Effect of Grape and its Derivatives on Cognitive Function: A Systematic Review of Clinical Trials

Introduction

Cognition is the ability of an individual to process information through sense and experience in trying to learn knowledge and decision making [1]. It has components, including memory, language, orientation, judgment, interpersonal communication, actions, and problem solving. Mild cognitive impairment (MCI) is a degree of cognitive impairment that does not require a diagnosis of dementia and maintains the basic activities of daily life, which can be a warning sign for Alzheimer's disease [2]. According to a meta-analysis of 7 studies in 2019, the incidence of MCI per 1000 people per year was 22.5 for the ages 75-79, 40.9 (7.7-97.5) for the ages 80-84, and 60.1 (6.7-159.0) for those aged over 85 years. [3] According to the world health organization (WHO), in 2019, around 50 million people suffered from dementia, worldwide; and approximately 60% of them lived in low- and middle-income countries. There are also nearly 10 million new cases every year. The number of people with dementia is predicted to reach 82 million in 2030 and 152 million in 2050. Dementia has physical, psychological, social, and economic effects on patients and their caregivers, families, and the community [4]. Risk factors include neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Louis body dementia, etc.), physiological (normal-pressure hydrocephalus) and metabolic disorders (vitamin B12 and folic acid deficiency, endocrinopathy such as hypothyroidism, chronic metabolic disorders, such as uremia), tumor, trauma, infection, cardiovascular disease, medications, toxins, APOE4 allele status, cerebrovascular events, and chronic
high cortisol levels [2]. On the other hand, the brain is prone to oxidative stress with high oxygen consumption and high fat content. Therefore, oxidative stress damage to the brain is a strong stimulus which negatively affects the normal functioning of the central nervous system [5].

Polyphenols are compounds with potentially diverse biological properties and can be useful against oxidative stress, inflammation, the negative effects of aging, and etc. [6]. The dietary polyphenols protect neurons from damage caused by neurotoxins, suppress neuronal inflammation, and improve memory, learning, and cognitive function [7]. The most important active compounds in grapes are phenolic compounds [8], the most prominent of
which are phenolic acid, flavanol, flavonol, anthocyanin, and acetylbene. These compounds have antioxidant, antibacterial, anti-inflammatory, anti-diabetic properties and also have protective effects on the skin, liver, heart, and the brain [9].

Some studies have shown the improving effects of grapes and their derivatives on cognition [10-12] and others have not listed any effect [13, 14]. We are not aware of a systematic review trying to separate the long and short-term effects of intervention with
grapes and their derivatives on cognition; therefore, the present study was conducted.

Method

Data sources and search strategy

This systematic review is reported based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [15]. The search strategy to find related studies in English language was applied in Pubmed, Scopus, and Proquest databases (to find thesis) up to June 12, 2020. The keywords titled "MeSH" and other related phrases selected in the search strategy are as follows:

(((Vitis*[MeSH] OR grape[tiab] OR raisin[tiab] OR currant[tiab]))) AND (Cognition[MeSH] OR cognitive[tiab] OR "neurobehavioural manifestations"[tiab] OR volition[tiab] OR delirium[tiab] OR dementia[tiab] OR amnestic[tiab] OR "response interference"[tiab] OR learning[MeSH] OR Memory[MeSH] OR "item recall"[tiab] OR remembering[tiab] OR reminiscence[tiab] OR amnesia[tiab] OR "neuropsychological status"[tiab] OR demention[tiab] OR perception[tiab] OR perceptual[tiab] OR "size detection"[tiab] OR "size discrimination"[tiab] OR "size perception"[tiab] OR attention[tiab] OR motivation[tiab] OR "motor control"[tiab] OR "psychomotor skill"[tiab] OR responsiveness[tiab] OR executive[tiab] OR Planning[tiab] OR calculation[tiab] OR language[tiab] OR naming[tiab] OR writing[tiab] OR reading[tiab] OR praxia[tiab] OR praxis[tiab] OR orientation[tiab] OR judgment[tiab] OR evaluation[tiab] OR reasoning[tiab] OR computation[tiab] OR "problem solving"[tiab] OR "decision making"[tiab] OR comprehension[tiab] OR Gnosis[tiab] OR "Visuospatial Skills"[tiab])

To manage data sources, eliminate duplicates, and facilitate the systematic review process, the studies were transferred from databases to Endnote (version X9) software.

Inclusion criteria

The studies included in this systematic review should have the following characteristics:

1) Studies with randomized controlled clinical trial design, 2) Studies which used grapes or one of its derivatives containing a set of its polyphenols and micronutrients and without change due to cooking and fermentation (and not just a specific type of polyphenols) for intervention and another source of polyphenols has not been used as an intervention (such as grapes + blueberries), 3) published in English language.

Study selection, quality control, and data extraction

After screening titles and/or abstracts, full-texts of the studies were carefully checked. The quality of each study was confirmed through two independent individuals by using Jadad quality control checklist [16], and the cases that do not agree on them were consulted, and the final result was recorded.

Data extraction

Two independent reviewers extracted the relevant data according to a specific table, through which general information (author's surname, year of publication, and type of study design), characteristics of the study participants (number, health status, age, sex, intervention, and placebo), purpose of the study (evaluation of the effect of intervention on cognition by method or questionnaire), and the results (often significant results with P <0.05 between the intervention and control groups) were collected.

Results

Search results

Until June 12, 2020, 2237 studies were identified from three databases. After eliminating duplicates, 1884 publications were remained that were screened, 1775 articles did not meet the inclusion criteria in terms of title and abstract. Of the remaining 9 cases, all
[10-14, 17-19] were used for qualitative analysis. The flow chart of the study is shown in Figure 1.

Figure 1: Identification process for eligible studies

In the remaining studies, the effects of grape juice (7 studies; 4 long-term studies [10-12, 19], and 3 short-term studies [13, 18, 20]), freeze-dried grape powder (1 case) [14], Enoant Syrup (1 study) [17] on different areas of cognition (memory, attention, response speed, executive function, visual-spatial performance, recall, psychomotor skills, language, and estimated verbal IQ by different methods), and driving skill (as a multiple skill from different cognitive domains by designed virtual driving) were evaluated.

Study characteristics

The 9 studies (211 individuals) used in the qualitative analysis are summarized in Table 1. These studies were conducted from 2008 to 2020 and had a sample size of 10 to 43 people. Participants ranged from healthy to elderly people with mild cognitive decline.

Systematic review

Short-term intervention studies

In a study by Haskell et al. [18] in 2017, in healthy individuals, purple grape juice significantly reduced the reaction time for attention in the intervention group compared to the placebo group. Other cognitive items did not change significantly. In another study by the same person [20] in 2013, the Concord grape juice increased the speed of attention in the intervention group compared to the placebo group, but this intervention had no effect on memory. On the other hand, in a study by Hendrickson [13] in young smokers, Concord grape juice showed no change in implicit memory in the intervention group compared to the placebo group.

Long-term intervention studies

The study by Helmer et al. [19] on veterans with Gulf War illness had a significant increase in executive function (using RCAT) after adjusting baseline differences in the intervention group compared to the placebo group at the end of the study. In the study by Lamport et al. in 2016 [10], immediate spatial memory was significantly increased in the intervention group compared to the placebo group, but no change was observed in other cognitive items, including executive function (examined using RVIP). In this study, driving performance as a multi-skill of cognitive domains had a significant improvement in the intervention group compared to placebo. In the Krikorian study in 2010 [12], learning performance was significantly improved in the intervention group (Concord grape juice) compared to the placebo group. In another study by the same person in 2012 [11], in the placebo group, interfering errors in memory was increased compared to the intervention group, indicating the protective effect of grape juice in reducing memory errors. In Brunner's study in 2013 [17], no significant change was observed between the two groups, but in the intervention group, compared to the first level, there was a significant increase in attention. In a study by Lee et al. in 2016 [14], with the intervention of grape powder, no change was observed between the intervention and placebo groups in terms of psychological tests, but a negative correlation was observed between the combined measure of two brain regions metabolism (rSPL and liLAT) with improved performance in two areas of cognition (attention / working memory) in the intervention group (r = -0.69, P = 0.04).

Discussion

In general, this systematic review was done to study the effect of grapes and their derivatives on cognitive function. The consumption of grapes and its derivatives improved a number of cognitive components (such as attention, executive function, and immediate spatial memory, learning, and driving skill) in the intervention groups compared to control groups. Modulation of neuro inflammation [21], improvement of cerebrovascular function [22], change in intestinal microbiota [23], glucoregulation [24], and increase in spinal density and neurogenesis especially in hippocampus [25] are potential direct and indirect mechanisms in improving cognition by polyphenols.

The results of three studies with short-term intervention (same-day effect study) [13, 18, 20] of grape juice in healthy individuals in the young age group, showed the ineffectiveness of this intervention on several parameters. Only cognitive case in the intervention group was significantly different from the placebo and the attention rate was in 2 studies. This ineffectiveness could be due to the very short duration of intervention versus long-term interventions (between 12 to 24 weeks for studies with significant results between the two groups studied in this study) [10-12, 19] and also the age of the participants (young participants).

Table 1: Characteristics of eligible studies.

CVLT: California verbal learning test, S-PAL: Spatial paired associate learning test, fMRI: functional magnetic resonance imaging, VVLT: visual verbal learning test, VSLT: visual spatial learning test, RVIP: rapid visual information processing, TOH: tower of Hanoi, WAIS: Wechsler Adult Intelligence Scale, CPT-3: Conner’s Continuous Performance Test-3, Trail A or B: Trail Making Test A or B, BVMT-R: Brief Visuospatial Memory Test-Revised, RCAT: Halstead Category Test—Russell Revised Version, GCFS: Global Cognitive Functioning Score, sVOI: standardized volumes of interest, SPM: statistical parametric mapping, ADAS-Cog: Alzheimer’s Disease Assessment scale, cognitive subscale, MMSE: Mini-mental Status Exam, VLT: Hopkins Verbal Learning Test – Revised, CFT: Category Fluency Test, WCST-64: Wisconsin Card Sorting Test -64, WATR: Wechsler Test of Adult Reading, LiLAT: Left Inferior Lateral Anterior Temporal Cortex, RsPL: Right Superior Parietal Cortex, MMPI: Minnessota Multiphasic Personality Inventory, COMPASS: Computerized Mental Performance Assessment System, WFC: word fragment completion

In studies with long-term intervention, it was observed that 2 studies showed an improved memory or reduced memory errors [10, 11], 1 study improved executive function [19], 1 study improved learning performance [12], and 1 study improved driving skill [10]. Also in a study by Lee et al., an inverse correlation of rSPL and liLAT combined measurements with performance improvement in two areas (attention/working memory) was observed in the intervention group. The fact that in all these studies not all parameters of cognition changed or a single parameter did not change in the studied cases, could be due to the use of different psychological methods with different sensitivity and specificity, small sample size, non-random clustering in cases with large baseline differences, the effect of practice in crossoverstudies (better response in the second phase than the first phase), and inadequate wash-out periods (insufficient even up to 4 weeks).

In two of the studies, the activity of brain regions was also examined. Both studies showed that the activity of the right upper parietal cortex in the grape intervention group was changed compared to the placebo group; the first study used PET-scan and showed a significant increase (P = 0.03) [14] and the second study used fMRI and showed  a marginal increase (P = 0.07) [11]. Therefore, it can be expected that improving the activity in this area with this intervention can lead to improvement in working memory and speed of attention, since this part plays a role in working memory and attention [26-30] and this result is a further confirmation of the results obtained from the mentioned effect of grapes on these cognitive domains.

The appropriate quality of articles in qualitative analysis and conclusions based on the duration of the intervention was the strength of this study. The low number of studies with the same psychological assessment tools and short-term clearance periods in
cross-over studies (2 weeks) (the effect of the intervention was not eliminated in the group that intervened first after the placebo group) were the limitations of the study.

Conclusion

In general, this study showed that the long-term intervention with grapes and their derivatives might lead to an improvement in memory in 2 studies, and executive function, learning performance, and driving skill. However, its short-term intervention was not very effective and only 2 studies showed improvement in attention speed. Given the high heterogeneity between studies, more research is needed using more similar cognitive assessment tools for better conclusions.

Acknowledgements

Nothing to declare

Authors’ contribution

The first and second authors were more involved in this project than others. All authors participated in the preparation of the final version.

Funding source

None

Conflict of Interest

The authors declare that there is no potential conflict of interests in this review.