A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease
Raymond Scott TurnerFrom 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, SCRonald G. ThomasFrom 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, SCSuzanne CraftFrom 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, SCChristopher H. van DyckFrom 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, SCJacobo MintzerFrom 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, SCBrigid ReynoldsFrom 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, SCJames B. BrewerFrom 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, SCRobert A. RissmanFrom 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, SCRema RamanFrom 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, SCPaul Aisenthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTFor the Alzheimer's Disease Cooperative StudyFrom 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, SCAlzheimer's Disease Cooperative Studythe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCJacobo MintzerFrom 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, SCBrent A. ReynoldsFrom 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, SCJason Karlawishthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCDouglas GalaskoFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCJudith L. Heidebrinkthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCNeel Aggarwalthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCNeill R. Graff‐Radfordthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCMary Sanothe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCRonald C. Petersenthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTKatheryn A. BellRachelle S. Doodythe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCAlisha J SmithCharles Bernickthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCA. Porteinssonthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCPierre N. TariotRuth A. Mulnardthe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaA. Lernerthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCLuisa‐Sophie Schneiderthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTJane C. Burnsthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCMurray A. Raskindthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCSteven H. Ferristhe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaGregory A. Jichathe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCM. QuicenoFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCThomas O. Obisesanthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTPaul B. Rosenbergthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCDaniel Weintraubthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCKarl Kieburtzthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTBruce L. Millerthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCRichard J. KryscioG. Alexopoulis
2015en
ABI
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.
Identifiers
Citations and references
Cited by 20 references