Article

Oral curcumin for Alzheimer's disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

Alzheimer's Research and Therapy (Impact Factor: 3.98). 10/2012; 4(5):43. DOI: 10.1186/alzrt146
Source: PubMed

ABSTRACT

Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.
We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.
Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).
Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.
Trial registration
ClinicalTrials.gov Identifier: NCT00099710.

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    • "Previous studies have demonstrated protective actions of curcumin in a wide spectrum of neurodegenerative conditions (Epstein et al., 2010; Hickey et al., 2012; Wang et al., 2011). Moreover, researches emphasized curcumin ameliorating effects on cognitive deficit and neuropathology in different types of dementia (Khurana et al., 2012; Ringman et al., 2012). Although many studies have stressed the intrinsic apoptotic signaling mechanisms in association with cell death in AD, few studies have addressed the contribution of death receptor-initiated extrinsic apoptosis (Ferrer et al., 2001; Su et al., 2003; Yew et al., 2004). "
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    ABSTRACT: Erythropoietin and curcumin showed promising neuroprotective effects in various models of Alzheimer's dementia. This study was designed to compare the beneficial effects of erythropoietin and/or curcumin in intracerebro-ventricular (ICV) streptozotocin-induced Alzheimer's like disease in rats. Rats received ICV injection of either saline (control, n=8 rats), or streptozotocin. Three weeks following surgery, streptozotocin-injected rats were assigned into 4 groups (8 rats each); vehicle, curcumin (80mg/kg/day, orally), erythropoietin (500 IU/kg every other day, intraperitoneally) and combined (curcumin and erythropoietin)-treated groups. After 3 months of treatment, rats were subjected to neurobehavioral testing, and then killed for biochemical and histological assessment of hippocampus. Fas ligand protein and caspase-8 activity as mediators of extrinsic apoptotic pathway, oxidative stress markers (malondialdehyde and reduced glutathione) and β-amyloid (1-40 and 1-42) peptides were measured. The results showed that administration of erythropoietin suppressed extrinsic apoptosis better than curcumin, while curcumin was more effective in combating oxidative stress in ICV-streptozotocin injected rats. Both erythropoietin and curcumin treatments (individually or combined) equally reduced the hippocampal β-amyloid accumulation and improved cognitive impairment in Morris water maze and passive avoidance tasks. The combined treatment was the most effective in ameliorating apoptosis and oxidative stress rather than behavioral responses or β-amyloid burden. In conclusion, ICV-streptozotocin-induced Alzheimer's dementia activates hippocampal Fas ligand-mediated apoptosis, which could be reduced by erythropoietin and/or curcumin treatment. Curcumin supplementation alone could ameliorate cognitive deficits and reverse biochemical alterations in ICV-streptozotocin Alzheimer's rat model without the hazardous polycythemic effect of long-term erythropoietin injection.
    Full-text · Article · Dec 2015 · European journal of pharmacology
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    • "months patients with mild-to-moderate AD improvements in cognition Rogers et al. 1993 Diclofenac + Misoprostol N/A 25 weeks patients with mild-to-moderate AD no changes in cognition Scharf et al. 1999 Prednisone 20 then 10mg/d 4 weeks then 1 year patients with AD no beneficial changes in cognitive tests Aisen et al. 2000 Hydrochloroquine 200 or 400mg/d 18 months patients with early AD no cognitive/behavioural improvements van Gool et al. 2001 Nimesilude 100mg twice daily 24 weeks patients with probable AD no effect on cognition, clinical status or behaviour Aisen et al. 2002 Rofecoxib 25mg/d 12 months patients with mild-to-moderate AD no delay in cognitive decline Aisen et al. 2003 Naproxen 220mg twice daily 12 months patients with mild-to-moderate AD no delay in cognitive decline Aisen et al. 2003 Rofecoxib 25mg/d 12 months patients with mild-to-moderate AD no improvements in cognition and behaviour Reines et al. 2004 Rofecoxib 25mg/d up to 4 years patients with MCI no improvements in cognition Thal et al. 2005 Celecoxib 200mg twice daily up to 7 years people 70 years or older with family history of AD no improvements in cognitive functions Martin et al. 2008 Naproxen 220mg twice daily up to 7 years people 70 years or older with family history of AD no improvements in cognitive functions Martin et al. 2008 Corticosteroids Estradiol 2mg/d 6 weeks women with senile dementia AD type improvements in cognition and mood in 3/7 women Fillit et al. 1986 Estrogen 1.25mg/d 16 weeks women with mild-to-moderate AD no improvements in cognition or mood Henderson et al. 2000 Curcumin Curcumin 1 or 4g/d 6 months patients with probable AD probable slower decline in cognition Baum et al. 2008 Curcumin C3 Complex 2 or 4g/d 24 weeks patients with mild-to-moderate AD no difference in clinical or biomarker efficacy measures Ringman et al. 2012 Ginkgo biloba EGb 761 240mg/d 24 weeks outpatients with presenile and senile AD better cognition and activities of daily living Kanowski et al. 1997 EGb 761 240mg/d 3 months patients wit mild-to-moderate AD better attention and memory Maurer et al. 1997 EGb 761 120mg/d 52 weeks outpatients with mild to severe AD better cognition and daily living Le Bars et al. 1997 EGb 761 120 or 240mg/d 26 weeks patients with AD no convincing differences in cognition Schneider et al. 2005 "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Bio- and histochemical evidence suggests a pivotal role of central and peripheral inflammation in its aetiopathology, linked to the production of free radicals. Numerous epidemiological studies support that the long-term use of non-steroidal anti-inflammatory drugs is preventive against AD, but these medications do not slow down the progression of the disease in already diagnosed patients. There are a number of studies focusing on traditional herbal medicines and small molecules (usually plant secondary metabolites) as potential anti-inflammatory drugs, particulary in respect to cytokine suppression. For instance, ω-3 polyunsaturated fatty acids and a number of polyphenolic phytochemicals have been shown to be effective against inflammation in animal and cell models. Some of these plant secondary metabolites have also been shown to possess antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects. This review will overview the the effects of catechins/proanthocyanidins from green tea, curcumin from turmeric, extracts enriched in bacosides from Brahmi, Ginkgo flavone glycosides, and ω-3 polyunsaturated fatty acids not only counteract one pathophysiological aspect of AD in numerous in vitro and in vivo studies of models of AD, but also ameliorate several of the above mentioned pathologies. The evidence suggests that increased consumption of these compounds might lead to a safe strategy to delay the onset of AD. The continuing investigation of the potential of these substances is necessary as they are promising to yield a possible remedy for this pervasive disease.
    Full-text · Article · Sep 2014 · CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders)
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    • "A 6-month RCT performed in patients with AD showed no beneficial results in cognitive performances (Baum et al., 2008). More recently, a randomized clinical trial with Curcumin C3 Complex -consisting of 95% curcuminoids with 70–80% comprised by curcumin, 15–25% demethoxycurcumin, and 2.5–6.5% bisdemethoxycurcumin-was conducted in mild to moderate AD with no evident benefit on cognitive functions (Ringman et al., 2012). "
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    ABSTRACT: Several chemical substances belonging to classes of natural dietary origin display protective properties against some age-related diseases including neurodegenerative ones, particularly Alzheimer's disease (AD). These compounds, known as nutraceuticals, differ structurally, act therefore at different biochemical and metabolic levels and have shown different types of neuroprotective properties. The aim of this review is to summarize data from observational studies, clinical trials, and randomized clinical trials (RCTs) in humans on the effects of selected nutraceuticals against age-related cognitive impairment and dementia. We report results from studies on flavonoids, some vitamins and other natural substances that have been studied in AD and that might be beneficial for the maintenance of a good cognitive performance. Due to the substantial lack of high-level evidence studies there is no possibility for recommendation of nutraceuticals in dementia-related therapeutic guidelines. Nevertheless, the strong potential for their neuroprotective action warrants further studies in the field.
    Full-text · Article · Jun 2014 · Frontiers in Pharmacology
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