Effect of berry-based supplements and foods on cognitive function: a systematic review

In the current decade, a growing body of evidence has proposed the correlation between diet and cognitive function or dementia in the ageing population. This study was designed to appraise discoveries from the randomized controlled trials to confirm the effects of berry-based supplements or foods on cognitive function in older adults. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, EMBASE, Google Scholar, and ProQuest as well as SID, Magiran, and Iranmedex electronic databases were explored for human interventional studies up to March 2021. In total, eleven articles were identified using frozen blueberry (n = 4 studies), blueberry concentrate (n = 2), beverage (n = 3), capsule (n = 1), extract and powder (n = 1). These studies had been performed among older people with no recognized cognitive impairment or mild cognitive impairment (MCI). The primary outcomes included global cognitive function, psychomotor function, learning and memory, working memory capacity, executive functions, and brain perfusion/activity. To our knowledge, this is the first systematic review of available clinical trials on the effects of berry-based supplements and foods on cognitive performances as well as brain perfusion parameters among the elderly with normal cognition or MCI. Existing evidence concludes that berry-based supplements and foods have beneficial effects on resting brain perfusion, cognitive function, memory performance, executive functioning, processing speed, and attention indices.


Methods
The main objective of the current systematic review was to evaluate the efficacy of whole berries or a berry-based products (e.g. smoothie, juice) or berry extract/capsule consumption in adult or old subjects with healthy cognitions or MCI. The present study has been prearranged according to the guidelines and checklist in Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) 54 and "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" statement 55,56 . The investigation question was structured based on the PICOS (participants, interventions, comparators, outcomes, and study design) criteria (Table 1) as follows: Do berry-based dietary supplements or foods affect at least one recognized cognition related outcome in adult or old subjects with healthy cognitions or MCI? 57 . Literature search. The online databases (MEDLINE, Web of Science, Cochrane Library, Scopus, EMBASE, Google Scholar, Clininaltrial.gov, Science direct, and ProQuest in addition to SID, Magiran, Irandoc, and Iranmedex for Persian language literature) were employed for search across the titles, abstracts, and keywords of all articles for eligibility up to March 2021. Duplicate studies were excluded. Further, a manual search of the references of the reviewed studies was applied as additional resources to identify other suitable articles that were missed by the electronic search. Outcomes regarding at least one of the following indices: episodic memory, long-term memory, short-term memory, working memory, executive function, psychomotor reaction time, attention Study design Randomized controlled clinical trial with a crossover or parallel design A web-based systematic literature exploration was executed by means of the subsequent MeSH terms: ("randomized controlled trial" OR "RCT" OR "controlled trial" OR "intervention trial" OR "intervention study") AND (Chokeberry OR "Chokeberry extract" OR blackberry OR "blackberry extract" OR raspberry OR "raspberry extract" OR blueberry OR "blueberry extract" OR strawberry OR "strawberry extract" OR cranberry OR "cranberry extract" OR cranberry OR "cranberry extract") AND ("memory"(all Fields) OR "cognitive"(all Fields) OR "cognition"(all Fields) OR "forgetfulness"(all Fields) AND ("older"(all Fields) OR "adult"(All Fields) OR "elderly"(all Fields) OR "older"(all Fields) NOT (animal OR mouse OR mice OR rat OR pig OR cell OR in vitro OR systematic review)). After the primary search, titles and abstracts were sent out from EndNote X8 into Microsoft Excel to be screened. All saved articles were evaluated independently by two investigators (NB and ND) regarding titles and abstracts. Any differences were considered and resolved through consensus or by a third independent investigator (YS).
Inclusion and exclusion criteria. Table 1 reports the PICOS (Participant, Intervention, Comparators, Outcomes, and Study design) criteria accepted in this systematic review of clinical trials. The articles were limited to those published in English or Persian. Inclusion criteria were interventional studies implemented on humans examining the effects of whole berries or a berry-based products (e.g. smoothie, juice) or a berry extract/capsule supplementation on the defined cognitive-related outcomes. The outcomes included global cognitive function, psychomotor function, learning and memory, working memory capacity, executive functions, and brain perfusion/activity in adults and elderlies appraised to have healthy cognitions or MCI. Studies were also excluded if the participants had dementia; if the outcome of the study was not cognitive-related or if the study design was review article, semi-empirical study without a control arm, animal study, trial protocol, letter to the editor, case report, case series, observational study (cross-sectional, case-control and cohort), and unpublished trials.
Data collection. The information of studies regarding the year of publication, participant characteristics, demographic details, location, study design/methodology, interventions (protocol and duration), sample size, dropout and primary outcomes were extracted for each included study by the investigators (NB, ND and YS).

Quality assessment.
To assess the risk of systematic errors in the involved trials fulfilling the eligibility criteria, two authors (ND and MH) independently estimated the potential risk of bias based on the Cochrane Collaboration's tool for evaluating the risk of bias 58 . Briefly, the trial quality principles consisted of evaluation of: "randomization sequence generation, outcome assessment, blinding of subjects, personal and allocation concealment, imperfect outcome data, and discerning outcome reporting, as well as other sources of bias". Any discrepancies were debated and resolved by agreement or by a third independent reviewer (YS) if required. All trials were determined for each series of bias separately, and the trials were considered to have a score of bias as "low risk, " "high risk, " or "unclear risk" if the information was insufficient.
The outcome measures. The review's primary outcomes included episodic memory, long-term, and short-term memory, working memory, executive function, psychomotor reaction time, and attention.

Results
Study selection process. A flowchart explaining the study selection steps is presented in Fig. 1. A total of 259 studies were recognized from the primary database searches, and after eliminating the duplicates, 225 studies remained. Of these, 208 were disqualified after screening the title and abstracts of studies. The remaining 17 studies were evaluated in full text whereby 11 studies fulfilled the eligibility criteria (Fig. 1). The results of quality assessment of included studies is presented as Fig. 2.

Study characteristics.
Of the included studies, seven were randomized parallel group (n = 7), two were crossover, and one was a pilot study (n = 1) ( Table 2).
Cognitive function. Global cognitive performance. Dodd et al. 59 in a cross-over RCT among 18 healthy older volunteers aged 60-75 years with MMSE score ≤ 25 reported significantly worse global cognitive performance subsequent the control drink between 2 and 5 h post-consumption, while there was no significant difference in global cognitive performance between 2 versus 5 h post-consumption of the blueberry beverage. This means that blueberries could be valuable in terms of preserving cognitive function in older adults. This research had a small sample size and the absence of statistical power may partially describe the non-significant findings in such a relatively heterogeneous sample.
Psychomotor function. Psychomotor performances comprise the combination of accurate motor reactions, attention, and problem-solving capabilities 60 .
Krikorian et al. 61 detected a trend demonstrating better psychomotor processing speed (shorter time on task) in freeze-dried blueberry powder-treated older adults with MCI in comparison with placebo powder-treated subjects on the Trail-Making Test, part A after 16 weeks of supplementation. One of the main limitations of current trial was the relatively small sample size. Although the findings have been inspiring, there is an obvious necessity for larger trials.
Schrager et al. 62 studied whether six weeks of daily intake of two cups of frozen blueberry would affect older adults (n = 20). They found no significant variations in either the blueberry or placebo groups in simple reaction time with supplementation. Additionally blueberry intake resulted in no significant changes in gait speed under www.nature.com/scientificreports/ the single-task condition. Substantial within-group improvement in single-task step errors was established in the blueberry group. After adjusting for gait speed, the trend toward a significant improvement in the blueberry group diminished compared to the placebo group in the single-task condition. This study had a small and heterogeneous sample which probably resulted in non-significant results.
Learning and memory. In the RCT by Bensalem et al. 63 6-month supplementation with polyphenol-rich extract from grape and blueberry (PEGB) led to the higher total number of accurate words at the immediate recall in comparison with the placebo among 60-70-year-old healthy subjects with a BMI between 20-30 and 26 < MMSE score ≤ 29. Additionally, performance at the verbal episodic and recognition memory-free recall (VRMFR) was revealed to be affected by PEGB. Furthermore, PEGB led to lower paired associates learning total errors adjusted (PALTEA) among healthy elderly participants in comparison with the baseline scores. A significant interaction was observed between the PEGB effect and the baseline PALTEA score. However, no significant difference was seen between PEGB and placebo groups at the end of the intervention across the entire trial population. PEGB supplementation was established to be considerably more efficient in enhancing cognitive performances among subjects with ≥ 57 errors in the baseline PALTEA (subjects with the highest cognitive impairments). A high variability in baseline PAL score was observed in this study. Furthermore, the people in the control group had a lower PALTEA score at the second appointment than at baseline, probably because of a test-retest effect. This effect would reduce the likelihood to observe a substantial between-group difference, so the PEGB effects presented in this study may have been underestimated.
In the study of Dodd et al. 59 intake of a single dose of blueberry beverage resulted in better performance in the immediate word recognition task compared to the control intervention. In spite of no substantial intervention by time interaction, significantly more words were recognized 2 h after the blueberry consumption compared to the control drink. However, intake of a single dose of blueberry beverage had no beneficiary effect on delayed word recognition task compared to the control intervention. The small sample size may describe the non-significant results of this study.
Bowtell et al. 64 showed that 12 weeks of daily intake of blueberry concentrate supplementation improved international shopping list task with no significant difference compared to the placebo among 26 healthy older adults. The primary limitation of this study was the small sample size.
Krikorian et al. 53 examined the efficacy of daily drinking of wild blueberry extract for 12 weeks in a sample of nine older adults with early memory changes. Blueberry juice significantly enhanced the word list recall and   www.nature.com/scientificreports/ paired associate learning. The discoveries of this trial propose that moderate-term supplementation with blueberry can provide a neurocognitive advantage. The small sample size and lack of a completely matched control product were the primary limitations of this study. However, the relatively greater glycemic content of the grape juice as the placebo beverage may have influenced the cognitive performance.
The word recognition procedure wants the participants to identify previously presented words from the main word list whereas ignoring words from another word list and further phonetically or semantically matched diverse words. It has been known that episodic memory performance would decrease in older people 65 .
In a double-blinded, placebo-controlled RCT by Whyte et al. 65 daily supplementation with purified wild blueberry extract at 100 mg (WBE111) for six months resulted in a significantly improved function in late word recognition in the Reys Auditory Verbal Learning Task (RAVLT) (in contrast with the placebo in 65-80-year-old healthy subjects with self-reported memory complaints). These impacts were not seen for whole wild blueberry powder at 500 mg (WBP500) and 1000 mg (WBP1000). Furthermore, daily WBE111 supplementation caused an improving trend in visuospatial Corsi Block function (the entire number of orders properly recalled) in contrast with the placebo after 3 months of supplementation. www.nature.com/scientificreports/ Miller et al. 66 showed that 3-month supplementation of 37 men and women (age 60-75 years) with MMSE score ≥ 24 with freeze-dried blueberry resulted in fewer repetition faults according to CVLT, 2nd Ed. 67 after the end of intervention than they did at the baseline.
In the RCT by Krikorian et al. 61 freeze-dried blueberry fruit powder supplementation resulted in a significantly better nonverbal memory performance (SPAL) compared to the placebo powder in adults aged 68 years and older with MCI. In spite of the obvious improvement in the Hopkins Verbal Learning Test (HVLT) recall favoring the blueberry group, it was not a significant effect. An effect was observed also for semantic access and not for phonological access favoring the blueberry-supplemented group. The relatively low sample size may partially describe the non-significant findings in this sample.
McNamara et al. 68 examined the effect of 24-week supplementation with daily fish oil (EPA and DHA) or blueberry or both in elderly men and women aged 62-80 years old with mild, self-perceived cognitive deterioration in a randomized, double-blind, placebo-controlled trial. This was monitored for a further 24 weeks. There was an effect demonstrating enhanced insight in recognition memory on the HVLT for the blueberry-treated group. The memory insight improvement in the blueberry group was not preserved at week 48 (24 weeks following cessation of the supplementation).
Working memory (WM) capacity. WM represents the limited quantity of info that can be kept in mind and used in the practical implementation of cognitive jobs. It has often been correlated to intelligence, data processing, executive function, understanding, problem-solving, and learning 69 .
Nilsson et al. 70 in a randomized crossover trial showed that supplementation for five weeks among 46 healthy men and women within 50-70 years of age with a berry drink based on a combination of berries (blueberries, blackcurrant, elderberry, lingonberries, strawberry, and tomatoes) enhanced the performance significantly in the WM-test at 30 min by nearly 5% in contrast to the control beverage. The test employed in the current study demonstrated an extension of the Radeborg et al. developed methodology 71 . The tests consisted of twelve sets of short indicative sentences that could be either meaningful 'the boy came back from school' , or absurd, such as 'the cat struck the concept' . The sentences were read to the participants, and instantly after each sentence the participant had to specify if the sentence was meaningful or not. After each set of sentences, the participants had to repeat the first noun in each of the sentences. An apparent limitation of this study was that it was not probable to blind the products to the participants because of the evident dissimilarities. Furthermore, the test product included a mix of berries which discard possibilities to provide any suggestion concerning individual berries.
Krikorian et al. 61 found no effect for task switching as measured by the Trail-Making Test, part B task following blueberry supplementation in older adults with MCI compared to the placebo. No notable effect of PEGB was observed either by Bensalem et al. 63 for the WM measured through the Spatial Span (SSP) and the Reverse SSP.
In an RCT by Whyte et al. 65 daily supplementation with WBP or WBE for six months was not associated with encouraging impacts in older adults. WM was assessed through implementation of two different tasks, involving serial subtractions as designated beforehand by Bell et al. 72 plus Sternberg memory scanning. Probably, an element of practice effect occurred whereby, participants enhanced their approach on performance in these memory tasks thus decreasing the task sensitivity to the treatment. Additionally, possible deterioration of the capsule active constituents at 6 months and increased tolerance to the WBE are other issues to be considered.
Executive function. Miller et al. 66 reported that 3-month supplementation of 37 men and women (ages 60-75 years) with MMSE score ≥ 24 with freeze-dried blueberry resulted in a greater reduction in switch stimuli errors between follow-ups in task-switching test (TST) [a practice visit (visit 1), a baseline visit (visit 2), and 45and 90-day interposition visits (visits 3 and 4, correspondingly)] in comparison with the control. When group differences in physical activity and computer use were measured, the interposition endured. Post hoc analysis showed that, within the blueberry group, performance on the baseline and 90-day intervention visits as well as 45-and 90-day interposition visits were meaningfully different even when the Bonferroni modification was exerted.
In the study by Dodd et al. 59 a tendency towards lower switch cost was detected following the blueberry usage in comparison with the control beverage at the 2-h time point; however, the overall intervention by time interaction proved insignificant.
Bowtell et al. 64 showed that 12 weeks of the daily intake of a blueberry concentrate in healthy older adults improved WM and also the Groton maze learning role in comparison with the placebo. The WM was assessed by means of an n-back task, including 1-back and 2-back memory task blocks. Although the trial did not report significant effects in cognitive function, the percentage change in presentation of the 2-back tests showed a piece of weak evidence for upgrading in the blueberry versus the placebo. Although the findings are encouraging, there is a clear need for larger trials.
Krikorian et al. 61 observed no effect for perceived cognitive efficiency in daily tasks as measured by the dysexecutive questionnaire (DEX) after 16 weeks of supplementation with blueberry powder in comparison with the placebo.
Daily consumption of two cups of frozen blueberry for 6 weeks resulted in a significant improvement in foot placement and balance control during computerized dual-task testing of gait compared to the placebo in the Schrager et al. 's study 62 .
In the Whyte et al.'s study 65 , daily supplementation with WBE or WBP was correlated with no promising impacts on executive function and attention measured by modified attention network task (MANT) as described by Whyte et al. 73 Meanwhile, there were only two blocks with a stimulus length of 500 ms, with no noise condition applied. www.nature.com/scientificreports/ Brain perfusion/activity. Bowtell et al. 64 showed that 12 weeks of the daily intake of a blueberry concentrate in healthy older adults resulted in significant improvements in brain activity in response to blueberry supplementation compared to the placebo group within Brodmann zones 4/6/10/21/40/44/45, precuneus, anterior cingulate cortex (ACC), and insula/thalamus, along with significant enhancements in grey matter perfusion in the parietal plus occipital lobes. Brodmann area 21 [middle temporal gyrus (MTG)] is implicated in sound recognition as well as word and picture semantic processing 74 , language processing 75 , decoding gaze direction, deductive reasoning 76 plus intelligible speech and processing of verbal mental arithmetic 77 . Brodmann area 40 (supramarginal gyrus) plays a role in visual word recognition, auditory memory processing, and emotion recognition [78][79][80] . The left-hemisphere Brodmann areas 44 and 45 are associated with language processing (including production and comprehension) 81 plus higher cognitive functions including music, calculus, and WM 82 . The area 44 is involved in conditions of vicarious learning, i.e., attentive consideration of activities of another 83 . ACC plays a substantial role in attention, performance monitoring, error processing, emotional information processing, and motivational behavior [84][85][86][87][88] . Improved ACC activity is related to faster speed in a reaction time task 89 . The insula has various roles in humans from sensory and affective processing to high-level cognition (attention plus salience processing and speech) 90 . The thalamus is an important node in linkages enduring cognitive performances, identified to deteriorate in usual aging, comprising procedures of memory as well as executive functions and information processing 91 .
Boespflug et al. 92 in a double-blind, placebo-controlled RCT assessed the effect of daily blueberry supplementation or placebo powder for 16 weeks on blood oxygen level-dependent (BOLD) signal in sixteen 68-year and older adults with MCI. Blueberry-treated patients displayed augmented BOLD activation in the left pre-central gyrus, left middle frontal gyrus (LMFG), and left inferior parietal lobe throughout working memory load situations. A rising number of investigations have studied how motivation interrelates with particular cognitive performances, comprising attention, WM, and other executive functions. It's true for a subset of brain regions, which included the left pre-central gyrus 93 . The LMFG plays a crucial role in the progress of executive attention, literacy, and word production [94][95][96] . Left inferior parietal lobe is implicated in language comprehension plus production and converges semantic information pathways 97,98 .

Discussion
To our knowledge, this is the first systematic review of available clinical trials on the effects of berry-based supplements and foods on cognitive performances and brain perfusion parameters in elderlies with normal cognition or MCI. This review of 11 clinical trials provided inconsistent findings across the measured outcomes. Given the heterogeneity of study design, intervention type/dose/duration, outcomes of interest and cognitive tasks used, the described trials have revealed that berry-based supplements and foods may have beneficial effects on global cognitive performance (one study) 59 , psychomotor function (two studies) 61,62 , learning and memory (nine studies) 53,59,61,[63][64][65][66]68 , WM capacity (three studies) 61,65,70 ,executive function (six studies) 59,61,62,[64][65][66] , and brain perfusion/ activity (two studies) 64,92 . Nine of 11 trials were of poor or modest methodological quality principally because of suspicions about the blinding of outcome assessment, allocation concealment and random allocation to groups. The exact interventions given in the included trials were heterogeneous and in some trials poorly explained.
Fruit juice and powder may be impressive approaches to enhancing the total fruit intake. Regarding the nutritional worth, freeze-dried powder that is free of water maintains concentrated bio-available antioxidants, fiber, and other ingredients 99 . Some studies have proposed that the juicing procedure can result in a poor content of fiber and some bio-actives comprising polyphenols, vitamins, and minerals 100,101 , while another study suggests that processing can improve the carotenoid bioavailability 102 . On the other hand, the microstructure of the extract in contrast to the powders must also be considered. The extract lacks fibers and is water-soluble, while the full spectrum powders are very rich in insoluble fibers to which the polyphenols are bound. It is thus likely to assume that the polyphenols in the powders would not be as bioavailable as in the extract, and may hence be less worthwhile.
Most included studies had small sample sizes which may explain the non-significant findings. In one study, the product involved a mix of berries which made it impossible to give any conclusion regarding individual berries. In studies with longer duration of treatment, possible deterioration of the capsule's active constituents and increased tolerance to the product are other concerns. In most included studies, beneficial properties were established with dosage, which is achievable for daily consumption. Although other studies used higher amounts, this may only be possible for a limited therapeutic period. Nonetheless, establishing the involvement of berry metabolites in the cognition is puzzling, chiefly because berries have a different phytochemical profile, which can be extremely different across varieties.
Berries can be found as various little red, purple, or blue fruits. The frequently consumed berries include the blackberries (Rubus spp.), blueberries (Vaccinium corymbosum), cloudberry (Rubus chamaemorus L.), cranberry (Vaccinium macrocarpon), red raspberries (Rubus idaeus), black raspberries (Rubus occidentalis L.), and strawberries (Fragaria x ananassa). Less frequently consumed berries are black currants (Ribes nigrum), chokeberries (Aronia melanocarpa), lingonberry (Vaccinium vitis-idaea L.) and mulberries (Morus alba L.). Berries are eaten both as fresh fruit in addition to processed food products (for example beverages, extracts, jams, jellies, and freeze-dried). Generally, berries have low calories and high fiber, and contain different natural antioxidants such as vitamins C and E, plus other nutrients such as folic acid, calcium, selenium, alpha and beta carotene, and lutein. Berries are rich in polyphenols, with significant amounts of flavonoids (anthocyanins, flavonols, and flavanols), condensate tannins (proanthocyanidins), hydrolyzable tannins (ellagitannins and gallotannins), phenolic acids (hydroxybenzoic and hydroxycinnamic acids, chlorogenic acid), stilbenoids, and lignans 103,104 . Anthocyanins are a major group of natural, water-soluble pigments and provide the bright appearance to berries. Around 400 www.nature.com/scientificreports/ anthocyanins have been distinguished, which are mostly concentrated in the fruit external layer, particularly berries. Red berries, strawberries, and cherries have also anthocyanins in their body 105 . When findings of the dietary intermediations systematically reviewed in this study are weighed together, it seems that there are numerous essential mechanisms whereby berries may potentially provide cognitive health properties. The brain is predominantly exposed to neuro-inflammation and oxidative stress. This susceptibility further grows with age 70 . Amplified reactive oxygen species (ROS) production or reduced antioxidant protection is described as oxidative stress, which may contribute to the increase in various disorders such as neurodegenerative diseases 106 . Several medicinal properties of berries against oxidative stress-related disorders have been associated with their great content of phenolic antioxidants, particularly anthocyanin and phenolic acids. The antioxidant effects of anthocyanins were evaluated in vitro, comprising 1,1-diphenyl-2-picrylhydrazyl, radical scavenging property, oxygen radical absorbance capability and ferric decreasing antioxidant potential [107][108][109] . Furthermore, berries have proved to contain an acceptable content of vitamin A, vitamin, C and vitamin E, which function as antioxidants 31 . On the other hand, it has been discussed that inflammatory cytokines in the circulation can cross the blood-brain barrier (BBB), initiate a neuro-inflammatory condition, disturb neuroendocrine performance as well as neurotransmitter arrangements, finally resulting in cognitive impairment 110 . The transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway has a critical role in organizing inflammatory reactions 111 . Anthocyanin shuts off the initiation of NF-κB and activation of nitric oxide synthase-2, cyclooxygenase-2, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in macrophages 112,113 . Furthermore, anthocyanins are correlated with down-regulation of inflammatory cytokine genes including interleukin-6 and monocyte chemo-attractant protein-1 in adipose tissue 114 . Berry polyphenols improve mitochondrial function in intestinal Caco-2/15 cells activated with lipopolysaccharide (LPS), which reduces intestinal inflammation 115 . Metabolites of anthocyanin imitate active agents such as the anti-inflammatory salicylic acid (2-hydroxybenzoic acid) and are associated with useful variations in biomarkers of inflammation in in-vitro models 35,116 . A rodent model also revealed that anthocyanin intervention suppressed the biological activity of cyclooxygenase-2 117 . So anthocyanins decrease the omega-6 eicosanoids turnover (for example, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4)). Additionally, anthocyanin microbial metabolites, such as 3,4-dihydroxybenzoic acid (protocatechuic acid), 4-hydroxy-3-methoxybenzoic acid (vanillic acid), 4-hydroxy-3,5-dimethoxybenzoic acid (syringic acid), and 3,4,5-trihydroxybenzoic acid (gallic acid), are related with advantageous variations in biomarkers of inflammation in in-vitro models 118 .
Meanwhile, phenolic compounds are shown to be extensively metabolized into simple phenolic metabolites through the action of microorganisms in the colon 119 . These compounds may modify gut microbiota by stimulating favorable bacteria and deterring pathogenic bacteria. In healthy individuals, the gut microbiota modulations largely result in an increase in Bifidobacterium, Lactobacillus and Akkermansia, thus proposing a prebiotic-like property of the berries or their compounds [119][120][121][122] . Epidemiological explanations and studies in animal models confirm a common schema that involves the gut microbiota over the microbiome-gut-brain axis in the pathogenesis of neurodegenerative diseases such as dementia 123 .
The current study had some limitations that should be considered in explaining the outcomes of this systematic review. First, despite the collective body of nutraceutical studies, the number of studies included in this explicit review after a systematic review of the medical literature was less than what would have been expected. Secondly, there are two aspects including possible publication bias and the selected search terms that could have influenced the results of the review. Some unpublished abstracts and articles have not been included due to their unavailability. Further, we nominated only the English and Persian language due to limited resources, which in turn would increase bias. These may significantly reduce the size of our sample and therefore our capacity to explain statistically important findings. Another weakness of this review was due to the heterogeneity of the selected studies which considered a variety of outcome events. The confounding effects of variations in background polyphenol intake among the studies must be considered in interpreting the results. As a final point, there may be some probable parts not considered in the current systematic review, such as the magnitude of IQ, region, diet, and race. Furthermore, this review relies on the findings of available published studies, so any limitations of these studies are unavoidable limitations of our review study as well. Despite the specified limitations, this systematic review has been the first systematic review of clinical trials investigating the effect of berry-based dietary interventions on cognitive function.
In included trials, the highest duration of berry-based food or supplement administration was 6 months. Furthermore, most studies had relatively low sample sizes. Future investigations should attempt to clarify the potential special effects of berry-based food or supplement consumption in a prolonged period of treatment to distinguish possible significant enhancements in cognition. Furthermore, the safety of these interventions should be described by means of a systematic method of recording probable adverse events based on a good clinical practice.
This review intended to collect and discuss scientific evidence concerning the beneficial role of consumption of berry-based products on the prevention of cognitive decline. In summary, from available human studies, intake of whole berries or berry-based products, principally consumed as fresh or frozen fruit, or as unsweetened beverages, may be endorsed as part of a healthy dietary approach to preventing cognitive decline among the elderly with healthy cognition or MCI. The future well-controlled dietary intervention-based investigations, preferably clinical trials, should more carefully choose appropriate supplements (as crude materials or whole berries) with different dosing regimens to determine the accurate dose. Individualized dietary and nutritional recommendations, definitely through metabotypes determination, seem to be an achievable approach for taking full advantage of any benefits provided by berries and their polyphenols.