Authors
- Krause, Debra BSc
- Roupas, Peter PhD
Abstract
Review question and Objective: Are individual dietary interventions effective in delaying the onset of cognitive decline in older adults?
The objective of this umbrella review is to determine the effectiveness of individual dietary interventions in delaying the onset of cognitive decline in older adults.
Background: Nutrition is one of the lifestyle factors that may contribute to the development and progression of chronic diseases such as atherosclerosis, cancer, cardiovascular disease, diabetes and neurodegenerative diseases. Increasing life expectancies have seen an increasing number of people affected by chronic diseases associated with ageing such as dementia. Neurodegenerative diseases such as Alzheimer's Disease (AD) are the most common cause of dementia, thought to be responsible for up to 70% of cases. Dementia broadly refers to a large group of illnesses which cause a progressive decline in a person's cognitive functioning. It is a broad term used to describe a loss of memory, intellect, rationality, social skills and normal emotional reactions. The major risk factor for AD is age with the prevalence doubling every 5 years after the age of 65. Other risk factors include the epsilon 4 allele of the apoliprotein E gene (APOE [epsilon]4), smoking, depression and diabetes.1
Mild cognitive impairment (MCI) can be associated with normal ageing or early dementia and is characterized by a measurable decline in cognitive abilities, including memory and thinking skills. The changes are generally not severe enough to interfere with daily life or independent function, but it does represent a higher risk for the development of AD.2-4 The clinical diagnosis of AD is challenging with multiple sets of well-established criteria aiming to establish if there is evidence of cognitive and functional decline that impacts on an individual's ability to carry out routine daily activities. Variations among the range of cognitive tests used to characterize cognitive domains can make comparison across studies challenging.5
The possible mechanisms associated with neurodegeneration have been hypothesized with a view to determining the cause of abnormalities in the transport, degradation and aggregation of proteins including amyloid -[beta] peptides, apolipoprotein E (APOE) and tau, a microtubule-associated protein in the brain. Free radicals and neuroinflammation processes are thought to underlie many of the neurodegenerative conditions.6 Natural compounds such as curcumin, carotenoids, acetyl-L-carnitine, vitamin D, polyphenols and other nutraceuticals have been studied for their potential to target multiple pathways in AD.7 Many of these natural compounds are widely available as nutritional supplements and have been studied for their potential role in neuroprotection.
Acetyl-L-carnitine (ALC) is an acetylated form of L-carnitine that is naturally produced by the body, although it is often taken as a dietary supplement. ALC has been reported to protect peripheral and nervous system synapses in neurodegenerative and ageing models.8 This has led to the study of the effect of ALC on cognitive decline in a series of clinical trials with conflicting outcomes.
Alpha lipoic acid (ALA) has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD.9 ALA is an endogenous antioxidant that interrupts cellular oxidative processes in both its oxidized and reduced forms. ALA increases acetylcholine production by activation of choline acetyltransferase and has the ability to chelate redox-active transition metals, thus inhibiting the formation of hydroxyl radicals, and also scavenges reactive oxygen species (ROS).10 ALA has therefore been postulated as a potential therapeutic in AD. Further studies have reported that AD sufferers lack the enzyme responsible for converting choline into acetylcholine within the brain. It has been proposed that lecithin, the major dietary source of choline, may accelerate synthesis of acetylcholine in the brain via increased availability of choline which has been the subject of several clinical trials.11
Inositol, also known as vitamin B8, is a simple polyol with eight naturally occurring stereoisomers. It is not an essential nutrient and nuts, seeds, beans, whole grains, cantaloupe and citrus fruits are a source of phytic acid (inositol hexaphosphate, IP6), which releases inositol when acted on by bacteria in the digestive tract. Clinical trials have been undertaken using varying doses of inositol or scyllo-inositoll.12-14 Scyllo-inositol has been shown to inhibit cognitive deficits in mice and can significantly decrease insoluble amyloid -[beta] 40 peptide, amyloid -[beta] 42 peptide and plaque accumulation in the brains of mice. However it does not incorporate into the phosphatidylinositol family of lipids and does not interfere with phosphatidylinositol lipid production.15
Polyphenols are a large group of naturally occurring secondary metabolites of plants and are characterized by the presence of at least one phenolic unit per molecule. There are several classes of polyphenols that have been studied for their potential anti-ageing and brain protective properties. These include flavonoids such as the anthocyanins which are typically found in berries, grapes and red wine and catechins often found in tea. Curcumin from turmeric and resveratrol from grapes and red wine are examples of bioactive species of the non-flavonoids chemical class.16 Curcumin has been reported to have effects such as decreased beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation and to improve the overall memory in patients with AD.17 Resveratrol has been reported to have effects in in vitro models of AD and in in vivo animal studies and moderate red wine consumption has been associated with a lower incidence of dementia and AD in epidemiological studies;18 however clinical studies in humans are lacking. Grape seed polyphenolic extracts have been reported to provide beneficial disease-modifying bioactivities in tau-associated neurodegenerative disorders by modulating tau-mediated neuropathologic mechanisms in in vitro studies.19 Similarly, epidemiological studies have reported that consumption of up to three servings of wine daily is associated with a lower risk of AD in elderly individuals without the APOE [epsilon]4 allele.20 Moderate drinkers with mild cognitive impairment who consumed less than one drink of wine per day showed a significantly lower rate of progression to dementia than abstainers.21
Omega 3 polyunsaturated fatty acids (PUFA) are essential fatty acids with docosahexanoic acid (DHA) being a major component of membrane phospholipids in the brain. Evidence from observational and epidemiological studies has suggested a possible inverse relationship between high dietary intake of PUFA and risk of dementia.22-24 Postulated mechanisms that might qualify omega 3 PUFA as an interventional target for the primary prevention of dementia include its anti-atherogenic, anti-inflammatory, anti-oxidant, anti-amyloid and neuroprotective properties.
In vitro and/or in vivo animal studies utilizing several of these compounds have demonstrated some success in slowing neurodegeneration and have led to further investigation in clinical trials of their likely role in preventing cognitive decline in humans.
However, the relationship between nutrition and cognitive functioning, particularly in elderly populations, is unclear, as many elderly people with cognitive impairment have low blood levels of some nutrients even in the absence of malnourishment.25 These findings have been reported in cross-sectional and longitudinal studies and further assessed in systematic reviews and meta-analyses with a view to pooling results to achieve some definitive conclusions. A preliminary search of Medline on PubMed, Web of Science and Cochrane Central (Database of Systematic Reviews and Cochrane Collaboration Central Register of Controlled Trials), has not identified any umbrella reviews on the topic.
Article Content
Inclusion criteria
Types of participants
Inclusion criteria
This umbrella review will consider systematic reviews of older adult humans with a mean age 60 years or older26 without clinically-diagnosed dementia/AD at baseline, including those who have reported difficulties with memory (memory complainers) and/or with mild cognitive impairment (MCI) as a result of the ageing process.
Exclusion criteria
The umbrella review will not include;
participants with a mean age of less than 60 years
participants with clinically-diagnosed dementia/AD at baseline
participants with cognitive impairment due to brain injury
studies of participants with vascular dementia
studies using animal models.
Types of intervention(s)
Inclusion criteria
This umbrella review will consider systematic reviews that have evaluated the effects of administration of any dose of the individual dietary interventions listed below for any duration. Dietary interventions included in this review are
alpha- lipoic acid
acetyl-L-carnitine
polyphenols
choline
inositol compounds
omega-3 polyunsaturated fatty acids.
Exclusion criteria
This umbrella review will not consider systematic reviews of;
combinations of individual dietary components or supplements
vitamin supplements
studies that combined drugs with a dietary intervention
studies of whole of diet approaches.
Types of outcomes
Inclusion criteria
Primary outcomes
This umbrella review will consider systematic reviews that include the following primary outcome measures:
cognitive function (as measured by psychometric tests).
Cognitive function tests diagnostic of MCI and AD include, but are not limited to, Alzheimer's Disease Assessment Subscale (ADAS-Cog), Clinical Dementia Rating Scale (CDR), Cambridge Cognitive Examination (CAMCOG), Mini Mental State Examination (MMSE), Telephone Interview of Cognitive Status (TICS).
Secondary outcomes
This umbrella review will consider systematic reviews that include the following secondary outcome measures:
analysis from brain imaging techniques including, volumetric cranial magnetic resonance imaging (MRI) scan, uptake of the radioligand 11 C-Pittsburgh compound B (PIB, which binds to fibrillar [beta]- amyloid (A[beta]) deposits in the brain by positron emission tomography (PIB-PET
analysis from blood biomarkers of MCI and AD risk (e.g. plasma Ab42,plasma Ab40, tau protein).
Exclusion criteria
This umbrella review will exclude cognitive function not measured quantitatively by a standard psychometric test.
Types of studies
The following criteria will be used to select systematic reviews for inclusion in the umbrella review.
Inclusion criteria
This umbrella review will consider systematic reviews, meta-analyses and pooled analyses identifying relevant scientific evidence from reviews;
Effectiveness - At least a comparator group (i.e. randomized controlled trials (RCTs), clinical controlled trials (CCTs), cohort studies)
Comprehensive systematic reviews (quantitative components only).
There may be an overlap of included studies in the identified systematic reviews, which will be apparent on full text examination. When this occurs, the frequency of overlap of studies will be noted.
Exclusion criteria
This umbrella review will not consider:
Critical reviews
Integrative reviews
Primary studies
Withdrawn/retracted publications
Literature reviews.
Search strategy
The search strategy will aim to find published systematic reviews and meta-analyses. A three-step search strategy will be utilized in this umbrella review. An initial limited search of MEDLINE and Web of Science will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the articles. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published from 1990 with no language restrictions will be considered for inclusion in this review. We selected 1990 as a conservative estimate for the earliest likely publication of a systematic review on this topic, as this pre-dates some of the earliest work in this field. Additionally, extending the search as far back as 1990 will help to identify whether a review is an update of a previous review.
The databases to be searched include:
Medline on PubMed, Web of Science, Cochrane Central (Database of Systematic Reviews and Cochrane Collaboration Central Register of Controlled Trials), Centre for Reviews and Dissemination Databases (Database of Reviews of Effects [DARE]) and the PROSPERO register, National Health Service Economic Evaluation Database (NHS EED and Health Technology Assessment Database), Joanna Briggs Institute (JBI) Library of Systematic Reviews and Implementation Reports and the Agency for Healthcare Research and Quality (US Department of Health and Human Services).
The search for unpublished studies will include:
The Alzheimer's Society register of projects, Google Scholar, Grey Literature Report (The New York Academy of Medicine) and National Technical Information Services. Systematic reviews embedded in reports and documents produced by government agencies or academic institutions will be considered.
Initial keywords to be used will be:
Systematic review, meta-analysis, Alzheimer, Alzheimer's, dementia, cognitive, cognition, memory, neuroprot*, brain; as well as terminology defined above in the inclusion criteria and relevant Medical Subject Heading (MeSH) terms. The asterisk (*) will be used as a wild card to represent any group of characters, including no character.
The keywords, index terms, titles and abstracts of retrieved studies relevant to the review topic will then be carefully assessed to identify all of the search terms for a comprehensive secondary search of the literature. This second phase will incorporate all of the identified search terms. This search will be followed by the third phase of searching the reference lists of all included studies.
Papers will be assessed for relevance utilizing the title, abstract and index terms, including papers found from searching reference lists of relevant papers. Screening will be conducted independently by two reviewers.
Assessment of methodological quality
Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute System for the Unified Management, Assessment and Review Instrument (JBI-SUMARI) and The Joanna Briggs Institute Reviewers' Manual 201427 as shown in Appendix I. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.
Data collection
The data of interest will be extracted using a standardized JBI instrument designed for umbrella reviews (Appendix II). The following information will be extracted:
* Type of review (i.e. meta-analysis or narrative summary)
* Countries where the studies were conducted
* Number of studies in the review
* Participants (number, age group)
* Type(s) of intervention(s)
* Outcomes identified (type/characteristics)
* Length and completeness of follow-up
* Primary outcome measures.
In the event that there is missing data, the authors of this umbrella review will endeavour to contact the author(s) of the paper in question to seek clarification.
Data summary
The above data extracted from selected reviews related to the interventions identified will be tabulated and accompanied by a narrative to address the review question in line with the inclusion / exclusion criteria and to answer the review question of whether the identified dietary interventions (as monotherapies) are effective in delaying the onset of cognitive decline in older adults. Tabular presentation of quantitative results describing overall effect sizes and a clear description of the intervention(s) will be presented with supporting interpretation. Tables will include a high level of detail for each included systematic review, including: the number of studies, total number of participants, heterogeneity of results, setting, age, co-morbidity and information about the intervention. Where possible, sensitivity of study findings will be considered based on the determinants of study quality, as assessed by critical appraisal.27
The results of the review will be provided in tabular format in a 'Summary of Evidence' table that includes the intervention name, the included systematic review(s) and a simple visual indicator of the effectiveness of the intervention using the three colors of the traffic-light: a beneficial or effective intervention (green), no effect or difference compared to a control treatment (amber), and a detrimental intervention or one that is less effective than a control treatment (red).27 The criteria that will be evaluated include methodological limitations, consistency, risk of bias and relevance to the study population.
Conflicts of interest
The authors have no conflict of interest.
Acknowledgements
This work was supported by CSIRO's Preventative Health Flagship.
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Appendix I:
JBI critical appraisal checklist for systematic reviews and research syntheses[Context Link]
Appendix II: JBI data extraction form for review for systematic reviews and research syntheses[Context Link]
Keywords: Alzheimer's disease; cognition; dementia; nutrition; dietary supplements; umbrella review