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Balk E, Chung M, Raman G, et al. B Vitamins and Berries and Age-Related Neurodegenerative Disorders. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Apr. (Evidence Reports/Technology Assessments, No. 134.)
This publication is provided for historical reference only and the information may be out of date.
Introduction
Disorders of the nervous system account for more long-term care, chronic suffering, and diminished quality of life than all other disorders combined. Age-related neurodegenerative disorders are chronic and progressive conditions that result from loss of the maintenance of neurons involved in cognitive, emotional, motor and sensory functions. The two most common age-related neurodegenerative disorders are Alzheimer's (AD) and Parkinson's diseases (PD). This report investigates the possible relationships both of B vitamin status and supplementation and of berry consumption with age-related neurodegenerative disorders.
This report was sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS), National Institutes of Health.
Methods
Key Questions
B Vitamins
- 1.
What is the evidence regarding mechanisms of action of the B vitamins B1, B2, B6, B12, and folate (singly and in combination) for preventing, decreasing the rate of progression of, or reversing the neurological changes associated with age-related neurodegenerative conditions such as Parkinson's or Alzheimer's disease?
- 2.
What is the evidence that the B vitamins B1, B2, B6, B12, and folate can prevent, decrease the rate of progression of, or reverse the neurological changes associated with age-related neurodegenerative conditions such as Parkinson's or Alzheimer's disease in humans
- 3.
What adverse events in humans have been reported in the literature for supplementation with the B vitamins B1, B2, B6, B12, and folate?
- a.
Do the frequency of adverse events vary with source, dose, or other evaluated factors?
Berries
- 1.
What are the constituents in berries with beneficial nerve- and brain-related health effects (from in vitro, animal, and human studies)?
- a.
In what other food sources are these constituents found?
- 2.
What is the evidence regarding mechanisms of action of berry constituents for preventing, decreasing the rate of progression of, or reversing the neurological changes associated with age-related neurodegenerative conditions, including Parkinson's or Alzheimer's disease?
- 3.
What is the evidence that the constituents of berries can prevent, decrease the rate of progression of, or reverse the neurological changes associated with age-related neurodegenerative conditions, including Parkinson's or Alzheimer's disease in humans
- a.
Is the source, species, dose, composition, characteristics, or processing of berries and berry constituents related to the effect of the intervention?
- 4.
What adverse events in humans have been reported in the literature for the constituents in berries?
- a.
Do the frequency of adverse events vary with source, dose, or other evaluated factors?
We reviewed all studies of berries and their constituents that addressed these questions, regardless of specific topic. However, for B vitamins we restricted the specific topics to the following:
B Vitamins: Human Studies
- Association between B vitamin treatment/intake with diagnosis or severity of AD or PD, cognitive function, or histopathology
- Association of B vitamin status and AD or PD diagnosis, histopathology, severity of disease, or cognitive function
B Vitamins: Animal / In Vitro Studies
- Effect of B vitamin supplementation or deficiency on cognitive function, movement disorders, histopathology, etc., in appropriate models
- Effect of B vitamins on the expression or function of AD-related genes
- Blood brain barrier and cerebrovascular endothelial function in relation to B vitamins
Approach To Analyzing the Literature
General Inclusion Criteria
Human studies. The common inclusion criteria for human studies consist of primary studies; English language publication, human adult subjects; analysis of the predictor or description, including quantification, of the intervention, and analysis of the following categories of outcomes: diagnosis or severity of AD, PD, other age-related neurocognitive disorders, or cognitive impairment; tests of cognitive function. We excluded other neuropsychiatric conditions and neuromotor diseases. For B vitamin interventions, we included only prospective trials.
Animal / in vitro studies. Animal and in vitro studies had to be published in full form in English language journals. We included all animal and in vitro models of diseases of interest and all outcome measurements related to the outcomes and/or associations of interest. We excluded studies that used inappropriate animal or in vitro models.
Literature Search Strategy. We conducted a comprehensive literature search to address the key questions. Final literature searches for English language publications on B vitamins and berries were conducted in MEDLINE® and the Commonwealth Agricultural Bureau (CAB) Abstracts™ between February and March 2005. The searches included both human, animal, and in vitro studies.
Both the B vitamin and berry searches used a common neurocognitive model that included the following terms: nervous system diseases, cognitive disorders, neurodegeneration, dementia, Alzheimer, Parkinson, Lewy body, neuron/nerve cells, brain, and related terms.
Additional studies were sought by contacting members of the TEP, and from reference lists of selected included articles, review articles and meta-analyses.
Data Extraction. The same data extraction forms were used for both the B vitamin and berry articles. Standard data extraction forms were used for human studies. For animal and in vitro studies, data extraction focused more on study hypotheses and conclusions than on design and quantitative results.
Grading of the Evidence
We used a 3-category grading system (A, B, C) to denote the methodological quality of each study. This system, with variations in criteria, was used for both human and animal studies. Separate criteria were used for human intervention studies, human association studies, and animal studies to account for different issues related to these types of studies.
- A.
Category A studies have the least bias and results are considered valid.
- B.
Category B studies are susceptible to some bias, but not sufficient to invalidate the results.
- C.
Category C studies have significant bias that may invalidate the results.
Human studies were also assessed for applicability:
Sample is
representative of the target population.
Sample is
representative of a relevant sub-group of the target
population.
Sample is
representative of a narrow subgroup of subjects only.
Results
B Vitamins
For B vitamins, 85 human studies and 17 animal or in vitro studies were evaluated. Although the review covers both neurocognitive function related to AD and related diseases and the movement disorders and motor systems degeneration related to PD and related diseases, only scant evidence was found regarding PD-related conditions.
Mechanisms of Action. Overall, research has shown that there were negative effects of thiamine, vitamin B6 and folate deficiency on animal's clinical status and/or histopathology, although not all deficient animals had worse performance in neurocognitive tests. Studies have found some positive effects of the supplementations of vitamin B6, vitamin B12, and folate on animal's performance in neurocognitive tests. Folate deficiency also showed a synergistic effect with both PD and AD pathology. Folate appears to protect against oxidative damage associated with ApoE gene knockout mouse models. Folate and B12 deficiency also induce presenilin-1, but do not appear to affect amyloid precursor protein. Thiamine (vitamin B1) is required for active transport of pyruvate across the blood brain barrier and maintaining integrity and normal permeability of the blood brain barrier. Folate is protective against homocysteine-induced cerebrovascular damage.
B Vitamin Intervention Trials
Vitamin B1. Three randomized controlled trials (RCTs), one non-randomized comparative trial and one uncontrolled cohort study that assessed the effect of thiamine intervention among people with either probable or possible AD were heterogeneous in their outcomes. Most found improvements in cognitive function or a slowed rate of deterioration using some measures of cognitive testing, either compared to control or in uncontrolled studies. However, either no difference between treatment and control or no improvement with thiamine supplementation was found in all studies with other measures of cognitive function. Only the uncontrolled cohort study reported blood levels of thiamine before intervention and included AD subjects with normal levels.
Vitamin B2. No prospective trial has evaluated the effect of B2 treatment on neurocognitive function.
Vitamin B6. Only two RCTs of cognitively intact population investigated the effect of B6 intervention on cognitive function. Participants had B6 levels within normal range in both trials. With treatment, a significant improvement was found in one of the RCTs with one cognitive function test. No other significant change was reported in the studies.
Vitamin B12. Five RCTs, one non-randomized comparative trial, and seven cohort studies assessed the effect of B12 intervention on cognitive function. Seven of these studies recruited participants with low B12 levels, while the remaining five studies assessed individuals with normal B12 levels. There was a large degree of heterogeneity across the studies. Although several studies suggested some improvement in cognitive function, few reached statistical significance. Results were frequently conflicting. Vitamin B12 was given intramuscularly in the only RCT that found a significant effect in the treatment group compared with the controls. Similarly, only cohort studies that used intravenous or intramuscular vitamin B12 reported a significant effect on cognitive function scores. However, the lack of data directly comparing oral and injected routes of vitamin B12 and the paucity of controlled trials limits any conclusions regarding the utility of different routes of administration.
Folate. Three RCTs and two uncontrolled cohort studies reported data on the effect of folate intervention. One RCT of subjects with dementia and normal folate levels found worse neuropsychological scores in the folate treatment group among subjects with dementia. Two other studies, one RCT and one cohort study, found significant improvement with folate supplementation compared to placebo in different populations. The study of patients with PD found no therapeutic benefit. Three studies reported blood folate levels before intervention, of which only two studies (one RCT and one cohort study) included patients with low folate levels.
Combination of B vitamins. Three RCTs and three uncontrolled cohort studies assessed the effects of a combination of B vitamins as interventions on cognitive function. Each used different daily doses of various B vitamins including folate, B6, and B12. All but one found no significant change in cognitive function after combination B vitamin supplementation. Only one RCT assessed the effects of combined vitamin intervention on patients with low blood folate levels; the remainder of the studies included patients with normal mean blood vitamin levels.
B Vitamin Dietary Intake Studies. Five longitudinal studies and five cross-sectional studies examined the association between the dietary intake levels of B vitamins and cognitive function or the risk of age-related neurodegenerative diseases. No significant associations were found between dietary intakes of B6 or B12 and PD, AD, cognitive function, or cognitive decline across three studies. One additional study found dietary intakes of B6 and B12 were positively associated with improvements in some, but not all, cognitive function measures. Two studies found opposite relationships between dietary intakes of folate and cognitive function in aging populations. Among the five cross-sectional studies, one found that subjects with low intake of thiamine, vitamins B2, B6, and folate, but not B12, scored significantly worse on verbal memory than those with relatively high intake levels. A second study found an association between vitamin B2 intake and cognitive testing in women, but not men. No association between dietary intake of B12 and cognitive function or diagnosis of AD was found in all five cross-sectional studies.
B Vitamin Status Studies
Overall. The association between thiamine status and age-related cognitive disorders is unclear. Half the studies found no associations and half found lower levels of thiamine or thiamine derivatives in tissues of patients with AD, cognitively impairment, and PD. However, none of these studies could differentiate between cause and effect (e.g., low thiamine levels resulting in disease vs. changes due to disease, including nutritional intake, resulting in low thiamine levels). The studies also failed to adjust for potential confounders. The cross-sectional studies of vitamin B2 found no association with diagnosis of AD, but low levels among people with PD (mean 101 ng/mL, where the normal range is 125 to 300 ng/mL). The large majority of vitamin B6 studies found no association between B6 status and the diagnosis of dementia or cognitive impairment, or cognitive function. A large number of studies have evaluated both vitamin B12 and folate status. Most of the longitudinal studies of vitamin B12 failed to find an association with diagnosis or severity of disease. While trends toward lower B12 levels among people with AD were found in cross-sectional studies, these associations were not consistent and proper adjustment for potential confounders was rarely performed. Both the longitudinal and case-control studies of folate status mostly reported an association between low folate levels (defined differently in different studies) and future diagnosis of AD and/or cognitive impairment. No association with PD was found.
Berries
One human study and 18 animal or in vitro studies (with 19 experiments) were evaluated.
Constituents of Berries. Only a limited number of the numerous constituents in berries have been examined separately from the rest of the fruit. These include tannins (procyanidin and prodelphinidin), anthocyanins and phenolics, from various berries.
Mechanisms of Action
Effects of the constituents in berries. One study showed that bilberry extract containing anthocyanins significantly increased rat brain uptake of triiodothyronine (T3). One study reported that 18 plant tannins, including those found in blueberry, red currant, and gooseberry, generally inhibit brain protein kinase C to a similar degree; however, the biological significance in live animals of this in vitro inhibition is unknown. One study demonstrated that that the anthocyanins in blueberry extracts were able to cross the blood brain barrier and the number of the total anthocyanins measured in the brain is associated with rats' learning performance. One study compared the effects of specific berry constituents on neurocognitive outcomes in rats. It did not appear that the anthocyanin component was solely responsible for improvements seen.
Effects of berry extract supplementation. Berry extracts were used to supplement animals' diet or added to in vitro study media in 14 studies with 15 experiments. Of these, only two studies used specific animal or in vitro models of AD. All of these studies were from the same group of investigators.
Blueberry and strawberry extract supplementation showed improved or protective effects on almost all biochemical markers and histology findings examined in the normal-aging rat brain, although only some of the neurocognitive tests and psychomotor functions were significantly improved.
Two studies used models of AD. The results suggested that it may be possible to reduce both the deleterious effects of dopamine and the putative toxic effects of amyloid β via various berry extracts. In mouse models with amyloid precursor protein and presenilin-1 mutations, blueberry extract supplementation seemed to prevent the deficits in Y-maze performance seen in the transgenic animals fed the control diets, although it did not affect amyloid β deposits.
Human Studies. Only one study evaluated any association between berry (or berry constituent) intake and neurocognitive function. A case-control study of patients with PD found that the preference to consume blueberries or strawberries was not statistically significantly associated with PD.
Adverse Events
Only 10 B vitamin studies reported adverse events among 254 subjects receiving B vitamin supplementation. These mostly reported no adverse events. The two studies reporting complaints cited mild gastrointestinal complaints in patients with AD taking high dose thiamine and possible mild neurological complaints with folate in patients with PD.
Limitations
Animal and In Vitro Studies
Few studies used specific, well-established models for AD or PD. Most were performed in normally aging rodents. It has also not yet to be established that the neurocognitive tests used in the experiments correspond to deficits seen in AD or PD. Most studies used models of severely vitamin deficient rodents. While these studies might elucidate which B vitamins are required for maintenance of brain function, they rarely addressed the question of the actual mechanism of action of the B vitamins. Almost all the studies of berries have been performed in a single laboratory. The grading of quality for animal and in vitro studies remains even less well validated than grading of human studies; however, improvements are clearly needed in the design and reporting of these studies.
Human Studies
Only a single, retrospective, human study of berries and PD has been reported. Among the human B vitamin studies, the majority were of poor quality. The majority of data come from cross-sectional studies, most of which failed to adjust for potential confounders. Among the trials of B vitamin supplementation, a large number were not RCTs.
All the B vitamin studies as a group also suffered from lack of standardization of B vitamin measurement technique, of normal ranges for B vitamins, of definitions of diagnoses of various dementias, and of tests of cognitive function. On the order of 50 different tests or subtests were used across the studies. There is scant evidence regarding the effect of B vitamins on PD.
Conclusions
The current research is largely inadequate to confidently assess the associations between B vitamin status and either disease or severity of disease, the effectiveness of B vitamin supplementation to prevent or ameliorate AD or PD, or putative mechanisms of action of B vitamins on age-related neurocognitive disorders.
In animal models, B vitamin deficiencies cause reproducible deficits and lesions and there is evidence to suggest a role for folate and vitamin B12 in regulating some genes and gene products related to AD.
There is limited evidence that injected vitamin B12 supplementation is of clinical benefit among demented or cognitively impaired patients, particularly when given soon after diagnosis of disease; however, overall the studies of B12 supplementation are inconclusive and the relative value of injected versus oral B12 remains unclear. Similarly, folate supplementation may also improve cognitive function but the clinical importance of the results remains unclear. Of note, though one study of folate supplementation found a significant worsening of cognitive function in treated patients with dementia. Other B vitamin treatments, including combination treatments, have not been shown to affect AD. Insufficient studies evaluated PD and no study evaluated vitamin B2 supplementation. The available literature does not conclusively support associations of B vitamin status as having an effect on age-related neurocognitive disorders. Conclusions are limited largely due to the poor quality of the research.
Almost all studies of berries and neurocognitive function have been performed by a single group of researchers. The large majority of studies have used blueberry and strawberry extract supplementation, both of which produced positive effects on biochemical markers and histology findings, and some neurocognitive tests and psychomotor functions. In studies of specific rodent models of AD, various berry extracts ameliorated the deleterious effects of the AD-related genetic defects. The human data are insufficient to make conclusions.
Future Research
Animal and In Vitro Studies
To clarify the actual biological or physiological responses that B vitamins may have on processes specific to age-related neurocognitive function, particularly PD, further studies would be needed. Studies in this field should be performed in a manner that will allow reproducibility, cross-species validation, and clear association with human brain processes. Likewise, understanding of what are the specific constituents in berries that appear to be of benefit, would require further investigation. Several questions of interest will continue to be difficult to address from human studies given ethical and practical limitations. Topics of particular interest that may be more suitable to animal research include sorting out the independent effects of elevated homocysteine and of low B vitamin levels and/or intake, and clarifying the relative harm of B vitamin deficiency (or benefit of B vitamin supplementation) in different stages of health or neurocognitive disease. Several large observational studies in humans have attempted to address the interaction with homocysteine, however, without the ability to closely control homocysteine and B vitamin levels (or intake) it is unlikely that human studies will definitively answer this question.
Human Studies
Due to either the limited amount of available data or the poor quality of the bulk of the research to date, well-performed, well-analyzed, large, prospective studies would be needed to address all the questions posed regarding the effects and associations between either B vitamins or berries and age-related neurocognitive function. Future studies should use only well-verified and commonly used measurement criteria for both predictors and outcomes. This may require additional research to verify the value of measurement tools for neurocognitive function. Further cross-sectional studies are of very limited value. Any human studies of both B vitamins and berries should be more of practical than theoretical value. For example, both dietary and supplementation studies should evaluate doses that a normal person can both easily incorporate into their lifestyle and afford, instead of testing regimens that could not be reasonably followed by most people.
- Executive Summary - B Vitamins and Berries and Age-Related Neurodegenerative Dis...Executive Summary - B Vitamins and Berries and Age-Related Neurodegenerative Disorders
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