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      Is Open Access

      A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease

      , MD, PhD, , PhD, , PhD, , MD, , MD, , NP, , MD, PhD, , PhD, , PhD, , MD For the Alzheimer's Disease Cooperative Study

      (Collab), , MD (Collab), , NP (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , PhD (Collab), , MD, PhD (Collab), , MD (Collab), , MD, PhD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , PhD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , PhD (Collab), , MD, PhD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , MD (Collab), , PhD (Collab), , MD. (Collab)

      Neurology

      Lippincott Williams & Wilkins

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          Abstract

          Objective:

          A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).

          Methods:

          Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.

          Results:

          Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.

          Conclusions:

          Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood–brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.

          Classification of evidence:

          This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

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          Most cited references 19

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          Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

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            High absorption but very low bioavailability of oral resveratrol in humans.

            The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.
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              Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides.

              Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease.
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                20 October 2015
                20 October 2015
                : 85
                : 16
                : 1383-1391
                Affiliations
                From the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DC; the Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La Jolla; the Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NC; the Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CT; and the Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SC.
                Author notes
                Correspondence to Dr. Turner: rst36@ 123456georgetown.edu

                Coinvestigators are listed on the Neurology® Web site at Neurology.org.

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by NIH.

                Article
                NEUROLOGY2015640441
                10.1212/WNL.0000000000002035
                4626244
                26362286
                © 2015 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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