18-Month Study of Memory Effects of Curcumin
Condition: Age-associated Cognitive Impairment; Mild Cognitive Impairment (MCI)
MeSH terms: Cognitive Dysfunction
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Curcumin; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Six Theracurmin capsules (containing 30 mg of curcumin each) per day for 18 months.; Six capsules per day for 18 months.
Other intervention name(s): Theracurmin CR-031P™ (Dietary Supplement); Sugar Pill
Intervention MeSH terms: Curcumin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Curcumin; Turmeric; Memory; Cognitive Impairment; Brain Imaging; Supplement