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Turner
RS, Thomas RG, Craft S, et al.; for the Alzheimer's
Disease Cooperative Study. A randomized, double-blind, placebo-controlled trial
of resveratrol for Alzheimer disease. Neurology.
2015;85(16):1383-1391.
Resveratrol
is a polyphenol that is a plant response to stress found in the skin of red
grapes (Vitis vinifera, Vitaceae) and several types of berries and peanuts (Arachis hypogaea, Fabaceae). In animal
models of Alzheimer's disease (AD), resveratrol may reduce some age-related
effects. The purpose of this randomized, placebo-controlled, double-blind,
multicenter, phase 2 trial was to evaluate the effects of resveratrol in
patients with mild to moderate AD. The primary objectives were to assess
resveratrol (1) safety and tolerability, (2) effects on AD biomarkers, and (3)
pharmacokinetics. Secondary objectives were to examine (1) effects on clinical
cognitive, functional, and behavioral parameters; (2) the influence of
apolipoprotein E (APOE) genotype; and (3) effects on insulin and glucose
metabolism.
Patients
(n = 119, aged > 49 years) with a diagnosis of probable AD by the National
Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's
Disease and Related Disorders Association criteria were recruited from 26 US
academic clinics affiliated with the Alzheimer's Disease Cooperative Study
(ADCS). The trial was conducted from June 2012 to March 2014. Inclusion
criteria included a Mini-Mental State Examination (MMSE) score of 14-26 at
screening, modified Hachinski Score < 5, normal laboratory values, stable
medications for 4 months, and stable use of cholinesterase inhibitors or
memantine. Excluded patients had non-AD dementia, Down syndrome, sensory
impairments precluding participation, pregnancy, contraindication to lumbar
puncture or magnetic resonance imaging (MRI), microhemorrhages on a recent MRI,
diabetes mellitus, were using resveratrol-containing supplements, or had an unsuitable
disorder or laboratory finding.
Patients
received placebo or resveratrol (synthesized and encapsulated by Aptuit Laurus,
Inc.; Kansas City, Missouri [now Catalent, Inc.; Somerset, New Jersey]) for 52
weeks. The dose of resveratrol was escalated by 500 mg every 13 weeks, starting
with 500 mg/day and ending with 2000 mg/day. Study visits occurred at
screening, baseline, and weeks 6, 13, 19, 26, 32, 39, 45, and 52. Each visit
included a review of concomitant medications and adverse events (AEs), physical
and neurological examinations, urinalysis, pill count, and blood collections
for laboratory, biomarker, and pharmacokinetic analyses. Brain MRIs to measure
brain volume were obtained at baseline and weeks 13 and 52. Electrocardiograms
(ECGs), cerebrospinal fluid (CSF) collections, and oral glucose tolerance tests
were conducted at baseline and week 52. A subgroup of 15 patients participated
in the 24-hour pharmacokinetic studies at each dosage (first dose at baseline
and weeks 13, 26, 39, and 52) wherein the plasma and CSF levels of resveratrol,
3-O-glucuronidated-resveratrol (3G-RES), 4-O-glucuronidated-resveratrol
(4G-RES), and 3-sulfated-resveratrol (S-RES) were analyzed. Clinical parameters
were measured with the MMSE, Alzheimer's
Disease Assessment Scale-cognitive (ADAS-cog), ADCS Activities of Daily Living
Scale (ADCS-ADL), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and
Neuropsychiatric Inventory (NPI).
The
AD biomarkers assessed included plasma and CSF levels of amyloid beta 42 (Aβ42),
Aβ40, tau, and phospho-tau 181. CSF and plasma decreases in Aβ42 are associated
with an increase in AD; the lower the Aβ42/Aβ40 ratio, the greater the cognitive
decline. Phospho-tau is associated with the pathogenesis of AD. An increase in
tau is associated with AD progression. Therefore, stabilization or an increase
in Aβ42 and Aβ42/Aβ40 ratio, and a decrease in tau and phospho-tau are considered
bioindicators of treatment benefit.
A
total of 104 patients completed the study, and 77 patients completed 2 CSF
collections. The placebo group had a longer duration of AD; otherwise, all
baseline characteristics were similar between groups. In regard to safety, there
were no significant differences between groups for vital signs, physical
examination, or neurologic examination. At least 1 AE was reported by 95% of
patients. The most commonly reported AEs were nausea and diarrhea, but the
incidence was not significantly different between groups. There were 36 serious
AEs, including death, but none were considered treatment-related. Body weight
and body mass index decreased in the resveratrol group and increased in the
placebo group (P < 0.05); this is considered an adverse effect. The pharmacokinetic
results confirmed treatment compliance and proved that resveratrol could cross
the blood-brain barrier because resveratrol and its metabolites were found in
the CSF.
At
study end, the decline in CSF Aβ40 was significantly less in the resveratrol
group than in the placebo group (P = 0.002). This difference was found in both
APOE4 carriers (P = 0.05) and non-carriers (P = 0.01). There was no significant
effect on Aβ42, but the trend was similar to Aβ40 (P = 0.08); subgroup analyses
showed a significant treatment effect in APOE4 carriers (P = 0.04) but not in non-carriers.
There was no significant effect on CSF tau or phospho-tau 181. Brain volume
significantly decreased (P = 0.025) and ventricle volume significantly increased
(P = 0.05) in the resveratrol group compared to the placebo group. Brain volume
decreased with treatment in APOE4 carriers (P = 0.02) but not in non-carriers. The
authors point out that "the etiology and interpretation of brain volume
loss observed here and in other studies are unclear, but they are not
associated with cognitive or functional decline." The study was
statistically underpowered to detect significant changes in clinical outcomes.
Accordingly, no significant changes in CDR-SOB, ADAS-cog, MMSE, or NPI scores
were detected; however, the resveratrol group had significantly less decline in
ADCS-ADL compared with placebo (P = 0.03). There was no effect on plasma
glucose or insulin metabolism.
The
authors conclude that resveratrol is safe, well tolerated, and alters some AD
biomarkers. The study showed that resveratrol and its metabolites can pass the
blood-brain barrier, and the biomarker changes suggest central nervous system effects.
However, the authors point out these results must be interpreted with caution as
they do not provide evidence of therapeutic benefit. Limitations of the study include
that it was not sufficiently powered to determine clinical efficacy and that
the placebo group had a longer duration of AD.
—Heather S. Oliff,
PhD | ||||||||||||||||||||||||||||||
Friday, 8 July 2016
Re: Phase 2 Trial Finds Resveratrol Safe and Well Tolerated in Patients with Alzheimer's Disease
