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

doi:10.1212/WNL.0000000000002035

Clinical Trial

. 2015 Oct 20;85(16):1383-91.

doi: 10.1212/WNL.0000000000002035. Epub 2015 Sep 11.

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

Collaborators, Affiliations

Collaborators

Alzheimer's Disease Cooperative Study:
J Mintzer, B A Reynolds, J Karlawish, D Galasko, J Heidebrink, N Aggarwal, N Graff-Radford, M Sano, R Petersen, K Bell, R Doody, A Smith, C Bernick, A Porteinsson, P Tariot, R Mulnard, A Lerner, L Schneider, J Burns, M Raskind, S Ferris, G Jicha, M Quiceno, T Obisesan, P Rosenberg, D Weintraub, K Kieburtz, B Miller, R Kryscio, G Alexopoulis

Affiliations

¹ 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. rst36@georgetown.edu.
² 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.

PMID: 26362286
PMCID: PMC4626244
DOI: 10.1212/WNL.0000000000002035

Clinical Trial

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

R Scott Turner et al. Neurology. 2015.

. 2015 Oct 20;85(16):1383-91.

doi: 10.1212/WNL.0000000000002035. Epub 2015 Sep 11.

Collaborators

Alzheimer's Disease Cooperative Study:
J Mintzer, B A Reynolds, J Karlawish, D Galasko, J Heidebrink, N Aggarwal, N Graff-Radford, M Sano, R Petersen, K Bell, R Doody, A Smith, C Bernick, A Porteinsson, P Tariot, R Mulnard, A Lerner, L Schneider, J Burns, M Raskind, S Ferris, G Jicha, M Quiceno, T Obisesan, P Rosenberg, D Weintraub, K Kieburtz, B Miller, R Kryscio, G Alexopoulis

Affiliations

¹ 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. rst36@georgetown.edu.
² 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.

PMID: 26362286
PMCID: PMC4626244
DOI: 10.1212/WNL.0000000000002035

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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Figures

**Figure 1. Flow diagram and disposition of the treatment groups**
MMSE = Mini-Mental State Examination.

**Figure 2. Effects of resveratrol on Aβ levels**
Resveratrol altered levels of CSF Aβ40 (A) and plasma Aβ40 (B) (ng/mL, mean ± SE). Similar but nonsignificant trends were found for CSF Aβ42 (C) and plasma Aβ42 (D) (ng/mL, mean ± SE). Note difference in scales. Sample sizes are indicated.

**Figure 3. Effects of resveratrol on brain volume**
Resveratrol increased brain volume loss (A, C) (mL, mean ± SE) with a corresponding increase in ventricular volume (B, D) (mL, mean ± SE). Sample sizes are indicated.

See this image and copyright information in PMC

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References

1. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–392. - PubMed
1. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012;16:706–722. - PMC - PubMed
1. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191–196. - PubMed
1. Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta 2015;1852:1114–1123. - PubMed
1. Patel NV, Gordon MN, Connor KE, et al. Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 2005;26:995–1000. - PubMed

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[1] Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–392. - PubMed

[2] Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–392. - PubMed

[3] Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012;16:706–722. - PMC - PubMed

[4] Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012;16:706–722. - PMC - PubMed

[5] Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191–196. - PubMed

[6] Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191–196. - PubMed

[7] Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta 2015;1852:1114–1123. - PubMed

[8] Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta 2015;1852:1114–1123. - PubMed

[9] Patel NV, Gordon MN, Connor KE, et al. Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 2005;26:995–1000. - PubMed

[10] Patel NV, Gordon MN, Connor KE, et al. Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 2005;26:995–1000. - PubMed

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

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

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