy subjects (n=47 healthy, n=46 overweight but otherwise healthy, and n=28 obese but otherwise healthy subjects), one enrolled 119 patients with mild-to-moderate AD, and one included 36 patients with type 2 diabetes. Each trial evaluated different resveratrol products, and two studies used combination products. Doses ranged from 75 mg/day to 2 g/day. Treatment duration ranged from 21 days to 26 weeks. Five of the six RCTs found that resveratrol did not significantly improve measures of cognitive function compared to placebo. One RCT in 46 overweight but otherwise healthy subjects (aged 50-80 years) reported that 200 mg/day resveratrol in a formulation with 320 mg quercetin (product not reported) taken for 26 weeks improved memory retention and improved the functional connectivity between the hippocampus and frontal, parietal, and occipital brain areas compared with placebo. However, four of the RCTs found significant improvements in various measures of cerebrovascular blood flow/responsiveness, and the study in patients with AD observed significant reductions in amyloid plaque levels after 52 weeks. Two of the studies assessed safety and concluded that resveratrol was safe and well tolerated.
All nine ongoing resveratrol studies are randomized, double-blind, placebo-controlled studies. The RCTs are planned to include a total of 697 patients with AD, patients with MCI, healthy subjects, subjects with memory complaints, or subjects with memory impairment. The RCTs will have a duration of eight days to 52 weeks. Each trial will evaluate a different resveratrol product, and doses will range from 100 mg/day to 1000 mg/day. Of the nine RCTs, one was withdrawn prior to enrollment and three were scheduled to be completed by December 2012, but results were not available before this article was published.
In summary, despite the promising experimental findings, the results of curcumin and resveratrol clinical trials have been disappointing, according to the authors. Limitations of the extant clinical data include the small number of published RCTs, each RCT has a different experimental design, many have small sample sizes, the doses vary greatly, and many studies have a duration that is too short to detect significant changes in cognitive function. In addition, both curcumin and resveratrol have poor oral bioavailability, and rapid metabolism and elimination. "To overcome these problems, different delivery systems, like adjuvants, nanoparticles, liposomes, micelles, phospholipid complexes and nanogels, have been investigated or are being developed as strategies to improve the bioavailability of the two polyphenols." The one positive curcumin RCT utilized a solid lipid particle preparation to improve bioavailability; the one positive resveratrol trial used a formulation with quercetin to improve bioavailability; and many of the ongoing clinical trials evaluate curcumin and resveratrol formulations designed to provide greater bioavailability. It is anticipated that these ongoing studies will give a better picture of the neuroprotective and therapeutic potential of these two polyphenols.
The authors point out that the experimental evidence indicates that curcumin and resveratrol modulate pathways involved in the early stages of pathology before clinical symptoms appear, suggesting that they may be most useful in preventing or slowing down neurodegeneration. Looking forward, they emphasize the importance of establishing the optimum dose, improving bioavailability, ensuring sufficient plasma levels are achieved clinically, and using well-characterized, standardized preparations in clinical studies. "Furthermore, the potential preventive activity of curcumin and resveratrol should be evaluated in long-term exposure clinical trials … ." The authors declare no conflict of interest.
—Heather S. Oliff, PhD
