The Protective Effect of Omega-3 Fatty Acid on Cognitive Function Among Patients With Mild Dementia
Condition: Alzheimer Disease; Dementia Disorder
MeSH terms: Alzheimer Disease; Dementia
Study type: Interventional

Summary: 
      Background： Dementia is a progressive, devastating, and fatal neurodegenerative disorder.
      Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than 50%
      of patients with dementia. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the
      major bioactive components of n-3 polyunsaturated fatty acids (n-3 PUFAs) , might connect to
      the etiology of several neuropsychiatric diseases. To our knowledge, it has never been
      studied to look at the different effects of DHA, EPA and their combination on associated
      symptoms of AD.

      Objectives To examine the effects of DHA, EPA and their combination on associated symptoms of
      AD, including cognitive function, depressive symptoms, and functional ability.

      Method This is a randomized, double-blind, placebo-controlled, 24-month follow-up study,
      enrolling 200-400 patients with mild AD (Mini-Mental Status Examination (MMSE) 19-26 or
      Clinical Dementia Rating (CDR) 0.5-1). Cognitive ability is assessed by the Alzheimer Disease
      Assessment Scale-Cognitive Subscale (ADAS-Cog) and the MMSE. Mood status is assessed by
      Geriatric Depression Scale (GDS). Functional ability is assessed by the Alzheimer Disease
      Cooperative Study activities of daily living (ADCS-ADL) and global function by the CDR,
      quality of life scale (QOL-AD). Brain function is assessed by resting state brain magnetic
      resonance imaging (MRI).
    

Detailed description: 
      Background Dementia is a progressive, devastating, and fatal neurodegenerative disorder
      (Cummings, 2004). As of 2010, there are an estimated 35.6 million people with dementia
      worldwide. By 2050, it is projected that this figure will have increased to over 115 million
      (1, 2). Therefore, dementia is not only an important medical disease but also a public health
      issue to demand immediate attention. A conservative estimate of economic burden from dementia
      (based on Alzheimer's Society's Dementia United Kindom (UK) report published in February
      2007) reaches 20 billion by the year 2010, which suggests an average cost of 25,472 per
      person annually. It indicated a heavy social financial expense for the whole world in
      general. Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60-80%
      of patients with dementia. Given that it is still lacking in effective treatments for AD,
      there has been growing interest in early detection and prevention for this disastrous
      illness. Delaying AD onset by 1 year could potentially lower its incidence by more than 9
      million cases over the next 40 years (3).

      Dementia could be resulted from numerous risk factors and medical conditions including
      vascular risk factors (e.g. hypertension, diabetes, and obesity), psychosocial factors (e.g.
      depression), and health behaviors (e.g. physical inactivity and smoking) (4, 5). Indeed,
      reflecting its heterogeneity, several hypotheses have been proposed for etiology of dementia,
      including genetic susceptibility, vascular changes, inflammatory process, oxidative stress,
      and recently, n-3 polyunsaturated fatty acids (n-3 PUFAs) (Fratiglioni et al., 2008;Samieri
      et al., 2008;Cole and Frautschy, 2010;Mucke and Pitas, 2004;Gomez-Pinilla, 2008). PUFAs are
      classified into mainly n-3 (or omega-3) and n-6 (or omega-6) groups. Docosahexaenoic acid
      (DHA) and eicosapentaenoic acid (EPA), the major bioactive components of n-3 PUFAs, are
      associated with neuronal membrane stability and fluidity, neurogenesis, neuroplasticity,
      neurotransmission and anti-inflammation, which might connect to the etiology of several
      neuropsychiatric diseases including depression and dementia (Horrobin and Bennett, 1999;Su et
      al., 2000;Chalon, 2006;Lukiw and Bazan, 2006;Su, 2009b;Lin et al., 2010a). On the other hand,
      arachidonic acid (AA), the major components of n-6 PUFAs, is a precursor of eicosanoids and
      is important to modulate proinflammatory effects, which might also link to the pathogenesis
      of neuroinflammatory and neurodegenerative diseases like dementia (Sanchez-Mejia and Mucke,
      2010;Lukiw and Bazan, 2010). Consistent with the theoretical relevance, evidences to link
      PUFAs to dementia have been reported extensively from more epidemiological studies. For
      example, it has been observed that regions with a high consumption of fish, which are good
      sources of n-3 PUFAs, appear to have a lower prevalence of dementia (Barberger-Gateau et al.,
      2002;Barberger-Gateau et al., 2007;Huang et al., 2005;Morris et al., 2003;Kalmijn et al.,
      1997) and Mild cognitive Impairment (MCI) ;(Roberts et al., 2010)). Although clinical studies
      until now have failed to demonstrate beneficial effects of n-3 PUFA supplementation in
      patients with moderate or severe AD (Freund-Levi et al., 2006a;Quinn et al., 2010a), it may
      benefit in patients with mild AD or MCI and those without apolipoprotein E(APOE) ε4 allele
      (Freund-Levi et al., 2006b;Chiu et al., 2008;Quinn et al., 2010b). In addition, the two main
      n-3 PUFAs have different biological effects. DHA is the main n-3 PUFAs in the brain and is
      important in neuroplasticity and neuroprotection. EPA, on the other hand, is very little in
      the brain but is important in modulate inflammation and immune function (Lin et al.,
      2010b;Su, 2009a). To our knowledge, it has never been studied to look at the different
      effects of DHA, EPA and their combination on different associated symptoms of AD. To provide
      more evidence for the association between n-3 PUFAs and associated symptoms of AD, including
      cognitive function, depression, and physical activity in AD, we propose to conduct this
      double-blind, placebo-controlled, 24-month research. In addition, neuroprotective effects of
      vitamin B, preliminary findings in recent studies have shown cognitive-protection effects of
      it among patients with MCI. Moreover, deficiency of vitamin B is known to cause nervousness,
      depression, and peripheral and central neuropathy. The importance of vitamin B in
      developmental processes of the brain is supported by the findings that vitamin B deficiency
      at certain stages of brain development interferes with brain cell proliferation, migration
      and maturation . Vitamin B affords survival-promoting activities on cultured brain neurons
      (6). This is probably the first study to evaluate the effects of vitamin B on cognitive
      protection among Asian patients with AD. Based on the review of the possible benefits from
      n-3 PUFAs supplement on cognitive function preservation after balancing for its slightest
      side effects, we here propose a randomized clinical trial study design to test whether
      Hypothesis Omega-3 PUFAs is protective against cognitive decline among people with mild AD.

      Primary Aim To examine whether consumption of n-3 PUFAs protects against cognitive decline in
      patients with mild AD.

      Secondary Aims

        1. To examine the different effects of DHA, EPA and their combination on different symptoms
           of AD.

        2. To examine whether consumption of n-3 PUFAs improves cognitive function in patients with
           mild AD.

        3. To examine whether consumption of n-3 PUFAs improves depressive symptoms in patients
           with mild AD.

        4. To examine whether consumption of n-3 PUFAs improves physical activity level in patients
           with mild AD.

      Significance of Study

        1. To provide a simple way through dietary supplement of n-3 PUFAs to prevent cognitive
           decline and improve depressive symptoms and physical activity in patients with mild AD.

        2. No placebo-controlled studies regarding n-3 PUFAs in cognitive prevention have been
           conducted among Asian people.
    

Intervention name(s): EPA; DHA; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): EPA 2000mg Soft capsules; DHA 2000mg Soft capsules; Placebo Soft capsules
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Dementia Alzheimer