Does resveratrol improve cognition in humans? A scientometric study to an in‐depth review

Abstract Aim In order to understand the different processes and mechanisms of cognitive function and resveratrol (RES) as an active participant in pathophysiological events that affect cognitive function. Methods First, the Web of Science (core collection) was selected as the data source. To ensure the comprehensiveness and accuracy of the search data, the index was selected as “SCI‐EXPANDED”, and the search formula was TS = resveratrol AND TS = (“cognitive” OR “memory” OR “cognition” OR “mood”). Next, details of authors, keywords, journals, countries, institutions, references, and more were analyzed by CiteSpace and VOSviewer software. Finally, we explored the mechanism by which RES could improve cognitive impairment, that involves healthy young adults, healthy elderly, post‐menopausal women, and diseases involving Alzheimer's disease (AD), diabetes‐related cognitive impairment, mental illness, post‐stroke cognitive impairment, and neonatal hypoxic–ischemic injury. Results 287 valid papers were obtained. The scientometric results demonstrated 287 papers used in this study came from 1601 authors from 443 organizations in 38 countries, published in 169 journals, and cited 13,680 literatures from 2431 journals. Depression, AD, cerebral ischemia, diabetic cognitive impairment, and cognitive function in the elderly are all keywords of the co‐occurrence network. Conclusion This study supports the hypothesis that chronic RES intake may positively affect brain function. But it has become challenging to determine the optimal dose, time and duration of RES and improve the bioavailability of RES, which many researchers need to overcome.


| INTRODUC TI ON
Cognition is the process by which the human brain tissue receives and processes information, converts information into psychological activities, and then obtains the required knowledge and information, including language, calculation, memory, judgment, and execution.
Although sometimes investigators will study each functional region separately, various domains of cognitive function are always interrelated and play a role together. 1,2 Cognitive impairment refers to the pathological process in which the human body has abnormal intellectual processing processes related to learning, memory and thinking as well as judgment, which causes severe learning and memory impairment, accompanied by changes such as aphasia, apraxia, agnosia, or disturbance in executive function. 3 There are many factors causing cognitive impairment, of which age is one of the important factors, and the cognitive function of the elderly will inevitably decline with age, 4 which may also be triggered by a variety of neurodegenerative diseases, vascular cognitive impairment, brain injury and other diseases. [5][6][7][8] With the deepening of the "silver wave" process, the aging of the population has gradually become a new normal that is difficult to reverse in society and has gradually become a new challenge faced by the whole society, meanwhile, cognitive impairment is an important threat factor in the process of healthy aging of the elderly, 9 so the search for effective drugs to treat or prevent cognitive impairment is the focus of many researchers. Resveratrol (RES) is a natural non-flavonoid polyphenol compound that is mainly present in various fruits such as grapes, berries, and peanuts, and it is indicated that RES has a variety of pharmacological effects, including anti-inflammatory, 10 antibacterial, antioxidant, neurological and cardiovascular protection. 11 Furthermore, RES has been found to have a strong anti-aging effect, enhancing memory and delaying brain function decline, 12 therefore more and more researchers have investigated whether RES can improve cognitive impairment. It is interesting and meaningful to study the effect of RES treatment on the regulation of cognitive function, there is no scientometric analysis of the regulation of cognitive function by RES has been performed to date.
Scientometrics first emerged in the early 20th century, and in 1969, it formed an independent discipline and was widely used in literature analysis. 13 Details such as authors, keywords, journals, countries, institutions, and references can be obtained during the analysis. We need to use CiteSpace 6. 1.3 and VOSviewer 1. 6.18 software in scientometric analysis. CiteSpace can clearly outline the process of knowledge evolution and the historical span of literature in a certain cluster in the time dimension and understand the development process and trends in this field. 14 VOSviewer uses a probability-based data normalization method, which provides a variety of visual views in the fields of keywords, co-institutions, and co-authors, with prominent characteristics of simple drawings and beautiful images. 15 Scientometric research can summarize the current hotspots and provide future research directions for a specific field. Therefore, scientometric methods were selected to explore and discover the research hotspots of RES in improving cognitive function in this study.

| Literature search, screening and download
In this study, Web of Science (core collection) 16 was selected as the data source, and in order to ensure the comprehensiveness and accuracy of the search data, the index was selected as "SCI-EXPANDED", and the search formula was TS = resveratrol AND TS = ("cognitive" OR "memory" OR "cognition" OR "mood"). 17

| Basic quantification analysis
The 287 papers used in this study came from 1601 authors from 443 organizations in 38 countries, published in 169 journals, and cited 13,680 literatures from 2431 journals.

| Scientometric analysis of the author
By analyzing the authors of the literature, representative scholars and core research forces in this research field can be obtained.

| Scientometric analysis of the journal
According to the statistics of the journals to which the literature belongs, it is found that in the past decade, most of the journals accepting papers in this field belong to the fields of neurosciences, pharmacology, and biochemistry molecular biology except for a small number of comprehensive journals, and Table 2 shows the journals with the top 10 articles. The journal with the largest number   Table 2 revealed that the journal with the most average citations was "Plos One", with a total of 5 articles, and the per article were cited up to 62 times, which indicated that the articles published in this journal were of high quality and received much attention in the field of RES and cognitive function.

| Scientometric analysis of the country
In order to understand which countries have contributed most prominently to the field of RES and cognitive function research, this study analyzed the number of documents issued in 38 countries. Partnerships between countries showed close cooperation between countries, and the results are shown in Figure 2B.

| Scientometric analysis of the organization
In order to understand which institutions have the most prominent contribution to the field of RES and cognitive function research, this study analyzed the number of documents issued by 443 institutions.
First, visualization was performed by VOSviewer, and the results are shown in Figure 2C. The larger the circular node indicates that the number of documents issued is more; the node connection represents the association strength, and the thicker the connection indicates that the more times the two countries cooperate to issue documents; the node color represents different clusters.
Further analysis of the high-productivity institutions in this field, Table 4 presents the institutions in the top 10 of the number of documents issued. According to the data in Table 4, Newcastle University from the United Kingdom published a total of 14 papers, accounting for 4.88% of the total number of documents issued in this field, and obtained a total of 500 citations. This was followed by Barcelona University from Spain, which issued a total of 12 articles and obtained 678 citations. The third place is Zhengzhou University from China, which issued a total of 8 articles and obtained a total of 220 citations. The institution with the most average paper citation times was Idibaps, 5 papers received 365 citations, and the average paper citation times reached 73 times.

| Literature and reference analysis
The 10 most cited articles on RES in cognitive function studies are shown in Table 5.

| Generation and analysis of keyword cooccurrence network
According to scientometric theory, keywords indicate hotspots and trends in the research field. Keyword analysis also provides a typical overview of research trends representing journals as they reflect the focus of the article or author. A co-occurrence network view of keywords was drawn using VOSviewer for 287 articles,

TA B L E 5
The top 10 most-cited articles in the RES and cognitive function research field. and keywords with a frequency greater than or equal to 5 among them were selected for visualization, and the results are shown in Figure 2D. The larger the circular node, the more times the keywords appear, and the more they represent the domain hotspots; the node connection represents the association strength, and the thicker the connection indicates that the two co-appear in the same literature more times; the node color represents different clusters, that is the research theme. As shown in Figure 2D, the largest node is RES and cognitive function is the same as the research topic, and "RES" versus "cognition" is a cross-keyword in these clusters, suggesting that RES may affect cognition. In fact, RES has been used clinically to improve cognition, and it has also been repeatedly verified in basic experiments that RES can improve cognition. This article will focus on the effects of RES on cognitive function. From

| HE ALTHY YOUNG ADULTS
Enormous studies have examined how RES treats metabolic and neurodegenerative illnesses in animal and human models. However, the specific effects of RES on cell, tissue and organ function in healthy individuals are still unknown. According to a population-based study, the high-calorie diet is related to an increased risk of mild cognitive dysfunction 21 or dementia in the elderly. 22 Notably, caloric restriction has been indicated to extend the lifespan and improve learning as well as memory functions. 23 in the hippocampal CA1 region of mice to play the neuroprotective role. 12 However, another study of RES effect on neural progenitor cells has shown that RES adversely affects hippocampal neurogenesis and cognitive function by activating AMP-activated protein kinase (AMPK) and suppressing cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling. 25 Blood-borne brain metabolic substrates like oxygen and glucose have been shown to improve cognitive function in young healthy in-

| HE ALTHY OLDER ADULTS
As we all know, aging and cognitive dysfunction are closely related because aging impairs emotional and spatial learning memory.
According to the most recent World Health Organization (WHO) statistics, there are expected to be 55 million people living with dementia in 2019 and 139 million people globally by 2050. 27 The hippocampus in the aging human brain undergoes microscopic alterations, such as the development of amyloid bodies, granulovacuolar degeneration (GVD), and hirano bodies. Also, the two most well-known pathology indicators of AD, amyloid plaques and neurofibrillary tangles, are observed in those who do not have dementia. 28 GVD is a neurodegenerative alteration frequently seen in normal aging after 60 years old, predominantly in the hippocampal formation. The most seriously damaged neurons are those in the hippocampal CA1 area, followed by those in the presubiculum, CA2, CA3, and CA4 areas, in decreasing order of severity. In addition, some data indicated that free radicals play an important role in aging. The theory of oxidative stress, which is related to the reactions of biomolecules with oxides and peroxides, is based on free radicals, or reactive oxygen metabolites (ROMs).
They cause many pathological degenerative changes that are related to aging ( Figure 4). 29,30 When the body faces oxidative stress, reactive oxygen species (ROS) are metabolic byproducts essential for physiological function and can become toxic at high levels. 31 (Figure 4). 34 Age-related learning and memory impairment is reversed by RES. The findings of this study imply that RES helps prevent cognitive deficits in aged rats by limiting the production of inflammatory cytokines. 35 Besides, RES has been shown to protect against age-related cognitive impairment, especially when administered over a long period (10 mg/ kg for 8 months of treatment). 36

| P OS T-MENOPAUSAL WOMEN
By raising endothelial nitric oxide (NO), estrogen activates the estrogen receptors (ER) on endothelial cells to promote vasodilation ( Figure 5). 37 Compared to men or younger women, women over 55 have a higher risk of cardiovascular diseases. 38 Thus, these differences can be partially attributable to the rapid loss of estrogen in circulation, which could hasten age-related arterial stiffening and decrease tissue perfusion by reducing endothelium-dependent vasodilatation. Undoubtedly, estrogen is crucial for maintaining F I G U R E 3 Scheme illustrating the role of RES on cognitive function in healthy young adults.

F I G U R E 4
Scheme illustrating the role of RES on cognitive function in healthy older adults by figdraw.
memory, regulating metabolism, and maintaining bone health in women. According to a meta-analysis, post-menopausal women perform worse than pre-menopausal women on verbal memory and executive function tests. 39 Therefore, the loss of estrogen may increase the risk of cardiovascular and cerebrovascular diseases resulting in impaired cerebral perfusion, which is connected to accelerated cognitive decline.
It has been demonstrated that RES, a phytoestrogen present in various foods like grapes, berries and nuts, improves the function of endothelium vasodilators in humans through multiple mechanisms, including activating endothelial ER and consequently enhancing NO production. 40 In a clinical experiment of chronic RES administration (for 14-week treatment) for post-menopausal women, an improvement in cognitive function was observed, accompanied with enhanced neurovascular coupling. 41 A longer-term study that reached 12 months of RES treatment showed the same clinical effect, including improved overall cognitive performance and decreased cerebrovascular response to cognitive stimuli. 42,43 Animal experiments have better revealed the mechanism of RES to protect cognitive function. It is indicated that RES worked not only by decreasing oxidant stress indices, maintaining the structure of mitochondria, and decreasing condensed chromatin in the pyramidal cells of the hippocampal CA1 region but also by avoiding the effects on the uterus. 44 Long-term supplementation with low-dose RES tended to improve post-menopausal women's cognition and cerebrovascular function, which may mean slowing the accelerated cognitive deterioration due to aging and menopause, particularly in late-life women.
Further, explore of RES is warranted to determine whether these cognitive benefits can lower the risk of cognitive impairment.

| RE S AND AL ZHEIMER ' S D IS E A S E
AD is a chronic neurodegenerative brain condition that steadily erodes memory and cognitive abilities. For elderly adults, it is the F I G U R E 5 Scheme illustrating the role of RES on cognitive function in postmenopausal women by figdraw.
most typical cause of dementia. 27 The most important hallmark of AD is the presence of amyloid beta (Aβ) peptide as well as neurofibrillary tangles resulting from tau hyperphosphorylation in the brain, which indicates that they may be the primary trigger for neuronal damage. 45,46 Until now, there are only six drugs for the treatment of AD certified by the U.S. Food and Drug Administration (FDA). Not only that, most drugs can only relieve symptoms and cannot slow the progress of the disease. 47 Clinical treatment of AD is facing enormous challenges.
In the last decades, RES has been found to be a potential protector compound for the treatment of neurodegenerative diseases (i.e., AD, Parkinson's disease, and amyotrophic lateral sclerosis) resulting from its antioxidant and anti-inflammatory properties. Notably, RES can also modulate different molecular pathways in neurodegenerative diseases by specifically activating silent information regulator-1 (SIRT1). The protein deacetylase SIRT1 is the mammalian homolog of the yeast silent information regulator-2 (SIRT2), a member of the sirtuin family that has received considerable interest as a potential mediator of lifespan extension in a number of model animals. 48 In the clinical experiment of AD patients, RES reduces Aβ levels, improves brain volume, reduces the Mini-mental status score, and improves AD scores. [49][50][51] Furthermore, it is indicated that physiological doses of RES are safe and well tolerated. 52 In addition to being clinically useful in treating AD, RES in combination with donepezil hydrochloride has also been demonstrated to be effective in enhancing inflammatory factor indicators, fostering cognitive function, and facilitating patient prognosis. 53 Similarly, RES combined with rifampicin significantly improved cognition, reduced Aβ peptide accumulation, and recovered synaptophysin levels in the hippocampus of mice. It is indicated that RES enhanced the levels of BDNF and its precursor, pro-BDNF in the hippocampus ( Figure 6). 54 RES can activate the human silent information regulator 2/ SIRT-1 and inhibit the nuclear factor-κB, 5-lipoxygenase and cyclooxygenase-2 (COX-2) to reduce the proinflammation pathways.
It is also associated with increased levels of interleukin (IL)-10, interferonγ and IL-17 are also decreased. 20 Long-term administration of RES tends to get a better curative effect and prevent dementia, whether for AD transgenic (3xTg-AD) mice or non-transgenic (No-Tg) mice. Mice were fed with a diet supplemented with 100 mg/kg of RES from 2 months of age during the 10 months. 55 Hippocampal injection of Aβ1-42 induced AD models in rats and mice have also been used to investigate the effect of RES. 56,57 The prevention of neurodegenerative illnesses, maintenance of these conditions, and facilitation of their recovery are all closely linked to anti-inflammatory and antioxidant activities.

| RE S AND D IAB E TE S -REL ATED COG NITIVE IMPAIRMENT
As one of the most common and important complications of diabetes, diabetes-related cognitive dysfunction seriously affects the quality of patients' life. Besides, more and more clinical and epidemiological data have shown that the incidence of cognitive impairment in T2DM patients is higher than that in non-diabetic patients. 58 The pathogenesis of diabetes-related cognitive impairment is complex and unclear, and current studies have found that the possible mechanisms by which T2DM increases the risk of cognitive impairment mainly include insulin resistance, neuroinflammation, and brain neuronal injury. 59 Experimental studies have found that the development of diabetes-related cognitive impairment is closely related to SIRT1, one of the modulators of insulin resistance that plays an important role in learning and memory. 60 Interestingly, RES is considered to be a natural activator of SIRT1. Furthermore, it has been found to be effective in improving learning and memory ability without changing SIRT1 expression levels, 61 which indicates that the effect of RES on cognitive improvement may be partially dependent on activating SIRT1. In F I G U R E 6 Scheme illustrating the role of RES on cognitive impairment in AD by figdraw.
addition to SIRT1, the damage of synapses in the brain structure of diabetic patients is also one of the reasons for diabetes-related cognitive decline (Figure 7). RES has been observed to significantly enhance learning ability in streptozotocin (STZ)-induced diabetic rats, mainly due to its antioxidant and anti-inflammatory activities, ultimately promoting synaptic plasticity in the hippocampal region. [62][63][64] Synaptic plasticity includes modifications in the structure and function of synapses, which are integral components of learning and memory. 65 Meanwhile, cognitive decline is associated with a gradual decrease in structural and functional plasticity in brain regions that play a crucial role in cognitive function. 66 These expand plasticity under physiological and pathological conditions in the brain in terms of molecular mechanisms by which RES improves cognitive function.
Clinical studies revealed that one potential mechanism of T2DM-related cognitive impairment could be chronic hypoperfusion of the brain, possibly due to progressive microvascular dysfunction associated with advanced glycation end products (AGEs) formation in T2DM. 67 Moreover, it has been shown that adequate CBF is crucial for brain function. 68 Interestingly, RES was found to be effective in enhancing vasodilation in two randomized controlled trials, thereby reducing cognitive impairment in patients with T2DM. 69,70 Besides, it was further explored that a single dose of 75 mg RES could significantly increase neurovascular coupling capacity, with the greatest improvement observed using the lowest dose.
In summary, the improvement of cognitive dysfunction by RES in diabetes has been studied in both animals and patients. RES im-

| RE S AND MENTAL ILLNE SS
Depression is one of the most common neuropsychiatric disorders, and schizophrenia is a serious mental disorder, both of which are associated with cognitive impairment. 71 As we all know, stress is one of the important causes leading to the development of depression.
The chronic unpredictable mild stress (CUMS) procedure is a classic animal model used to reveal depression-like behavior and cognitive deficits in rodents. 72 In numerous animal models, it has been found that depression is closely associated with reduced hippocampal neurogenesis, altered synaptic morphology, and decreased BDNF expression. 73 BDNF, a crucial member of the neurotrophin family, is broadly distributed in the cerebral cortex and hippocampus. 74 BDNF is beneficial to the survival of existing neurons, promotes the growth and differentiation of neurons and synapses, 75 and also promotes long-term memory formation. 76 It has been indicated that RES improved cognitive impairment by up-regulating BDNF expression in the rat hippocampus. 77 Additional research showed that the ERK-CREB signaling pathway, which is linked to learning, memory, and neuroplasticity and essential for controlling various brain activities, is strongly tied to BDNF production. 78 According to experimental research, the enhanced BDNF expression via the ERK-CREB pathway in the hippocampus

F I G U R E 7 Presumed causes of memory impairment in patients with diabetes by figdraw.
of stressed rats may be the cause of the neuroprotective action of RES (Figure 8). 79 In addition to BDNF, SIRT1 is also essential for maintaining cognitive function, 80 and RES can reverse depressionlike behavior by activating SIRT1. 81 Clinical studies have found that  83 There are several variables that affect the bioavailability of polyphenols, including food composition, dietary habits, and the pathophysiological and nutritional circumstances of a person. 84 There are many reasons why RES lacks efficacy in human studies, which need to be further explored by researchers.

| RE S AND P OS T-S TROK E COG NITIVE DISORDER
Stroke is an acute cerebrovascular disease caused by cerebral blood supply disorders, which is one of the top three causes of death in the population of developed countries. 85 86 and oxidative stress has the greatest effect on hippocampal damage, thus leading to memory impairment. 87 It has been shown that RES effectively reduced inflammatory response and oxidative stress by regulating the activation of JAK/ERK/STAT signaling pathway, and then improved hippocampal neuron loss and cognitive impairment in ischemia-reperfusion (I/R) rat models (Figure 9). 88 While Piceatannol, a natural hydroxylated analogue of RES, 89

| RE S AND NEONATAL HYP OXI C-ISCHEMI C INJ URY
Neonatal hypoxic-ischemic (HI) injury causes brain dysfunction in children, such as permanent limb injury, cerebral palsy, epilepsy, and cognitive impairment. 92 Compared with adults, immature neonatal brains are more susceptible to oxidative stress. Previous studies have found that thiobarbituric acid-reactive substance (TBARS), a marker of lipid peroxidation, increased in the hippocampus of HI models compared with the normal group. Lipid peroxidation in the hippocampus is mainly due to increased ROS during hypoxia, which in turn leads to neuronal cell membrane damage, [93][94][95] suggesting that oxidative stress is one of the potential triggers of HI behavioral disorders. In addition, clinical studies have found that HI injury is mainly characterized by neuroinflammation, and anti-inflammatory activity has been observed to improve brain damage after HI. 96 As we all know, RES is effective in inhibiting nitric oxide production and increasing the activity of antioxidant enzymes (e.g., glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase) during hypoxia ( Figure 10). 97 oxidative stress, programmed cell death, inflammation and brain injury in neonatal rats by regulating the HO-1 signaling pathway to improve cognitive impairment. 105 In addition, the timing of RES administration has been investigated by numerous investigators. Prior to HI, early supplementation with RES was effective in improving long-term cognitive impairment due to HI, 106  injury, which are closely related to cognitive dysfunction. Therefore, the ability of RES to target different underlying mechanisms highlights its potential to treat a wide range of cognitive impairments.
Although the benefits of RES for improving cognitive function have been well documented in experimental animals, human clinical trials are only beginning to be explored. 107 Conflicting results exist regarding the effects of RES in humans, with some studies finding that RES improves cognitive function, but others finding that RES F I G U R E 9 Scheme illustrating the role of RES on cognitive impairment in post-stroke cognitive disorder by governing the JAK/ERK/STAT signaling pathway.
does not improve cognitive function. 33 Taken together, these studies support the hypothesis that chronic RES intake may positively affect brain function. Possibly, beneficial effects on the brain may translate into behavioral improvements following RES ingestion for sufficiently long periods of time. But why does RES lack efficacy in some human studies?
First, the optimal dose, timing, and duration of RES are unknown.
Second, RES has relatively low bioavailability due to its massive and rapid hepatic metabolism. Therefore, it has become challenging to determine the optimal dose, time and duration of RES and improve the bioavailability of RES, which many researchers need to overcome. All authors read and approved the final manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

ACK N OWLED G M ENTS
This work was supported by the National Natural Science Foundation of China (No. 81622051, 82174047).

CO N FLI C T O F I NTE R E S T S TATE M E NT
All authors declare there is no potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.