Clinical trial NCT01383161
Conditions: Age-associated Cognitive Impairment Mild Cognitive Impairment (MCI)
Keywords: Curcumin Turmeric Memory Cognitive Impairment Brain Imaging Supplement
Sponsor: University of California, Los Angeles
Start date: 2012-03-01; Completion date: 2017-04-01
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This project is designed to study the effects of the dietary supplement curcumin on age-related cognitive impairment. In particular, the study seeks to determine the effects of curcumin on cognitive decline and the amount of abnormal amyloid protein in the brain. Genetic risk will also be studied as a potential predictor of cognitive decline.

Subjects will be randomly assigned to one of two treatment groups: either a placebo twice daily or the curcumin supplement (Theracurmin®, containing 90 mg of curcumin). The investigators expect that the volunteers receiving the curcumin supplement will show less evidence of decline after 18 months than those receiving the placebo. The investigators predict that cognitive decline and treatment response will vary according to genetic risk for Alzheimer's.

The investigators will study subjects with memory complaints aged 50-90 years. Initially, subjects will undergo a clinical assessment, an MRI and a blood draw to determine genetic risk and to rule out other neurodegenerative disorders linked to memory complaints. Subsequently, subjects will undergo an -(1-{6-\[(2-\[F-18\]fluoroethyl)(methyl)amino\]-2-naphthyl}ethylidene)malononitrile (FDDNP) PET scan and a baseline neuropsychological assessment to confirm a diagnosis of MCI or normal aging. Once enrolled, subjects will begin taking the supplement (either curcumin or a placebo). Some of the initial subjects will be asked to return every three months for regular MRIs. Every 6 months, subjects will also receive neuropsychological assessments. At the conclusion of the study, subjects will be asked to complete a final neuropsychological assessment, MRI scan, PET scan and blood draw. Additional blood will be drawn at baseline and at 18 months and frozen to assess inflammatory markers if cognitive outcomes are positive.

FDDNP-PET scans will be used to measure the amount of abnormal amyloid plaque- and tau tangle-proteins in the brain; the MRIs will be used to monitor supplement side effects and measure brain structure; the neuropsychological assessments will monitor rates of cognitive decline; the blood draws will be used to determine genetic risk and to test levels of inflammatory markers.

Detailed description:
Several lines of evidence suggest that the neuropathological and clinical decline leading to Alzheimer disease (AD) begins years before patients develop the full AD clinical syndrome (NINCDS-ADRDA diagnostic criteria; McKhann et al, 1984). Mild memory complaints build gradually years before patients develop dementia. The neuropathological hallmarks of AD, "preclinical" neuritic plaques (Braak \& Braak, 1991) and neurofibrillary tangles (Price \& Morris, 1999), are also present years prior to clinical diagnosis. These abnormal protein deposits correlate strongly with cognitive decline.

Preclinical amyloid deposits may begin decades prior to dementia onset. In fact, diffuse plaques in non-demented elderly persons are associated with an accelerated age-related cortical cholinergic deficit, consistent with preclinical AD (Beach et al, 1997; Arai et al, 1999). Also consistent with a prolonged preclinical disease stage is our own work showing that position emission tomography (PET) measures of cerebral glucose metabolism vary according to AD genetic risk (apolipoprotein E-4 \[APOE-4\]) and predict cerebral metabolic and cognitive decline in people with mild cognitive complaints (age-associated memory impairment \[AAMI\]; Small et al, 2000). Such observations have stimulated interest in preclinical AD markers or biomarkers of brain aging that may assist in tracking treatments of AAMI and related conditions. New PET imaging methods now make it possible to provide in vivo measures of cerebral amyloid neuritic plaques (e.g., florbetapir-PET; Clarke et al, 2011) and tau neurofibrillary tangles (e.g. FDDNP-PET; Small et al, 2006, 2009).

Despite these previous research findings, clinical trials (including those using biomarkers as response measures) and subsequent treatment recommendations have been limited to patients with the full clinical dementia syndrome or mild cognitive impairment (MCI), a condition that increases the risk for developing dementia (Petersen et al, 2001). Cholinesterase inhibitors are currently the only drugs that have FDA clearance for treatment of AD, but previous studies (e.g., Ringman et al, 2005) suggest that other interventions, such as dietary or herbal supplements, may benefit cognition, and possibly interrupt the accumulation of abnormal amyloid protein deposits in the brain. For example, curcumin (diferulomethane), a low molecular weight molecule with antioxidant and anti-inflammatory activities that is derived from dietary spice, may have both cognitive-enhancing and anti-amyloid properties (Ringman et al, 2005; Yang et al, 2005).

To address such issues, the investigators propose to build upon our group's previous longitudinal brain imaging and genetic risk studies in people with age-related memory decline. Because previous studies suggest that curcumin may improve cognitive ability and prevent the build-up of age-associated plaques and tangles in the brain, the investigators will perform a double-blind, placebo-controlled trial of curcumin to test the following hypotheses:

1. People with age-related cognitive decline (i.e., MCI, AAMI or normal aging),, who receive curcumin 90 mg twice each day will show less evidence of cognitive decline (as measured with neuropsychological assessments) than those receiving placebo after 18 months.
2. People with age-related cognitive decline who receive an oral dose of curcumin 90 mg twice each day will show less build-up of plaques and tangles (as measured with FDDNP-PET imaging) than those receiving placebo after 18 months.
3. People with age-related cognitive decline, who receive curcumin 90 mg twice each day, will show decreased measures of inflammation in the blood compared with those receiving placebo after 18 months.
4. Cognitive change, FDDNP-PET measures, and treatment response will vary according to genotypes found to influence age at dementia onset (e.g., apolipoprotein E \[APOE\] TOMM40).

Because curcumin may alter inflammatory markers in the blood, the investigators will draw blood samples at baseline and at 18 months and freeze them for later analyses.

To test theses hypotheses, subjects with age-related cognitive decline will be enrolled (Crook et al, 1986; Petersen et al, 2001). Subjects will be randomized, using a double-blind design, to one of two treatment groups: curcumin (three 30 mg capsules twice each day) or placebo, and followed for 18 months. FDDNP-PET scanning will be performed at baseline and at 18 months. Magnetic resonance imaging (MRI) scans also will be performed for co-registration of PET and assistance in identifying regions of interest. Neuropsychological assessments will be performed at baseline, 6 months, 12 months and at the conclusion of the clinical trial (18 months). Blood will be drawn at baseline to perform genotyping.

Arms: arm 1: Theracurmin (180mg/day) arm 2: Sugar Pill
Interventions: intervention 1: Curcumin intervention 2: Placebo
Intervention descriptions: intervention 1: Six Theracurmin capsules (containing 30 mg of curcumin each) per day for 18 months. intervention 2: Six capsules per day for 18 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
Official Title: 18-Month Double-Blind, Placebo-Controlled Study of Curcumin 
NCT Number: NCT01383161 
Document Date: December 2, 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


18-Month Study of Curcumin  
Page 1 
 
Protocol for 18-Month Double-Blind, Placebo-Controlled Study of Curcumin 
 
Specific Aims  
 
Several lines of evidence suggest that the neuropathological and clinical decline leading to 
Alzheimer disease (AD) begins years before patients develop the full AD clinical syndrome 
(NINCDS-ADRDA diagnostic criteria; McKhann et al, 1984). Mild memory complaints build 
gradually years before patients develop dementia. The neuropathological hallmarks of AD, 
“preclinical” neuritic plaques (Braak & Braak, 1991) and neurofibrillary tangles (Price & Morris, 
1999), are also present years prior to clinical diagnosis. These abnormal protein deposits 
correlate strongly with cognitive decline.  
 
Preclinical amyloid deposits may begin decades prior to dementia onset. In fact, diffuse 
plaques in non-demented elderly persons are associated with an accelerated age-related 
cortical cholinergic deficit, consistent with preclinical AD (Beach et al, 1997; Arai et al, 1999).  
Also consistent with a prolonged preclinical disease stage is our own work showing that 
position emission tomography (PET) measures of cerebral glucose metabolism vary according 
to AD genetic risk (apolipoprotein E-4 [APOE-4]) and predict cerebral metabolic and cognitive 
decline in people with mild cognitive complaints (age-associated memory impairment [AAMI]; 
Small et al, 2000).  Such observations have stimulated interest in preclinical AD markers or 
biomarkers of brain aging that may assist in tracking treatments of AAMI and related 
conditions.  New PET imaging methods now make it possible to provide in vivo measures of 
cerebral amyloid neuritic plaques (e.g., florbetapir-PET; Clarke et al, 2011) and tau 
neurofibrillary tangles (e.g. FDDNP-PET; Small et al, 2006, 2009). 
 
Despite these previous research findings, clinical trials (including those using biomarkers as 
response measures) and subsequent treatment recommendations have been limited to 
patients with the full clinical dementia syndrome or mild cognitive impairment (MCI), a 
condition that increases the risk for developing dementia (Petersen et al, 2001). 
Cholinesterase inhibitors are currently the only drugs that have FDA clearance for treatment of 
AD, but previous studies (e.g., Ringman et al, 2005) suggest that other interventions, such as 
dietary or herbal supplements, may benefit cognition, and possibly interrupt the accumulation 
of abnormal amyloid protein deposits in the brain. For example, curcumin (diferulomethane), a 
low molecular weight molecule with antioxidant and anti-inflammatory activities that is derived 
from dietary spice, may have both cognitive-enhancing and anti-amyloid properties (Ringman 
et al, 2005; Yang et al, 2005).  
 
To address such issues, we propose to build upon our group’s previous longitudinal brain 
imaging and genetic risk studies in people with age-related memory decline. Because previous 
studies suggest that curcumin may improve cognitive ability and prevent the build-up of age-
associated plaques and tangles in the brain, we will perform a double-blind, placebo-controlled 
trial of curcumin to test the following hypotheses: 
 
1. People with age-related cognitive decline (i.e., MCI, AAMI or normal aging),, who 
receive curcumin 90 mg twice each day will show less evidence of cognitive decline (as 
measured with neuropsychological assessments) than those receiving placebo after 18 
months. 
2. People with age-related cognitive decline who receive an oral dose of curcumin 90 mg 
twice each day will show less build-up of plaques and tangles (as measured with 
FDDNP-PET imaging) than those receiving placebo after 18 months. 
3. People with age-related cognitive decline, who receive curcumin 90 mg twice each 
day, will show decreased measures of inflammation in the blood compared with those 
receiving placebo after 18 months. 
4. Cognitive change, FDDNP-PET measures, and treatment response will vary according 
to genotypes found to influence age at dementia onset (e.g., apolipoprotein E [APOE] 
TOMM40). 
 
Because curcumin may alter inflammatory markers in the blood, we will draw blood samples at 
baseline and at 18 months and freeze them for later analyses.  


18-Month Study of Curcumin  
Page 1 
 
To test theses hypotheses, up to 132 subjects, with age-related cognitive decline will be 
enrolled (Crook et al, 1986; Petersen et al, 2001). Subjects will be randomized, using a 
double-blind design, to one of two treatment groups: curcumin (three 30 mg capsules twice 
each day) or placebo, and followed for 18 months. FDDNP-PET scanning will be performed at 
baseline and at 18 months.  Magnetic resonance imaging (MRI) scans also will be performed 
for co-registration of PET and assistance in identifying regions of interest.  Neuropsychological 
assessments will be performed at baseline, after 9 months of treatment and at the conclusion 
of the clinical trial (18 months).  Blood will be drawn at baseline to perform genotyping. 
 
Background and Significance  
 
Prevalence and Impact of Age-Related Memory Loss 
Forgetfulness and memory loss are common experiences of aging. The mildest form of age-
related memory decline is known as age-associated memory impairment or AAMI (Crook et al, 
1986). Only about 1% of such cases develop dementia each year. A more severe form of 
memory loss is mild cognitive impairment or MCI, often defined by significant declines in 
delayed recall but without other functional impairments. Approximately 10% of people 65 
years or older suffer from MCI, and approximately 10% develop AD each year (Petersen et al, 
2001). More severe forms of cognitive impairment, such as AD, afflict between 5% and 10% 
in this same age group and account for the most striking rise in dementia incidence in the very 
old (Small et al, 1997). The disorder progresses gradually, altering memory, higher intellectual 
function, language, praxis, and visual-spatial and other cognitive abilities. Patients eventually 
become bedridden and require total care. Neuropathological characteristics include neuritic 
plaques, neurofibrillary beta-amyloid peptide tangles, neuronal and neuritic damage and 
excessive deposition. 
 
Neuropathological Changes in Non-Demented Persons 
Neuropathological, neuroimaging, and clinical research support the idea that the dementing 
process leading to AD begins years before a clinical diagnosis of probable AD can be confirmed 
(McKhann et al, 1984). Post-mortem studies of non-demented older people (Price & Morris, 
1999) indicate that tangle density in healthy aging correlates with age, but that some cases 
demonstrate widely distributed neuritic and diffuse plaques throughout neocortex and limbic 
structures. This preclinical AD group also shows increased tangles. Braak and Braak (1991) 
have shown that neurofibrillary tangle density increases in some individuals, presumably those 
who will eventually develop AD, very early in adult life, perhaps even by the fourth decade. 
The diffuse amyloid deposits in middle-aged non-demented subjects are consistent with an 
early stage of AD pathology and suggest that the pathological process progresses gradually, 
taking 20 to 30 years for the clinical manifestation of dementia (Arai et al, 1999). Beach and 
co-workers (1997) found high diffuse plaque density in non-demented older persons in the 
entorhinal cortex and inferior temporal gyrus, in association with acetylcholinesterase fiber 
density. Our studies (Small et al, 1995, 2000), confirmed by others (Reiman et al, 1996), 
indicate lower regional brain metabolism in middle-aged and older persons with a genetic risk 
(APOE-4), lending further support for a prolonged presymptomatic AD stage. 
 
Early Detection Measures  
Numerous approaches to early detection of AD have been studied, including antemortem 
measures from various human tissues (skin, blood, and cerebrospinal fluid), brain imaging, 
and neuropsychological performance (Reagan Institute, 1998). For this project, FDDNP-PET 
will be used to measure binding of amyloid neuritic plaques (NPs) and neurofibrillary tangles 
(NFTs). 
 
FDDNP-PET Scan 
We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic 
and psychiatric evaluation and PET. On the basis of cognitive testing, 25 volunteers were 
classified as having AD, 28 as having MCI, and 30 as having no cognitive impairment (healthy 
controls). PET was performed after injection FDDNP.  All subjects also underwent 2-deoxy-2-
[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent MRI.  Global values for FDDNP-PET 
binding (average of the values for the temporal, parietal, posterior cingulate, and frontal 
regions) were lower in the control group than in the group with mild cognitive impairment 


18-Month Study of Curcumin  
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(P<0.001), and the values for binding in the group with mild cognitive impairment were lower 
than in the group with Alzheimer’s disease (P<0.001). FDDNP-PET binding differentiated 
among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI.  We 
concluded that FDDNP-PET scanning can differentiate persons with MCI from those with AD 
and those with no cognitive impairment. This technique is potentially useful as a noninvasive 
method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary 
tangles. 
 
In another study (Small et al, 2009) we assessed a volunteer sample of 76 middle-aged and 
older persons without dementia (mean age, 67 years) including 36 with mild cognitive 
impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers.  For all regions 
studied, cognitive status was associated with increased FDDNP binding (P<.02 to .005). Older 
age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 
demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment 
group, age was associated with increased medial and lateral temporal FDDNP binding, and 
APOE-4 carriers had higher medial temporal binding than noncarriers.  We concluded that 
impaired cognitive status, older age, and APOE-4 carrier status are associated with increased 
brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and 
postmortem studies associating these risk factors with amyloid plaque and tau tangle 
accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and 
cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-
PET. 
 
Curcumin  
Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry 
powder), has been used for centuries as a treatment for inflammatory diseases. Extensive 
research within the past two decades has shown that curcumin mediates its anti-inflammatory 
effects through the down-regulation of inflammatory transcription factors, enzymes and 
cytokines (Aggarwal & Sung, 2009).   
 
Research also has focused on the potential cognitive and anti-amyloid benefits of the curry 
spice curcumin (Ringman et al, 2005). Prepared from the turmeric plant, curcumin has been 
taken orally as a remedy for a variety of ailments, ranging from dyspepsia to liver disease. 
Recent studies have found it to be well tolerated.  Yang and associates (2005) have found that 
curcumin inhibits the formation of amyloid beta oligomers and fibrils and that it binds to 
plaques and reduces amyloid in vivo. Curcumin also has potential cholesterol-lowering and 
anti-inflammatory properties, which could further benefit brain health (Ringman et al, 2005). 
Curcumin has the capacity to bind amyloid plaques and possibly prevent their aggregation and 
thus the potential to alter FDDNP binding values in normal aging and patients with MCI.  
 
In a study in patients with high-risk or pre-malignant lesions (Cheng et al, 2001), curcumin 
was taken orally for 3 months with a starting dose of 500 mg/day. If no toxicity was observed, 
then the dose was escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 
12,000 mg/day. The concentration of curcumin in serum and urine was determined by high 
pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. 
There was no treatment-related toxicity up to 8,000 mg/day.  Beyond 8,000 mg/day, the 
bulky volume of the drug was unacceptable to the patients. The serum concentration of 
curcumin usually peaked at 1 to 2 hours after oral intake of curcumin and gradually declined 
within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 
8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 
microM, respectively. Urinary excretion of curcumin was undetectable. The investigators 
concluded that curcumin was not toxic to humans up to 8,000 mg/day when taken by mouth 
for 3 months (Cheng et al, 2001).  
 
In a phase I clinical trial of oral curcumin (Sharma et al, 2004), 15 patients with advanced 
colorectal cancer consumed 0.45 to 3.6 grams daily for up to 4 months.  Patients tolerated 
daily oral doses of 3.6 grams, which the authors advocated for evaluation of cancer prevention 
treatments. 
 


18-Month Study of Curcumin  
Page 1 
 
In order to improve absorption and bioavailability of curcumin, curcumins dispersed with 
colloidal nanoparticles have been developed.  The form of curcumin to be used in the proposed 
study (Theracurmin) is such a nanoparticle form.  Dose-escalation, safety, and 
pharmacokinetic studies of Theracurmin have been performed at Kyoto University Hospital in 
Japan (Kanai et al, 2011). Theracurmin was studied in 6 healthy human volunteers at a single 
oral dose of 150 mg.  After an interval of 2 weeks, the same subjects then received 
Theracurmin at a single dose of 210 mg. Plasma curcumin levels were measured at 0, 1, 2, 4, 
6, and 24 hours after Theracurmin intake using HPLC.  One subject reported grade 1 diarrhea 
after intake of 150 mg Theracurmin. No other toxicities were observed. C (max) for 
Theracurmin at 150 and 210 mg was 189 ± 48 and 275 ± 67 ng/ml (mean ± SEM), 
respectively, and the area under the curve for 24 h was estimated to be 2,649 ± 350 and 
3,649 ± 430 ng/ml × h (mean ± SEM), respectively. The t (1/2) was estimated to be 9.7 ± 
2.1 h for 150 mg and 13.0 ± 3.3 h for 210 mg.  The investigators concluded that Theracurmin 
can safely increase plasma curcumin levels in a dose-dependent manner at least up to 210 mg 
without saturating the absorption system. 
 
The absorption efficacy of this form of curcumin has been compared with that of curcumin 
powder (Sasaki et al, 2011). Healthy human volunteers were administered orally 30 mg 
Theracurmin or curcumin powder. The area under the curve of Theracurmin was 27-fold higher 
than that of curcumin powder.  Because of this higher potential absorption, we will be using 
much lower doses of Theracurmin (180 mg daily) compared with that found to be tolerable 
using standard curcumin oral preparations (3,600 to 8,000 mg daily).  Although systemic 
human safety studies provide data for only 4 months of treatment and the proposed study is 
for 18 months, we will be monitoring subjects every 3 months for safety, tolerability and 
emergence of adverse events. 
 
Other Safety and Dosage Considerations 
Theracurmin exhibits pharmacological safety based on trials in humans demonstrating the 
bioavailability of single doses and clinical trials using curcumin in both animals and humans. 
The absorption of curcumin into the blood has been documented previously (Anand et al, 
2007).
 
 Curcumin has low bioavailability due to its poor water solubility and absorption, rapid 
metabolism, and rapid systemic elimination. A study by Yang and associates (2007)
 
showed 
that 10 mg/kg of curcumin given intravenously to rats yielded a maximum serum curcumin 
level of 0.36±0.05 μg/mL, whereas 500 mg/kg of curcumin administered orally only yielded a 
0.06±0.01-μg/mL maximum serum level in rats. The absorption of curcumin in this study was 
only about 1%. A number of delivery strategies, including adjuvants, nanoparticles, liposomes, 
micelles, and phospholipid complexes, have been explored to enhance the intestinal 
absorption of curcumin (3-7).
  
Sharma and colleagues (2001)
 
showed that there was no 
detectable curcumin or its metabolites in the blood or urine after the administration of 440–
2,200 mg of curcuma extract per day (containing 36–180 mg of curcumin) for up to 29 days 
to patients with advanced colorectal cancer. Cheng and co-workers (2001) demonstrated that 
the peak concentrations of curcumin in the serum after administration of 4, 6, and 8 g of 
curcumin (given in the form of tablets obtained from a commercial source, with each tablet 
containing 500 mg curcumin) were 0.51, 0.64, and 1.77 mM, respectively. Moreover, these 
investigators found that doses below 4 g were barely detectable. Lao et al. (2006) could not 
detect curcumin in the serum of volunteers given 0.5, 1.0, 2.0, 4.0, 6.0, or 8.0 g of curcumin. 
This was provided in a capsule form as a standardized powder extract, obtained commercially, 
containing a minimum 95% concentration of the three curcuminoids of curcumin, 
bisdemethoxycurcumin, and demethoxycurcumin. However, these authors found that 
curcumin levels reached 50.5 and 51.2 ng/ml sera by 4 hours in 2 subjects administered 10 
and 12 g of curcumin, respectively. 
 
The safety and pharmacokinetics of the preparation to be used in the proposed studies 
(Theracurmin) was tested in six healthy human volunteers. Following single oral doses of 150 
mg and 210 mg respectively separated by a two week washout period, plasma curcumin levels 
were measured at 0, 1, 2, 4, 6, and 24 h after Theracurmin intake using high performance 
liquid chromatography (HPLC) (see figure below) . One subject reported grade 1 diarrhea after 
intake of 150 mg of Theracurmin. No other toxicities were observed in this study. Cmax for 
Theracurmin at 150 mg and 210 mg was 189 ± 48 and 275 ± 67 ng/ml (mean ± S.E.M.), 


18-Month Study of Curcumin  
Page 1 
 
respectively and the area under the curve for 24 h was estimated to be 2649 ± 350 and 3649 
± 430 ng/ml × h (mean ± S.E.M.).  
 
The absorption efficacy of this form of curcumin has been compared with that of curcumin 
powder (Sasaki et al, 2011). Healthy human volunteers were administered orally 30 mg 
Theracurmin or curcumin powder. The area under the curve of Theracurmin was 27-fold higher 
than that of curcumin powder.  Because of this higher potential absorption, we will be using 
much lower doses of Theracurmin (180 mg daily) compared with that found to be tolerable 
using standard curcumin oral preparations (3,600 to 8,000 mg daily).  Although systemic 
human safety studies provide data for only 4 months of treatment and the proposed study is 
for 18 months, we will be monitoring subjects every 3 months for safety, tolerability and 
emergence of adverse events. 
 
 
 
Figure 1: Plasma curcumin level in ng/ml following single doses of  150 or 210 mg of 
Theracurmin in healthy volunteers.  
 
 
Research Design and Methods  
 
The study is a double-blinded, randomized clinical trial.  Subjects, investigators, 
psychometrists and research coordinators will be blinded to the type of supplement (curcumin 
versus placebo).  
 
Theravalues Corporation will compound the study drug under the name of “Theracurmin,” 
packaged in 465 milligram capsules, 30 of which are curcumin. The capsules will be provided 
to the UCLA Investigational Drug Pharmacy for dispensation.  The company will also provide 
placebo capsules.  The capsules will be labeled as A or B by the manufacturer. 
 
Subjects in all portions of the study will have the procedures outlined below.  
The following procedures are performed solely for research purposes. 
 
Visit 1 (Intake):  
2 hours total 
• 
Informed Consent and Clinical Assessment (1 hour) 


18-Month Study of Curcumin  
Page 1 
 
• 
Routine Laboratory Blood Draw, DNA Blood Draw and Electrocardiogram (EKG) (1 
hour) 
 
Visit 2 (Baseline): 
4.5 hours total 
• 
Neuropsychological Evaluation (2 hrs) 
• 
[F-18]FDDNP-PET/CT scan (1 hr)*  
• 
MRI Scan (30 min)* 
• 
Initial supply of supplement or placebo: done once all procedures above are complete.  
 
*May be completed on separate visit 
 
Visit 3 (3 months): 
20 minutes in person or by mail/phone 
• 
Review of possible adverse events 
• 
Supplement compliance check and re-supply of supplement or placebo 
 
Visit 4 (6 months): 
2 hours total 
• 
Neuropsychological Evaluation  
• 
Review of possible adverse events 
• 
Supplement compliance check and re-supply of supplement or placebo 
 
Visit 5 (9 month):  
20 minutes in person or by mail/phone 
• 
Review of possible adverse events 
• 
Supplement compliance check and re-supply of supplement or placebo 
 
Visit 6 (12 months): 
2 hours total 
• 
Neuropsychological Evaluation  
• 
Review of possible adverse events 
• 
Supplement compliance check and re-supply of supplement or placebo 
 
Visit 7 (15 months): 
1 hour total 
• 
Review of possible adverse events 
• 
Supplement compliance check and re-supply of supplement or placebo 
 
Visit 8 (18 month):  
3.5 hours total 
• 
Neuropsychological Evaluation (2 hrs) 
• 
[F-18]FDDNP-PET/CT scan (1 hr)*  
• 
Blood draw (15 minutes) 
• 
Review of possible adverse events 
• 
Supplement compliance check 
 
*May be completed on separate visit 
 
Informed consent, clinical assessment routine laboratory screening and EKG are done at the 
subject's first visit. These procedures are performed in a private office or at the Clinical 
Research Center (CRC) in a private room. The routine laboratory blood samples, DNA blood 
sample and EKG are performed at the CRC.  The following includes additional details on the 
study visits. 
 
Visit 1 
A. Informed Consent: 
If a potential subject calls the UCLA Longevity Center and indicates he/she is interested in the 
study, the following would happen: 
 
1. The potential subject would be screened over the phone, by research personnel, to 
determine eligibility.  
2. If eligible, the potential subject would come to the center and be evaluated by the clinician 
and screened for possible inclusion into the research study.  
3. If the potential subject meets eligibility criteria, and once he or she agrees to participate, 
the subject would sign the consent form and be enrolled into the study.  


18-Month Study of Curcumin  
Page 1 
 
4. With the subject’s permission, the data collected by the clinician during the initial evaluation 
would be used in research study.  
5. The data would then be reviewed by research personnel and if appropriate added to the 
research database.  
6. If any of the procedures were performed within six months of enrollment, the subject would 
not have to repeat the PET or PET/CT scan or neuropsychological testing. 
 
B. Clinical Assessment: This assessment includes a psychosocial history and mental status 
examination. The following standardized rating scales and questionnaires are used to verify 
the history, quantify degree of impairment, and assign subjects to diagnostic groups:  
 
1. Beck Depression Inventory II (BDI-II)  
2. Family History Questionnaire (completed by the Staff Research Associate) 
3. Cognitive Screening: Montreal Cognitive Assessment Scale (MOCA) 
4. Functional Activities Questionnaire (FAQ) 
5. Profile of Mood States (POMS) 
6. STOP-BANG Questionnaire for Sleep Apnea 
7. Pittsburgh Sleep Quality Index (PSQ-I) 
8. 7-day Sleep Diary 
 
C. Routine Laboratory Blood Draw, DNA Blood Draw and EKG: After the informed consent and 
clinical assessment is completed, subjects will be taken to the Clinical Research Center (CRC) 
and enrolled as outpatients.  
  
The following tests are performed: 
• CBC, PLT, DIFF 
• Free T4 Index 
• TSH 
• Vitamin B12  
• Chem Panel  
• Uric Acid  
• RPR with FTA Confirmation 
• Routine EKG 
• Blood Draw for DNA Analysis. Additional blood will be drawn and frozen to assess 
inflammatory markers. 
 
Visit 2 
Once the results from Visit 1 have been reviewed by one of the investigators and deemed 
within normal limits, subjects will undergo the following procedures as baseline measures. 
 
A. Neuropsychological Evaluation: The neuropsychological test battery includes: 
• 
• Tests Estimating Premorbid Intellectual Functioning (Baseline only) 
o 
Advanced Clinical Solutions Word Reading Test (formerly the Wechsler Test of 
Adult Reading). 
• 
 Core Battery 
o 
Brief Visuospatial Memory Test Revised (BVMT-R) [Visit 2 Only]. 
o 
Buschke Selective Reminding Task (BSRT); 
o 
New York University Story Recall Test; 
o 
Conners’ Continuous Performance Test;  
o 
CFL letter fluency test; 
o 
Animal Naming category fluency test  
o 
Trails A  
Every Six Months: Completion of Sleep Diary and PSQ-I 
Last Visit: Beck Depression Inventory II (BDI-II) and Profile of Mood States (POMS), Sleep 
Bang 
 
Subjects are tested in a private office. Healthy and motivated subjects can generally complete 
the battery in a three-hour period, including time for periodic rest breaks. 
 


18-Month Study of Curcumin  
Page 1 
 
B. [F-18]FDDNP-PET Scan or PET/CT Scan: Subjects undergo the [F-18]FDDNP-PET scan at 
the UCLA 200 Medical Plaza Nuclear Medicine Clinic. While in the scanner in a dimmed room, 
all subjects receive a 10 mCi intravenous injection of [F-18]FDDNP. During the scanning, each 
subject is kept quiet and exposed only to ambient room sound in a dimmed room, with eyes 
open and ears unplugged. The procedure will take 45 minutes of the subject's time. 
 
Twenty-one blood samples (12 in the first two minutes and one each at 3, 4, 5, 7, 10, 20, 30, 
45 and 60 minutes) are taken from a hand vein in a warm water bath (42 degrees 
centigrades) over 65 minutes for radiation counts that allow the calculation of the input 
function. 
 
Scanning is performed on a CTI/Siemens 831-08 tomograph (Siemens Corp, Hoffman Estates, 
111) in three-dimensional acquisition mode (inter-plane septa removed), using double the 
previous standard axial sampling (Cherry et al, 1991, 1992). Imaging commences 
immediately after administration of the radiolabeled dye and lasts for 45 minutes.  
 
Once subjects have completed the neuropsychological assessment and the PET scan in Visit 2, 
they will begin taking the supplement or placebo. Both the curcumin supplement and the 
placebo will be packaged in 465 milligram capsules to maintain blindness in both research 
personnel and subjects. Subjects will take three 465 milligram capsules twice a day (once in 
the morning and once at night). Unless otherwise notified by the investigator, subjects will be 
instructed to continue taking the supplement dose until the study’s completion 18 month later.  
 
C. MRI Scan: Subjects will undergo an MRI scan of the brain which will include fluid-
attenuation inversion recovery (FLAIR) and 2D T2*-weighted gradient-recalled-echo (GRE) 
sequences. The MRI scan will also include an MPRage sequence for registration and cortical 
surface extraction with the PET scans. Scanning will be done using the 3-Tesla MRI scanner in 
the Staglin IMHRO Center for Cognitive Neuroscience at UCLA or the 1.5-Tesla MRI in the 
UCLA Department of Radiology. Sequences will have a slice thickness of less than 5mm and 
Echo Time (TE) of more than 20 ms. Subjects with more than 4 cerebral microhemorrhages 
(regardless of their anatomical location or diagnostic characterization as “possible” or 
“definite”), a single area of superficial siderosis, or evidence of a prior macrohemorrhage at 
screening or baseline will be excluded. MRI analysis will be performed by Neuroradiologist 
Noriko Salamon, MD, PhD or other UCLA radiologist.  
 
*MRI may take place visit 1 or visit 2 depending on scheduling. 
 
Visit 3 
At 3 months, to ensure that subjects are taking the supplement or placebo, staff will review 
for potential adverse events and safety of the supplement or placebo, and check to determine 
if subjects are taking them as prescribed.  Subjects will be provided a new supply of 
supplement or placebo. 
 
Visit 4 
At 6 months, to ensure that subjects are taking the supplement or placebo, staff will review 
for potential adverse events and safety of the supplement or placebo, and check to determine 
if subjects are taking them as prescribed.  Subjects will be provided a new supply of 
supplement or placebo.  
 
Visit 5 
At the 9-month mark, subjects will be asked to return to complete another neuropsychological 
assessment. This evaluation contains the same tests as the aforementioned assessment.  To 
ensure that subjects are taking the supplement or placebo, staff will review for potential 
adverse events and safety of the supplement or placebo, and check to determine if subjects 
are taking them as prescribed.  Subjects will be provided a new supply of supplement or 
placebo.  
 
Visit 6 


18-Month Study of Curcumin  
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At 12 months, to ensure that subjects are taking the supplement or placebo, staff will review 
for potential adverse events and safety of the supplement or placebo, and check to determine 
if subjects are taking them as prescribed.  Subjects will be provided a new supply of 
supplement or placebo. 
 
Visit 7 
At 15 months, to ensure the subjects are taking the supplement or placebo, staff will review 
for potential adverse events and safety of the supplement or placebo, and check to determine 
if subjects are taking them as prescribed.  Subjects will be provided a new supply of 
supplement or placebo. 
 
Visit 8 
At the conclusion of the study, the 18-month mark, subjects will be asked to return to 
complete a final neuropsychological assessment, [F-18]FDDNP-PET Scan and blood draw. 
Additional blood be drawn and frozen to assess inflammatory markers if curcumin outcomes 
are positive.  To ensure that subjects were taking the supplement or placebo, staff will review 
for potential adverse events and safety of the supplement or placebo, and check to determine 
if subjects are taking them as prescribed.  
 
Subjects who are unable to come to UCLA before running out of supplement may be mailed a 
refill via FedEx. Correct delivery will be ensured by mandatory signature upon receipt. 
Theracurmin pills are available on the market and can be ordered online and shipped home; 
no specific conditions are required. Although subjects will have to come to UCLA for thee MRI, 
the review session may be conducted over the phone.  
 
All study investigators will be notified of the possible occurrence of cerebral vasogenic edema, 
its imaging manifestations, and the clinical signs and symptoms that may accompany this 
phenomenon. They will also be instructed on the measures to be taken should cerebral 
vasogenic edema occur. Those measures include: discontinuation of study medication, more 
frequent serial MRI scans until the imaging abnormalities resolve, and consideration of 
treatment with high-dose dexamethasone should symptoms be severe. 
 
Statistics and Data Analysis 
 
Hypotheses:  
1. People with age-related cognitive decline (e.g., MCI and/or AAMI) who receive a an oral 
dose of curcumin 90 mg twice each day, along with lifestyle counseling on healthy nutrition 
and exercise, will show less build-up of plaques and tangles (as measured with FDDNP-PET 
imaging) than those receiving placebo after 18 months. 
2. People with age-related cognitive decline, who receive curcumin 90 mg twice each day 
along with healthy lifestyle counseling, will show less evidence of cognitive decline than those 
receiving placebo after 18 months. 
3. Cognitive change, FDDNP-PET measures, and treatment response will vary according to 
genotypes found to influence age at dementia onset (e.g., apolipoprotein E [APOE] and 
TOMM40). 
 
To test Hypotheses 1 and 2, the intervention and control groups will be compared on changes 
in performance on cognitive memory measures and FDDNP signals using a repeated measures 
analysis of variance. Based on our previous studies, we estimate an attrition rate of 10% in 
this age group of subjects. Hence we expect 60 subjects to complete the protocol in each 
group. Given an alpha level of 0.05 and power of 0.8, with 60 subjects per group, we can 
detect a moderate effect size of 0.51 of the change across testings between groups. Of course, 
the subject number for the intent-to-treat analysis will be higher since drop-outs will be 
included in this analysis.  
 
To investigate the influence of genotype, we will determine, using a t-test, if the APOE-4 
carriers in the intervention group show a significant improvement from baseline on the 
cognitive and amyloid measures compared to the non-APOE-4 carriers. We anticipate 
approximately 30 APOE-4 carriers out of the 60 subjects completing the intervention, so an 


18-Month Study of Curcumin  
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effect size of 0.72 would be detectable, at an alpha level of 0.05 and power of 80%. Assuming 
a common standard deviation of change for the two genetic groups, this effect size implies a 
difference between the genetic groups in the change across testings of 7.6 and 1.25 for the 
Buschke-Fuld Total and Benton Visual Retention Scores respectively.  
 
Biomarker levels will be analyzed between doses of curcumin using basic t-tests and/or 
ANOVAs. For the RCT, differences in cognitive and imaging markers will be analyzed between 
groups (active supplement vs. placebo) using the same basic statistics. For any more complex 
analyses in the dosing study or the RCT, we will consult our group statistician for the 
appropriate statistical procedures. 
 
Inclusion Criteria 
 
a) Agreement to participate in the 18-month double-blind, placebo-controlled clinical trial 
of curcumin.  
b) Diagnostic criteria for mild cognitive impairment (MCI) or any age related memory 
decline according to standard criteria (Petersen et al, 2001; Crook et al, 1986). 
c) Age 50 to 90 years. 
d) No significant cerebrovascular disease: modified Ischemic Score of < 4 (Rosen et al, 
1980). 
e) Adequate visual and auditory acuity to allow neuropsychological testing. 
f) 
Screening laboratory tests and EKG without significant abnormalities that might 
interfere with the study.  
 
 
Exclusion Criteria  
 
a) Diagnosis of probable Alzheimer’s disease (AD) or any other dementia (e.g., vascular, 
Lewy body, frontotemporal) (McKhann et al, 1984).  
b) Evidence of other neurological or physical illness that can produce cognitive 
deterioration. Volunteers with a history of stroke, TIA, carotid bruits, or lacunes on 
MRI scans will be excluded.  
c) Inability to undergo MRI.  
d) Evidence of Parkinson’s disease as determined by the motor examination (items 18-
31) of the Unified Parkinson's Disease Rating Scale (Fahn et al, 1987). 
e) History of myocardial infarction within the previous year, or unstable cardiac disease. 
f) 
Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100). 
g) History of significant liver disease, clinically-significant pulmonary disease, diabetes, or 
cancer. 
h) Current diagnosis of any major psychiatric disorder according to the DSM-IV TR 
criteria (APA, 2000). 
i) 
Current diagnosis or history of alcoholism or substance addiction. 
j) 
Regular use of any medication that may affect cognitive functioning including: 
centrally active beta-blockers, narcotics, Clonidine, anti-Parkinsonian medications, 
antipsychotics, benzodiazepines, systemic corticosteroids, medications with significant 
cholinergic or anticholinergic effects, anti-convulsants, or Warfarin. Occasional chloral 
hydrate use will be allowed, but discouraged, for insomnia. 
k) Use of more than one multivitamin per day. Vitamins other than the standard 
multivitamin supplement will not be allowed.  
l) 
Use of medications known to affect FDDNP-PET binding (e.g., ibuprofen, naproxen). 
m) Use of more than one daily baby aspirin (81mg) and/or use of any medication 
containing curcumin.  
n) Use of cognitive enhancing supplements (e.g. Ginkgo biloba). 
o) Use of any investigational drugs within the previous month or longer, depending on 
drug half-life. 
p) Pregnancy. 
q) HIV infection. 
r) 
Evidence of vasogenic edema; specifically, evidence of more than 4 cerebral 
microhemorrhages (regardless of their anatomical location or diagnostic 


18-Month Study of Curcumin  
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characterization as “possible” or “definite”) or a single area of superficial siderosis), or 
evidence of a prior macrohemorrhage at screening or baseline. 
 
 
Potential Benefits 
During the course of the screening and subject identification, untreated medical conditions 
may be recognized. However this study will not improve a subject's health or condition. 
 
Although there is no known benefit to society at this time, it is hoped that society will benefit 
from the knowledge gained from this study. In particular, the results of the study may lead to 
the development of new treatments for memory decline and Alzheimer’s disease. 
Potential Risks/Discomforts and Management Strategies  
 
1. SCREENING  
Subjects may feel uncomfortable answering some of the screening questions. They do not 
have to answer any questions they do not wish to answer and they may stop at any time. 
Their participation in the screening is voluntary. A decision whether or not to participate in the 
screening will not affect their relationship with UCLA. Subjects will be told that they may not 
directly benefit from the screening.  
 
Subjects’ answers will be confidential. No one will know the answers except for the research 
team. If the subject decides to answer the questions of the screening interview, that will 
determine their eligibility for the research. If the subject qualifies for the study, the subject 
will be asked to read through and sign an informed consent. Their answers will be kept with 
their other research generated records. If they do not qualify for the study, their answers will 
be destroyed.  
 
2. MAGNETIC RESONANCE IMAGING  
Subjects may experience anxiety and/or claustrophobia from being in an enclosed space. They 
can ask to be taken out of the scanner at any time. Earplugs will be given during the MRI 
procedure. 
 
3. CURCUMIN SUPPLEMENT 
Nutritional supplements may cause some side effects or other reactions. Curcumin’s 
widespread use in food without adverse effects supports its safety. Although rare, the most 
frequent side effects associated with curcumin are nausea and diarrhea. Any subjects who do 
not tolerate the curcumin will be discontinued from the study.   
 
In small cancer prevention studies that assessed doses of up to 12,000 mg per day, curcumin 
was found to be safe in humans, although doses above 8,000 mg were found to be 
unpalatable.  At doses higher than 12,000 mg, gastric irritation was reported.    
 
4. PLACEBO 
Subjects will be informed that there is a 50% chance of receiving placebo during the course of 
the study and the investigators do not anticipate any long-term benefits from use of placebo. 
 
5. RADIATION EXPOSURE 
We are exposed to radiation on a daily basis, both from natural (sun and earth) and man-
made sources. In addition to the radiation that subjects may be exposed to as part of their 
clinical care, the subject may potentially receive one 10 mCi FDDNP- PET/CT scan in a year 
while participating in this research study.  This amount is well under the amount considered 
safe. 
 
If the FDDNP-PET/CT scan is performed, the total estimated radiation dose to the whole body 
would be 153 millirem, or 3% of the 5,000 millirem annual whole body limit allowed for adult 
radiation workers. The total estimated radiation dose to the primary critical organ (gallbladder 
wall) would be 544 millirem or 11% of the 5,000 millirem single dose limit allowed for 
radiation workers. The total estimated radiation dose to the secondary critical organ (liver) 


18-Month Study of Curcumin  
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would be 497 millirem, or 10% of the 5,000 millirem single dose limit allowed for radiation 
workers.  
 
6. BLOOD DRAW FOR ROUTINE BLOOD ANALYSIS AND DNA SAMPLE 
The risks include problems associated with blood drawing. This is a routine procedure 
performed under standard and sterile medical conditions. The potential side effects of 
removing blood may include momentary discomfort during the puncture, lightheadedness, 
faintness, and soreness and discoloration of the area for several days. In very rare instances, 
either bleeding or infection can develop at the venipuncture site. There is no more discomfort 
encountered than when blood samples are taken during periodic medical examinations or 
when blood is donated at a blood bank. 
 
7. GENETIC ANALYSIS  
The data collected for genetic analysis will not be kept in the subject’s medical record and will 
remain strictly confidential. The potential side effects of genetic analysis of blood may, 
however, involve certain psychological and social risks in the advent of inadvertent disclosure. 
These risks include:  
a. Broad sharing of phenotype and genomic data (e.g. genotype, DNA sequence, 
expression profiles, etc.); 
b. Computer security breaches; 
c. 
Other unanticipated distributions arising from maintaining data in an electronic format; 
d. Privacy breaches (both those known and those unforeseen at this time); 
e. Uncertainty of findings related to genetic risk for a given disease or trait; 
f. 
Risks to relatives or identifiable populations or groups; 
g. Physical risks (such as those associated with collecting blood or other tissues 
samples). 
 
Effective November 2009, federal legislation (The Genetic Information Nondiscrimination Act, 
or GINA) was passed to provide baseline protection against discrimination in employment and 
health insurances decisions across the nation.  
 
8. NEUROPSYCHOLOGICAL EVALUATION 
Subjects may experience feelings of failure, frustration, or anxiety induced by 
neuropsychological testing. The psychologist administering the tests is experienced in 
assessing persons and will convey a relaxed and confident attitude. Subjects have the right to 
refuse to answer any questions that they may not wish to answer. If a subject does have the 
above reaction to the evaluation, it should go away at the completion of the test. If the 
subject finishes the test and feels anxious, then the subject can talk to the psychologist who 
administered the test.  
 
In the event that the subject tells the research staff that they are thinking about killing 
themselves or they answer yes to a question about having thoughts about suicide, the 
investigator will ask the subjects more questions about these thoughts. Depending on the 
answers to these questions, the research staff may: 
a. Provide the subject with referrals for treatment; 
b. Work with the subject to contact their personal physician, trusted family member, or 
therapist to discuss these thoughts of harming themselves; 
c. Work with the subject on a plan that may include getting them to a hospital for safety. 
 
9. INJECTION DURING PET SCAN 
The potential side effects of removing venous blood may include momentary discomfort during 
the puncture, lightheadedness, fainting, and soreness and discoloration for several days. In 
very rare circumstances, either bleeding or infection can develop at the venipuncture site.  
 
10. UNFORESEEN RISKS 
This study may include unforeseen risks.  However, risks will be minimized because subjects 
will be monitored closely for the occurrence of any side effects, and the study treatments will 
be discontinued promptly if there appears to be a distressing reaction.  Regular monitoring 
including physical examinations and vital signs (including weight) will be done during this 


18-Month Study of Curcumin  
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study to detect any possible adverse effects from treatment.  Subjects will be advised to 
contact the study physician if they experience any unexpected reaction while participating.  
Also, subjects will be advised not to start any new medication, including over-the-counter 
medications, or have an elective surgery without approval of the study physician.   
 
RISK/BENEFIT ANALYSIS  
 
Both the risks and benefits are minimal for individual subjects. The results of the study could 
lead to more effective prevention and treatment of memory decline and Alzheimer’s disease. 
The investigators believe the potential benefits from participation in this study outweigh the 
risks and, therefore, the risk benefit ratio is thought to be favorable. 
 
DATA AND SAFETY MONITORING 
 
An independent data and safety monitoring committee will be established and will review data 
on three occasions during the study.  The committee will be informed of the occurrence of any 
serious adverse events if they arise. 
 
SUBJECT COMPENSATION 
Subjects will be paid as follows, up to a total of $300.00. Parking will be covered by the study. 
 
Project Period 
 
Amount to be paid 
Initial Study Visit  
 
$25.00 total 
6 Week Mark   
 
$75.00 total 
6 Month Mark   
 
$75.00 total 
1 Year Mark   
 
 
$75.00 total 
18 Month Mark/End of study  
$50.00 total 
 
If the investigator terminates the study or the participant decides to withdraw, the participant 
will be paid based on the last project period completed.   
 
 
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