The Protective Effect of Omega-3 Fatty Acid on Cognitive Function Among Patients With Mild Dementia

Alzheimer Disease Clinical Trial

Official title:

Department of Psychiatry, Taichung Veterans General Hospital

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04972643
• Other study ID #: SF12109A
• Status: Completed
• Phase: N/A
• Start date: September 23, 2012
• Est. completion date: September 23, 2018

Study information

• Verified date: July 2021
• Source: Taichung Veterans General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 163
• Est. completion date: September 23, 2018
• Est. primary completion date: May 12, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 105 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Dementia

Intervention

Dietary Supplement:
• EPA
EPA 2000mg Soft capsules
• DHA
DHA 2000mg Soft capsules
• Placebo
Placebo Soft capsules

Locations

Country	Name	City	State
Taiwan	Taichung Veterans General Hospital	Taichung	No.450,Sec.1,Dongda Rd.,Xitun Dist.

Sponsors (1)

Lead Sponsor	Collaborator
Taichung Veterans General Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (6)

Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 2011 Sep;10(9):819-28. doi: 10.1016/S1474-4422(11)70072-2. Epub 2011 Jul 19. Review. — View Citation

Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007 Jul;3(3):186-91. doi: 10.1016/j.jalz.2007.04.381. — View Citation

Daviglus ML, Bell CC, Berrettini W, Bowen PE, Connolly ES Jr, Cox NJ, Dunbar-Jacob JM, Granieri EC, Hunt G, McGarry K, Patel D, Potosky AL, Sanders-Bush E, Silberberg D, Trevisan M. National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. Ann Intern Med. 2010 Aug 3;153(3):176-81. doi: 10.7326/0003-4819-153-3-201008030-00260. Epub 2010 Jun 14. — View Citation

Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M; Alzheimer's Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005 Dec 17;366(9503):2112-7. — View 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. — View Citation

World Alzheimer Report 2010. Alzheimer's Disease International, 2010.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Aspartate Aminotransferase (AST)		Day 0
Primary	Aspartate Aminotransferase (AST)		Day 24 month
Primary	Alanine Aminotransferase (ALT)		Day 0
Primary	Alanine Aminotransferase (ALT)		Day 24 month
Primary	Albumin level		Day 0
Primary	Albumin level		Day 24 month
Primary	Fasting blood glucose		Day 0
Primary	Fasting blood glucose		Day 24 month
Primary	Blood Urea Nitrogen (BUN)		Day 0
Primary	Blood Urea Nitrogen (BUN)		Day 24 month
Primary	Creatinine level		Day 0
Primary	Creatinine level		Day 24 month
Primary	Sodium (Na)		Day 0
Primary	Sodium (Na)		Day 24 month
Primary	Potassium (K)		Day 0
Primary	Potassium (K)		Day 24 month
Primary	Calcium (Ca)		Day 0
Primary	Calcium (Ca)		Day 24 month
Primary	Magnesium (Mg)		Day 0
Primary	Magnesium (Mg)		Day 24 month
Primary	Triiodothyronine (T3)		Day 0
Primary	Triiodothyronine (T3)		Day 24 month
Primary	Free tetraiodothyronine (free T4)		Day 0
Primary	Free tetraiodothyronine (free T4)		Day 24 month
Primary	Thyroxin stimulating hormone (TSH)		Day 0
Primary	Thyroxin stimulating hormone (TSH)		Day 24 month
Primary	Triglycerides		Day 0
Primary	Triglycerides		Day 24 month
Primary	Total cholesterol		Day 0
Primary	Total cholesterol		Day 24 month
Primary	High density lipoprotein cholesterol (HDL)		Day 0
Primary	High density lipoprotein cholesterol (HDL)		Day 24 month
Primary	Low density lipoprotein cholesterol (LDL)		Day 0
Primary	Low density lipoprotein cholesterol (LDL)		Day 24 month
Primary	Vitamine B12 level		Day 0
Primary	Vitamine B12 level		Day 24 month
Primary	Folic acid		Day 0
Primary	Folic acid		Day 24 month
Primary	Rapid plasma reagin for Syphilis test (RPR)		Day 0
Primary	Rapid plasma reagin for Syphilis test (RPR)		Day 24 month
Primary	Mini Mental Status Evaluation (MMSE) total score	Minimu:0, Maximum: 30, Higher scores mean a better outcome.	Day 0
Primary	Mini Mental Status Evaluation (MMSE) total score	Minimu:0, Maximum: 30, Higher scores mean a better outcome.	Day 24 month
Primary	Clinical Dementia Rating Scale (CDR) total score	Minimu:0, Maximum: 3, Higher scores mean a worse outcome.	Day 0
Primary	Clinical Dementia Rating Scale (CDR) total score	Minimu:0, Maximum: 3, Higher scores mean a worse outcome.	Day 24 month
Primary	Hachinski ischemic score total score	Minimu:0, Maximum: 18, Higher scores mean a worse vascular outcome.	Day 0
Primary	Hachinski ischemic score total score	Minimu:0, Maximum: 18, Higher scores mean a worse vascular outcome.	Day 24 month
Primary	Alzheimer's Disease Assessment Scale-cognitive section (ADAS-Cog) total score	Minimu:0, Maximum: 70, Higher scores mean a worse outcome.	Day 0
Primary	Alzheimer's Disease Assessment Scale-cognitive section (ADAS-Cog) total score	Minimu:0, Maximum: 70, Higher scores mean a worse outcome.	Day 24 month
Primary	Alzheimer's Disease Assessment Scale-activities of daily living section (ADCS-ADL) total score	Minimu:0, Maximum: 54, Higher scores mean a better outcome.	Day 0
Primary	Alzheimer's Disease Assessment Scale-activities of daily living section (ADCS-ADL) total score	Minimu:0, Maximum: 54, Higher scores mean a better outcome.	Day 24 month
Primary	Geriatric Depression Scale (GDS) total score	Minimu:0, Maximum: 15, Higher scores mean a worse outcome.	Day 0
Primary	Geriatric Depression Scale (GDS) total score	Minimu:0, Maximum: 15, Higher scores mean a worse outcome.	Day 24 month
Primary	Quality of Life- Alzheimer Dementia (QOL-AD) total score	Minimu:13, Maximum: 52, Higher scores mean a better outcome.	Day 0
Primary	Quality of Life- Alzheimer Dementia (QOL-AD) total score	Minimu:13, Maximum: 52, Higher scores mean a better outcome.	Day 24 month
Primary	MRI examination 1	Total brain volume: MRI examination will be performed on the 1.5 Telsla machine (GE, USA)	Day 0
Primary	MRI examination 2	Total brain volume: MRI examination will be performed on the 1.5 Telsla machine (GE, USA)	Day 24 months