Clinical trial NCT04972643: The Protective Effect of Omega-3 Fatty Acid on Cognitive Function Among Patients With Mild Dementia
Official title: Department of Psychiatry, Taichung Veterans General Hospital
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer Disease
Dementia Disorder
Keywords: Dementia Alzheimer
Lead sponsor: Taichung Veterans General Hospital
Sponsor class: OTHER
First posted: 2021-07-22
Enrollment: 163
Sex: ALL
Minimum age (years): 65
Maximum age (years): 105
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Patients may be included in the study if they meet the following criteria:

  1. Males and females over 65 years of age.
  2. Diagnosis of Alzheimer's Dementia disorder.
  3. Each individual must have a level of understanding sufficient to perform all tests and examinations required.
  4. Individuals must be willing to accept all laboratory examinations and MRI examination.
  5. Individuals must be willing to provide a small sample of blood for evaluation.
  6. Individuals must be willing to participate in a short 30-60 minute clinical interview.

Exclusion Criteria:

* Patients may be excluded from the study for any of the following reasons:

  1. Serious unstable illness such that death is anticipated within 1 year or intensive care unit hospitalization for the condition is anticipated within 6 months.
  2. Diagnosis of Vascular Dementia disorder.
  3. Uncorrected hypothyroidism or hyperthyroidism
  4. Participants will be excluded if they had evidence of epilepsy; focal brain lesion; head injury with loss of consciousness or confusion after the injury; DSMIV-TR (text revision) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, or alcohol or substance abuse; or potential bleeding tendency.
  5. History of allergy to fish or omega-3 polyunsaturated fatty acids.

Primary outcomes:
measure: Aspartate Aminotransferase (AST)
timeFrame: Day 0
measure: Aspartate Aminotransferase (AST)
timeFrame: Day 24 month
measure: Alanine Aminotransferase (ALT)
timeFrame: Day 0
measure: Alanine Aminotransferase (ALT)
timeFrame: Day 24 month
measure: Albumin level
timeFrame: Day 0
measure: Albumin level
timeFrame: Day 24 month
measure: Fasting blood glucose
timeFrame: Day 0
measure: Fasting blood glucose
timeFrame: Day 24 month
measure: Blood Urea Nitrogen (BUN)
timeFrame: Day 0
measure: Blood Urea Nitrogen (BUN)
timeFrame: Day 24 month
measure: Creatinine level
timeFrame: Day 0
measure: Creatinine level
timeFrame: Day 24 month
measure: Sodium (Na)
timeFrame: Day 0
measure: Sodium (Na)
timeFrame: Day 24 month
measure: Potassium (K)
timeFrame: Day 0
measure: Potassium (K)
timeFrame: Day 24 month
measure: Calcium (Ca)
timeFrame: Day 0
measure: Calcium (Ca)
timeFrame: Day 24 month
measure: Magnesium (Mg)
timeFrame: Day 0
measure: Magnesium (Mg)
timeFrame: Day 24 month
measure: Triiodothyronine (T3)
timeFrame: Day 0
measure: Triiodothyronine (T3)
timeFrame: Day 24 month
measure: Free tetraiodothyronine (free T4)
timeFrame: Day 0
measure: Free tetraiodothyronine (free T4)
timeFrame: Day 24 month
measure: Thyroxin stimulating hormone (TSH)
timeFrame: Day 0
measure: Thyroxin stimulating hormone (TSH)
timeFrame: Day 24 month
measure: Triglycerides
timeFrame: Day 0
measure: Triglycerides
timeFrame: Day 24 month
measure: Total cholesterol
timeFrame: Day 0
measure: Total cholesterol
timeFrame: Day 24 month
measure: High density lipoprotein cholesterol (HDL)
timeFrame: Day 0
measure: High density lipoprotein cholesterol (HDL)
timeFrame: Day 24 month
measure: Low density lipoprotein cholesterol (LDL)
timeFrame: Day 0
measure: Low density lipoprotein cholesterol (LDL)
timeFrame: Day 24 month
measure: Vitamine B12 level
timeFrame: Day 0
measure: Vitamine B12 level
timeFrame: Day 24 month
measure: Folic acid
timeFrame: Day 0
measure: Folic acid
timeFrame: Day 24 month
measure: Rapid plasma reagin for Syphilis test (RPR)
timeFrame: Day 0
measure: Rapid plasma reagin for Syphilis test (RPR)
timeFrame: Day 24 month
measure: Mini Mental Status Evaluation (MMSE) total score
timeFrame: Day 0
measure: Mini Mental Status Evaluation (MMSE) total score
timeFrame: Day 24 month
measure: Clinical Dementia Rating Scale (CDR) total score
timeFrame: Day 0
measure: Clinical Dementia Rating Scale (CDR) total score
timeFrame: Day 24 month
measure: Hachinski ischemic score total score
timeFrame: Day 0
measure: Hachinski ischemic score total score
timeFrame: Day 24 month
measure: Alzheimer's Disease Assessment Scale-cognitive section (ADAS-Cog) total score
timeFrame: Day 0
measure: Alzheimer's Disease Assessment Scale-cognitive section (ADAS-Cog) total score
timeFrame: Day 24 month
measure: Alzheimer's Disease Assessment Scale-activities of daily living section (ADCS-ADL) total score
timeFrame: Day 0
measure: Alzheimer's Disease Assessment Scale-activities of daily living section (ADCS-ADL) total score
timeFrame: Day 24 month
measure: Geriatric Depression Scale (GDS) total score
timeFrame: Day 0
measure: Geriatric Depression Scale (GDS) total score
timeFrame: Day 24 month
measure: Quality of Life- Alzheimer Dementia (QOL-AD) total score
timeFrame: Day 0
measure: Quality of Life- Alzheimer Dementia (QOL-AD) total score
timeFrame: Day 24 month
measure: MRI examination 1
timeFrame: Day 0
measure: MRI examination 2
timeFrame: Day 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
state: No.450,Sec.1,Dongda Rd.,Xitun Dist.
Study officials:
affiliation: National Yang Ming Chiao Tung University
name: Tsuo-Hung Lan, MD, PhD.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Wang XD, Kashii S, Zhao L, Tonchev AB, Katsuki H, Akaike A, Honda Y, Yamashita J, Yamashima T. Vitamin B6 protects primate retinal neurons from ischemic injury. Brain Res. 2002 Jun 14;940(1-2):36-43. doi: 10.1016/s0006-8993(02)02587-8.