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

R Scott Turner, Ronald G Thomas, Suzanne Craft, Christopher H van Dyck, Jacobo Mintzer, Brigid A Reynolds, James B Brewer, Robert A Rissman, Rema Raman, Paul S Aisen, 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, R Scott Turner, Ronald G Thomas, Suzanne Craft, Christopher H van Dyck, Jacobo Mintzer, Brigid A Reynolds, James B Brewer, Robert A Rissman, Rema Raman, Paul S Aisen, 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

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.

© 2015 American Academy of Neurology.

Figures

Figure 1. Flow diagram and disposition of…
Figure 1. Flow diagram and disposition of the treatment groups
MMSE = Mini-Mental State Examination.
Figure 2. Effects of resveratrol on Aβ…
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…
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.

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.
    1. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012;16:706–722.
    1. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191–196.
    1. Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta 2015;1852:1114–1123.
    1. Patel NV, Gordon MN, Connor KE, et al. Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 2005;26:995–1000.
    1. Wang J, Ho L, Qin W, et al. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J 2005;19:659–661.
    1. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer's disease amyloid-β peptides. J Biol Chem 2005;280:37377–37382.
    1. Karuppagounder SS, Pinto JT, Xu H, et al. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic mouse model of Alzheimer's disease. Neurochem Int 2009;28:1393–1405.
    1. Hooper PL, Hooper PL, Tytell M, Vigh L. Xenohormesis: health benefits from an eon of plant stress response evolution. Cell Stress Chaperones 2010;15:761–770.
    1. Bastianetto S, Menard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta 2015;1852:1195–1201.
    1. Pasinetti GM, Wang J, Ho L, et al. Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment. Biochim Biophys Acta (in press 2015).
    1. Aguirre A, Fernandez-Quintela A, Aria N, Portillo MP. Resveratrol: anti-obesity mechanisms of action. Molecules 2014;19:18632–18655.
    1. Walle T, Hsieh F, DeLegge MH, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 2004;32:1377–1382.
    1. Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res 2010;54:7–16.
    1. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, et al. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharmacol Des 2013;19:6064–6093.
    1. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINDCS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984;34:939–944.
    1. Folstein MF, Folstein SE, McHugh PH. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
    1. Rosen WG, Terry RD, Fuld PA, et al. Pathological verification of ischemic score in differentiation of dementia. Ann Neurol 1980;7:586–588.
    1. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatr 1984;141:1356–1364.
    1. Galasko D, Kershaw PR, Schneider L, et al. Galatamine maintains ability to perform activities of daily living in patients with Alzheimer's disease. J Am Geriatr Soc 2004;52:1070–1076.
    1. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412–2414.
    1. Cummings LM, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2304–2314.
    1. Donohue MC, Moghadam SH, Roe AD, et al. Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials. Alzheimer's Dement Epub 2014 Oct 6.
    1. Brewer JB, Magda S, Airriess C, Smith ME. Fully-automated quantification of regional brain volumes for improved detection of focal atrophy in Alzheimer disease. AJNR Am J Neuroradiol 2009;30:578–580.
    1. Kovacevic S, Rafii MS, Brewer JB. High-throughput, fully automated volumetry for prediction of MMSE and CDR decline in mild cognitive impairment. Alzheimer Dis Assoc Disord 2009;23:139–145.
    1. Heister D, Brewer JB, Magda S, et al. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology 2011;77:1619–1628.
    1. Jovicich J, Czanner S, Greve D, et al. Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. Neuroimage 2006;30:436–443.
    1. Sled JG, Zijdenbos AP, Evans AC. A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 1998;17:87–97.
    1. Arnold JB, Liow JS, Schaper KA, et al. Qualitative and quantitative evaluation of six algorithms for correcting intensity nonuniformity effects. Neuroimage 2001;13:931–943.
    1. Fischl B, Salat DH, Busa E, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341–355.
    1. Holland D, Dale AM; the Alzheimer's Disease Neuroimaging Initiative. Nonlinear registration of longitudinal images and measurement of change in regions of interest. Med Image Anal 2011;15:489–497.
    1. Holland D, McEvoy LK, Dale AM. Unbiased comparison of sample size estimates from longitudinal structural measures in ADNI. Hum Brain Mapp 2012;33:2586–2602.
    1. Witte AV, Kerti L, Margulies DS, Floel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci 2014;34:7862–7870.
    1. Donmez G, Wang D, Cohen DE, Gaurente L. SIRT1 suppresses beta-amyloid production by activating the alpha secretase gene ADAM10. Cell 2010;142:320–332.
    1. Pallauf K, Rimbach G. Autophagy, polyphenols and healthy ageing. Ageing Res Rev 2013;12:237–252.
    1. Fox NC, Black RS, Gilman S, et al. Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005;64:1563–1572.
    1. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009;73:2061–2070.
    1. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370:322–333.
    1. Mercken EM, Mitchell SJ, Martin-Montalvo A, et al. SRT2014 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 2014;13:787–796.
    1. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related disease. Trends Pharmacol Sci 2014;35:146–154.

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