Potential for diet to prevent and remediate cognitive deficits in neurological disorders

Potential for diet to prevent and remediate cognitive deficits in neurological disorders Abstract The pathophysiology of many neurological disorders involves oxidative stress, neuroinflammation, and mitochondrial dysfunction. There is now substantial evidence that diet can decrease these forms of pathophysiology, and an emerging body of literature relatedly suggests that diet can also prevent or even remediate the cognitive deficits observed in neurological disorders that exhibit such pathology (eg, Alzheimer’s disease, multiple sclerosis, age-related cognitive decline, epilepsy). The current review summarizes the emerging evidence in relation to whole diets prominent in the scientific literature—ketogenic, caloric restriction, high polyphenol, and Mediterranean diets—and provides a discussion of the possible underlying neurophysiological mechanisms. caloric restriction, cognition, fasting, ketogenic, Mediterranean, polyphenol INTRODUCTION Diet is increasingly understood to impact on neurological function. Animal studies show that consumption of a Western diet, high in saturated fat, refined sugar, and processed foods, impairs learning and memory and is associated with oxidative stress, inflammation, and mitochondrial dysfunction.1,2 On the other hand, various aspects of diet (eg, polyphenols) and diet patterns (eg, Mediterranean diet) have antioxidant and anti-inflammatory properties.3,4 Although neurological conditions, such as epilepsy, multiple sclerosis, and traumatic brain injury, have distinct disease processes, each exhibit increased oxidative stress, neuroinflammation, and disrupted energy metabolism, and reducing this pathology has the potential to improve neuronal function, repair, and growth (eg, for reviews see Halaris5 and Mattson et al.6). In light of the fact that these pathophysiological factors can be influenced by dietary means, it is reasonable that diet could alter the course and outcomes of these neurological conditions. Although the effects of diet on physical symptoms and pathology have been explored in many studies and reviews and the literature regarding the effect of diet on cognition in aging and neurodegeneration is becoming well-established, there has not as yet been a review of the evidence regarding the effect of diet on cognition in neurological disorders. This is surprising because preservation of cognition is often a predominant concern for patients with neurological disorders, perhaps due to the substantial impact on occupation, social relationships, activities of daily living, and quality of life.7 Perhaps more important still, diet is something patients can exert control over; therefore it is an appealing target for change. There is increasing public awareness of the potential link between diet and cognition; for example, a recent review showed that healthy diet was identified as a protective factor for cognitive health by respondents in 10 of 17 studies examined.8 This awareness appears to be manifesting in changed patient behavior; for instance, 64.7% of 428 people with multiple sclerosis surveyed in South Australia reported using dietary intervention, with approximately 30% of those citing improved memory as a reason.9 There is then a need to effectively review and summarize the objective scientific findings to date. There are several papers that provide an analysis of the ability for diet to remediate specific disease mechanisms and physiological symptoms (eg, seizures, mobility), and these are provided in Table 110–27 for the interested reader. However, none provide a summary of the ability for diet to ameliorate cognition specifically in neurological conditions. Although this has been done in terms of the relationship between diet and cognition in aging and dementia, there is no review that combines this literature with a wider range of neurological conditions. This article therefore aims to provide a summary of and draw attention to the links between these niche literatures, which to date have remained relatively separate. Improved understanding of the aspects of diet that the scientific literature has demonstrated to have therapeutic benefit in either preventing or remediating cognitive deficits will be useful for patients seeking self-efficacy in improving cognition, for clinicians in providing evidence-based recommendations for their patients, and to guide the direction of future research. Table 1 Reviews addressing the relationship between diet and cognition in various conditions, and diet as a treatment for neurological conditions more generally Diet type  Cognition in mental health  Cognition in aging and neurodegenerative conditions  Cognition in other neurological conditions  Diet as a treatment for various neurological conditions  Ketogenic  Not available  Baranano and Hartman (2008)10,a  Hallböök et al. (2012)15,b  Strafstrom and Rho (2012)13,c,d Baranano and Hartman (2008)c,d,10  Caloric restriction/fasting  Not available  Wahl et al. (2016)17,a  Not available  Maalouf et al. (2009)11,c,d  Polyphenolic  Trebaticka and Durackova (2015)26,a Zainuddin and Thuret (2012)27,a  Macready et al. (2009)12 Lamport et al. (2012)14  Not available  Pathak et al. (2013)21,e Riccio et al. (2011)22,d Bhullar et al. (2013)18,c,d Grosso et al. (2013)19,c,d  Mediterranean  Not available  Hardman et al. (2016)16 Lourida et al. (2013)20  Not available  Psaltopoulou et al. (2013)24,c,d,e Lai et al. (2014)23,e  Dietary Approach to Stop Hypertension (DASH)f  Not available  Tangney (2014)25  Not available  Tangney (2014)25,c  Very low sugar  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Gluten-free  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Paleolithic  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Diet type  Cognition in mental health  Cognition in aging and neurodegenerative conditions  Cognition in other neurological conditions  Diet as a treatment for various neurological conditions  Ketogenic  Not available  Baranano and Hartman (2008)10,a  Hallböök et al. (2012)15,b  Strafstrom and Rho (2012)13,c,d Baranano and Hartman (2008)c,d,10  Caloric restriction/fasting  Not available  Wahl et al. (2016)17,a  Not available  Maalouf et al. (2009)11,c,d  Polyphenolic  Trebaticka and Durackova (2015)26,a Zainuddin and Thuret (2012)27,a  Macready et al. (2009)12 Lamport et al. (2012)14  Not available  Pathak et al. (2013)21,e Riccio et al. (2011)22,d Bhullar et al. (2013)18,c,d Grosso et al. (2013)19,c,d  Mediterranean  Not available  Hardman et al. (2016)16 Lourida et al. (2013)20  Not available  Psaltopoulou et al. (2013)24,c,d,e Lai et al. (2014)23,e  Dietary Approach to Stop Hypertension (DASH)f  Not available  Tangney (2014)25  Not available  Tangney (2014)25,c  Very low sugar  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Gluten-free  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Paleolithic  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  The shaded columns indicate those included in this review. a Cognition not main focus but mentioned when relevant. b Focus mainly on epilepsy. c Aging and neurodegenerative conditions. d Other neurological conditions. e Mental health. f Not sufficient literature to warrant review in this manuscript but mentioned because evidence is emerging or diet is in popular use. This article aims to summarize the available evidence for the ability of diet to prevent or remediate cognition in neurological disorders and the putative underlying mechanisms. Because there have been systematic reviews conducted within the specialized areas, a narrative review approach was undertaken, with the aim of providing an overview of the emerging and exciting findings in this field together. As such, broader inclusion criteria (as outlined further below) for studies were allowed. This approach allowed for the provision of description of the epidemiological basis for thinking the selected diets (ketogenic, fasting, polyphenolic, and Mediterranean) should improve cognition, as well as inclusion of studies to describe the underlying mechanisms that suggest there is a causal basis for their effects. So as to be as inclusive as possible in the search for relevant studies, searches using combinations of diet-related terms (ketogenic, caloric restriction, polyphenol*, flavon*) and cognition-related terms (cognit*, neuropsy*, memory) were performed. Databases searched included PubMed and PsychINFO. The * or $ was used (dependent on database) for truncation to ensure all possible suffixes were covered (eg, cognition, cognitive). Reference lists of the included studies were also searched. The number of papers identified using these search terms is provided in Table 2, together with the final number of papers deemed relevant through search of the titles and abstracts with papers excluded for 1) repetition or 2) because the content was not relevant, largely for the following reasons: i) no focus on diet; ii) no assessment of cognition or cognitive domains; and iii) no focus on the searched neurological condition. The review is not limited to only these studies because inclusion of background studies and those dealing with the role of diet in specific disease mechanisms and the mechanisms thought to underlie improvements in cognition was desired. Table 2 Number of papers obtained using the listed search terms for each diet type and neurological disorder, as well as the final number of papers selected for review in the current manuscript (in brackets) Diet type  Epilepsy  Traumatic brain injury  Multiple sclerosis  Autism  Aging and neurodegenerative conditions  Ketogenic  64 (25)  1 (1)  2 (2)  4 (1)  23 (4)  Caloric restriction  1 (0)  2 (2)  1 (1)  0 (0)  4 (2)a  Polyphenolic  8 (7)  10 (6)  1 (0)  1 (1)  155 (16)b  Mediterranean  0 (0)  1 (0)  4 (4)  0 (0)  5 (3)c  Diet type  Epilepsy  Traumatic brain injury  Multiple sclerosis  Autism  Aging and neurodegenerative conditions  Ketogenic  64 (25)  1 (1)  2 (2)  4 (1)  23 (4)  Caloric restriction  1 (0)  2 (2)  1 (1)  0 (0)  4 (2)a  Polyphenolic  8 (7)  10 (6)  1 (0)  1 (1)  155 (16)b  Mediterranean  0 (0)  1 (0)  4 (4)  0 (0)  5 (3)c  a Search results since most recent review published January 2016.28 b Search results since most recent review published January 2012.29 c Search results since most recent review published May 2017.30 In sum, the present article is aimed at providing an overview of the literature suggesting that diet has the ability to ameliorate cognition in a wide range of neurological conditions. The diets selected as the focus of the article were driven by the literature (ie, prominence and level of evidence available); the other diets that were considered but not reviewed are detailed in Table 1.10–27 Note that the aim was to examine whole diet pattern, rather than specific nutrients. This distinction becomes blurry when considering polyphenols; however, it seemed reasonable to include epidemiological studies that examined diets rich in polyphenols or supplement studies where the supplement was a dietary source (eg, juice or cocoa). Neurological conditions that were searched were based on those for which there was evidence in the literature that diet could alter the course or outcome of those disorders (see Table 1 for reviews that provide this information). Thus, epilepsy, multiple sclerosis, traumatic brain injury, stroke, autism, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis were included. The reader will observe that many of these are not mentioned at all in the article because, although there may be evidence that diet can attenuate the neuropathology or physical outcomes, no studies specifically investigating cognition—the focus here—were found. Where the cognition-related literature had recently been reviewed (typically in relation to age-related or neurodegenerative disorders), only summaries of past reviews are provided, along with an update on any subsequent studies. Psychiatric conditions were not included. Although the authors recognize that these also involve neurological pathology, it was felt that their exclusion was reasonable considering the generally accepted distinction between psychiatry and neurology, as illustrated by the existence of 2 separate medical specialties. Nevertheless, any review papers in relation to diet and mental health have been included in Table 1 as an additional resource for the interested reader. KETOGENIC DIET The ketogenic diet has been used for treatment of drug-resistant epilepsy for a number of decades and is also being studied for its therapeutic effect in other neurological disorders. The ketogenic diet is high in fat and low in carbohydratea, typically at a ratio of 3–4:1. Fat type or chain length is not specified, but typically a ketogenic diet includes mostly saturated fats, often obtained from cream, butter, or oils.31 Variations of this diet include the modified Atkins diet, low glycemic index treatment, and medium-chain triglyceride diet. The primary mechanism through which these diets are thought to exert their effects is a reduction in glycolysis and a promotion of ketone body formation. The brain is able to use ketones to generate cellular energy. This shift in energy metabolism appears to reset cellular metabolic dysfunction and neuronal activity,32,33 although the exact mechanisms remain unclear and are currently the subject of further research. Various theories propose that ketone body generation alters metabolism of neurotransmitters such as glutamate and gamma-amino butyric acid (GABA), improves mitochondrial function, decreases oxidative stress, and activates energy-sensing signaling pathways such as the peroxisome proliferator-activated receptor (PPAR), mammalian target of rapamycin (mTOR), and AMP-activated kinase (AMPK) pathways. The beneficial effects of these diets for enhancing cellular metabolism and mitochondrial function have been described in more detail previously,32,33 whereas the effects specific to cognition have not been subject to the same extensive review. This article aims to summarize the current knowledge specific to the effects of ketogenic diet on cognition. Epilepsy The original ketogenic diet was described by Wilder in 1921 and proposed to treat epilepsy.34 There is now considerable evidence that the diet results in seizure reduction in up to three-quarters of drug-resistant epilepsy patients. Importantly, these findings include randomized controlled trials (RCTs).35 Although the seizure-reducing effects are quite well-established, studies that claim improvements in cognition have not been as rigorous. Animal studies In some animal studies, ketogenic diet has actually been proposed to impair learning and memory. For example, although ketogenic diet reduced seizure frequency in weanling rats with induced status epilepticus, rats on the ketogenic diet had impaired spatial learning and memory compared with rats on the control diet.36 Similarly, following kainic acid induced status epilepticus, rats on a ketogenic diet had fewer spontaneous seizures but poorer spatial learning than rats on a control diet.37 However, in both of these studies, the ratio of fat to protein/carbohydrate was far higher than is typically used clinically (≈8–9:1), and rats in the ketogenic diet groups failed to gain weight at the same rate as rats fed the control diet. Thus, rats in the ketogenic diet group were gaining weight at a reduced rate, indicating they may have been undernourished, without the adequate nutrient levels for normal growth and development of both body and brain. In contrast, animal studies where rats were placed on a 4:1 “classic” ketogenic diet showed a reduction in seizures and no accompanying deficits in spatial learning and memory.38 Furthermore, 2 studies that investigated induced recurrent seizures showed that ketogenic diet attenuated spatial learning deficits, suggesting the diet actually has a beneficial effect on hippocampal-dependent aspects of cognition, which are presumed to be mediated by this structure.35,39 To investigate the underlying mechanism of these effects, Kim et al.40 showed that administration of ketone bodies alone was sufficient to reduce seizures and improve spatial memory deficits in epileptic mice. Children with epilepsy In children with epilepsy, improvements in cognition following ketogenic diet appear to fluctuate with seizure control41 and can occur prior to the reduction of antiepileptic drugs.42 This suggests that effects on cognition are not just due to the ability to withdraw from medication and are intimately tied to reduced pathology associated with seizure reduction. As such, in the discussion of the effects of diet, it has been noted where cognitive improvements are accompanied by seizure reduction. Single case studies. Several single case reports describe improvements in cognition following ketogenic diet in different conditions that cause epileptic seizures. Two single case reports on glucose transporter 1 (GLUT1) deficiency syndrome, which causes frequent seizures, document improved processing speed and executive functioning, as well as seizure control, following ketogenic diet in a child aged 10 years43 and modified Atkins diet in a child aged 6 years.44 Similarly, drug-resistant seizures were controlled following ketogenic diet in a 5-year-old girl with Landau-Kleffner syndrome, and the patient regained normal cognitive functioning on formal neuropsychological testing, compared with complete unresponsiveness prior to diet administration.45 Quasi-experimental studies. Parental reports of improvements in problematic behaviors, attention, alertness, concentration, language, and school performance have been described in several group studies of ketogenic46–49 and modified Atkins diet.50 Several studies have reported on neuropsychological data obtained before and after diet initiation, with some studies finding no improvement41 and others showing varying degrees of improvement.42,51–53 However, these studies are typically small in numbers (n = 3–11) and use a nonrandomized, pre/post-intervention design due to difficulties in defining a suitable control group. Further, given children who experience seizures from a young age typically experience developmental delay, it is difficult to discern whether a lack of change from baseline scores might actually represent normal developmental trajectories after starting on the diet. Randomized controlled trials. To the authors’ knowledge, only 1 RCT has assessed cognitive functioning following ketogenic diet to reduce seizures. Twenty-six children and adolescents between the ages of 1–18 years who received the ketogenic diet for 4 months showed reduced seizure frequency and severity, compared with the 22 patients in the care-as-usual group.54 Note that although there was a wide age range overall, groups were matched for age. Cognitively, the ketogenic diet groups had greater improvement in receptive vocabulary and simple reaction time but no improvements in tasks assessing motor activation or integration of visual and motor abilities.55 Although receptive vocabulary can be used as a predictor of general cognitive functioning, more comprehensive neuropsychological assessment, including measures of attention, working memory, memory, and executive functioning, are warranted. Adults with epilepsy Quasi-experimental studies. In adults with refractory epilepsy, there are subjective reports of improvements in alertness and concentration following ketogenic diet.56,57 However, studies of adults placed on a ketogenic diet for 6–12 months, which have used objective neuropsychological testing, have not shown any clear change in cognition despite reductions in seizure frequency.58,59 It may be the case that early intervention with ketogenic diet is necessary to prevent developmental delay from occurring. This interpretation is supported by studies that suggest improvements appear to be largest in the youngest children.52 Other neurological disorders There are 2 putative mechanisms that are proposed to underlie the beneficial effects of ketogenic diet on neurological function. First, ketogenic diet reduces oxidative stress by decreasing reactive oxygen species,60 increasing levels of antioxidant agents,61 increasing mitochondrial biogenesis,62 and reducing inflammation.63 Second, ketones offer an alternative to glucose as a source of fuel to the brain. Thus, ketogenic diet may improve neurological function in conditions such as multiple sclerosis, traumatic brain injury, and Alzheimer’s disease because these conditions demonstrate increased oxidative stress,64–66 neuroinflammation,67–69 and impaired glucose metabolism in the brain.70–72 Similarly, the ketogenic diet has been suggested as an additional therapy for individuals with autism in light of observed disturbances in mitochondrial energy production in this condition.73 The focus in previous reviews10,13 has typically been on reducing pathology in these conditions (eg, demyelinating lesions in multiple sclerosis or axonal cell death in traumatic brain injury) and resultant effects on level of physical disability, with these papers referenced in Table 1. In contrast, there have been no papers summarizing the effects on cognition. Here what is known regarding the effects of ketogenic diet on cognition in traumatic brain injury, multiple sclerosis, age-related cognitive decline, and autism is discussed. Traumatic brain injury Ketogenic diet administered for 7 days after traumatic brain injury in adolescent rats improved recovery of memory function,74 with several studies suggesting the underlying mechanism to be reduced alterations in cell metabolism and cell death.75–77 However, there are no human studies to our knowledge that investigate ketogenic diet and cognition in traumatic brain injury. Multiple sclerosis In an animal model of multiple sclerosis, ketogenic diet reduced neuroinflammation, with corresponding attenuation of memory dysfunction.63 One RCT has been carried out in 20 patients with multiple sclerosis. Ketogenic diet (<50 g of carbohydrates, >160 g of fat, and <100 g of protein intake daily) for 6 months improved self-rated mental and cognitive health, compared with 20 patients maintained on diet as usual.78 The scale used was self-report and included ratings of concentration, attention, and memory. However, it is difficult to establish a blinded control condition in such trials due to the nature of the intervention; therefore, future studies would benefit from objective neuropsychological testing rather than subjective report of cognitive improvement. Autism In a prospective study examining 30 children with autistic behavior who were placed on a ketogenic diet for 6 months, 23 of the patients adhered to the diet, with the other 7 reporting gastrointestinal symptoms or dislike of the diet. Improvement on the Childhood Autism Rating Scale was noted in all 18 patients who were able to adhere to the diet.73 The rating scale contains several items that assess cognitive and behavioral characteristics, although specific item scores were not reported. The mechanism of action was hypothesized to be an increase in ketone bodies attenuating disturbed mitochondrial function and improving the synthesis of γ-aminobutyric acid (GABA). Age-related cognitive decline Animal studies In aged rats, ketogenic diet administered for 3 weeks improved learning and memory.79 This was associated with increased angiogenesis and capillary density, suggesting the ketogenic diet may support cognitive function through improved vascular function. Randomized controlled trials In 20 older adults with Alzheimer’s disease or mild cognitive impairment, consumption of a drink containing medium-chain triglycerides to elevate serum ketone body levels improved performance on a brief screening tool covering several cognitive domains, including attention, memory, language, and praxis.80 However, this effect was observed only for those individuals without the Apolipoprotein-E (APOE) e4 allele, suggesting these individuals are better able to use ketones than APOE e4 carriers. In 23 older adults with mild cognitive impairment, ketosis was induced using a very low carbohydrate diet (5%–10%) and was shown to improve verbal memory performance compared with a high carbohydrate diet (50%), with improved memory positively correlated with ketone levels.81 One other RCT in 152 individuals with Alzheimer’s disease administered an agent to increase serum ketone bodies, finding improved performance on cognitive screening (Alzheimer’s Disease Assessment Scale–Cognitive Subscale) compared with placebo. Although this is a pharmacologic intervention, it lends further support for increasing ketone bodies via dietary means to improve cognition in Alzheimer’s disease.82 Conclusion In sum, the findings regarding the effect of ketogenic diet on cognition in neurological conditions are limited but interestingly suggestive at this stage. Although animal models do provide some evidence for a causal role, they do not always accurately represent the underlying pathogenesis of neurological conditions. Most of the human studies to date have been quasi-experimental, using a pre/post-intervention design but without randomization or an adequate control group. However, the RCTs that have been conducted have demonstrated a beneficial effect of ketogenic diet on verbal receptive vocabulary and reaction time in children with epilepsy and self-rated attention, concentration, and memory in adults with multiple sclerosis. Although neuropsychological testing could have been more comprehensive in both of these studies, the results do provide causal evidence and suggest that further studies are warranted to document the cognitive effects of the 4:1 ketogenic diet, both in epilepsy and other neurological conditions. FASTING/CALORIC RESTRICTION Prior to ketogenic diet, calorie restriction was recognized as an effective treatment for epileptic seizures and, more recently, has been recognized as a potential means for increasing lifespan and reducing the incidence of age- and lifestyle-related disorders such as diabetes, cancer, and cardiovascular disease.83,84 Protocols for implementing dietary restriction are varied. Restriction can be achieved through an overall reduction in daily calorie intake, with reductions typically between 30% and 40%.85 Alternatively, intermittent fasting can be implemented, with periods of reduced or no calorie intake interspersed with ad libitum feeding. Similar mechanisms appear to underlie the neuroprotective mechanisms of caloric restriction and ketogenic diet. As with the ketogenic diet, a central feature is a reduction in glycolysis and an increase in the body’s production of ketone bodies, resulting in reductions in inflammatory mediators, proapoptotic factors, and oxidative stress, as well as improved mitochondrial function.11 These mechanisms are proposed to underlie the ability for caloric restriction to reduce neuronal pathology in Alzheimer’s disease, Parkinson’s disease, ischemic stroke, and multiple sclerosis.78,86,87 A few studies have additionally examined the effects of caloric restriction on cognition in neurological disorders. A brief discussion of the findings in relation to age-related cognitive decline has been included herein because previous reviews have a greater focus on protection and repair at the neuronal level,88 but the authors are not aware of any review focusing on cognition. Age-related cognitive decline The most recent review of the literature on this topic was conducted in 2016 and evaluates the literature regarding the beneficial effects of caloric restriction on brain aging and Alzheimer’s disease.28 In the summary below, the findings from this review that are related to cognition have been included, and a brief review of papers published since the review has been provided. Animal studies In terms of cognition, several studies have shown that dietary restriction reduces age-related learning and memory impairments in rats.89–91 Dietary restriction does not appear to require lifelong adherence to obtain benefit. Rats that were fasted every second day for a period of 3 months in late life showed improvement in learning and memory, accompanied by improved mitochondrial function and synaptic protein expression.92 Since the publication of Cauwenberge et al.’s 2016 review, there have been 2 animal studies published that have investigated the effects of caloric restriction on cognition in rodent models of aging or neurodegeneration. In aged mice, caloric restriction preserved memory performance and reduced the rate of decline in cerebral blood flow usually associated with age. Caloric restriction in ApoE-deficient mice resulted in better memory performance, which was associated with decreased tau-phosphorylation and increased synaptic plasticity. Randomized controlled trials Consistent with the animal literature, dietary restriction for 3 months was shown to improve verbal memory compared with controls in normal-to-overweight older individuals (mean age, 60.5).93 In obese elderly individuals with symptoms of mild cognitive impairment, caloric restriction–induced weight loss was associated with improvements in verbal memory, verbal fluency, executive function, and global cognition.94 The 2016 review noted no other trials in aging or neurodegenerative diseases that have investigated cognition, and a search did not reveal any articles that have been published since then. Other neurological disorders Traumatic brain injury Animal studies. In a rat model of traumatic brain injury, fasting animals for 24 hours following moderate injury improved recovery of memory function, which was associated with improved mitochondrial function and reduced cell death at the site of the injury.95 Maintaining rats on a calorie-restricted diet (70% normal food intake) for 3 months prior to head injury substantially attenuated memory deficits, increased brain-derived neurotrophic factor, and reduced the size of the cortical contusion.96 Multiple sclerosis Animal studies. Three cycles of fasting (3 days of fasting out of 7 days) stimulated remyelination and ameliorated both disease severity and clinical symptoms in experimental autoimmune encephalitis, a mouse model of multiple sclerosis.78 Randomized controlled trials. Following success of the mouse model, the same researchers investigated a potential “fasting-mimicking diet” in humans. Considering the innately undesirable nature of fasting, they aimed to design a diet that would be tolerable, involving consuming only 800 kcal on day 1, followed by 200–250 kcal of vegetable broth or juice plus 3 tablespoons of linseed oil on days 2–7 and reintroduction of solid foods on days 8–10. Twenty individuals with multiple sclerosis were placed on the fasting-mimicking diet for 10 days, then the Mediterranean diet for the remainder of the 6 months. Compared with a regular diet group, a clinically meaningful improvement was demonstrated in mental health–related quality-of-life scores, which include a self-rated improvement in general cognition (attention, concentration, and memory).78 The diet group had lower lymphocyte counts and higher white blood cell counts, as well as improved estimated disability status scale scores. Because the fasting-mimicking diet and Mediterranean diet were administered to the same group, it cannot be stated definitively that effects were due to fasting-mimicking diet or the following period of Mediterranean diet; however, there is at least now evidence of safety and tolerability of cycles of caloric restriction in multiple sclerosis. Conclusion In sum, the animal data strongly suggest a causal role for caloric restriction in reducing the effects of aging on memory function. The results of 2 RCTs in older individuals and overweight individuals with mild cognitive impairment support the animal data. In traumatic brain injury, animal models show improved memory function, although there have been no human trials. In a rodent model of multiple sclerosis, intermittent fasting reduced clinical symptoms, and the same diet improved self-reported attention and memory. Overall, there is mounting evidence that caloric restriction can improve longevity and health span, although fewer studies have investigated effects on cognition. The research summarized above is promising; however there are few human clinical trials, perhaps due to difficulty recruiting individuals who will commit themselves to such stringent diets as implemented in the animal studies. Therefore, research may instead focus on biochemical compounds that mimic the physiological effects of caloric restriction. POLYPHENOLS Polyphenols are natural compounds found in plant-based foods, which are proposed to be beneficial to cognition due to their antioxidant and anti-inflammatory properties.3 They are classed into subgroups, including flavonoids, lignans, phenolic acids, and stilbenes. This aspect of diet is included in the review because the polyphenolic compounds are also readily obtained through dietary sources. Although many of the supplement studies are at concentrations that would be difficult to obtain solely through diet,97,98 the epidemiological studies discussed herein do suggest that dietary consumption of polyphenols at levels that could be achieved through diet (eg, >600 mg/d of polyphenols or > 495 mg/d of flavonoids have been used as cutoffs14,99) is associated with improved cognition. This would be achievable through diet, with 200–300 mg of polyphenols per 100 g of various fruits (eg, grapes, apples, dark berries) or 100 mg of polyphenols per cup of tea or large coffee.100 Further, the supplement literature can guide which diet sources should be sought out. Age-related cognitive decline Two relatively recent systematic reviews have summarized the evidence for the beneficial effects of flavonoids12 and all polyphenol groups on cognition.29 Briefly, Lamport et al.29 found that across 28 epidemiological and intervention studies consumption of added polyphenols in the diet in healthy or mildly cognitively impaired older adults had beneficial effects on cognition, in particular for declarative and spatial memory. The most beneficial polyphenol sources appeared to be berry fruit juices and isoflavone sources such as soy protein or soy isoflavone supplements. Across 15 RCTs that examined the effects of flavonoids on cognition, Macready et al.12 found a positive association between flavonoid consumption and cognitive function, with all but 3 studies showing improvements in cognition. The greatest benefit appeared to be conferred to memory and executive function, with some increases also seen in general cognition and processing speed. Both reviews noted a lack of consistency among cognitive tests used, dose, and duration of interventions, making study comparisons difficult. Since the publication of these reviews, a few studies that examined the effect of dietary polyphenol intake and cognition in aging and neurodegenerative conditions have been published. They are reviewed below. Animal studies In rat models of Alzheimer’s disease, grape seed,101 curcumin,102 lychee,103 dark chocolate,104 green tea,105 red wine,106 and cinnamon 107 have been shown to improve learning and memory performance. Observational studies In a cross-sectional study, urinary biomarkers of polyphenol intake were associated with better scores in immediate memory in individuals aged 55–80 years.108 In 652 individuals aged 65 years or greater, higher urinary biomarkers of polyphenol intake over 3 years were associated with lower risk of cognitive decline on a brief cognitive screening tool and in processing speed on Trail Making Test A.99 In a large-scale prospective study in 2574 middle-aged adults,109 high total polyphenol intake measured using dietary records was associated with better language and verbal memory assessed after a follow-up of 13 years. Randomized controlled trials Several studies investigating the effects of supplementation with various phenolic compounds to remediate cognitive decline in aging have been conducted. Cocoa is high in polyphenols, including epicatechin, catechin, and oligomeric procyanidins.110 In individuals aged 40–65 years, consumption of a cocoa-containing drink for 30 days enhanced positive mood compared with placebo, but no effects were observed for cognition.111 In another RCT, healthy elderly individuals who consumed a high cocoa diet for 3 months had improved memory function on a pattern separation task, which was accompanied by enhanced activity in the dentate gyrus, the area of the hippocampus responsible for neurogenesis.112 Grape juice is rich in polyphenols, including resveratrol, anthocyanins, and flavonoids.113 Healthy women aged 40–50 years who consumed grape juice for 12 weeks consistently showed benefits over a taste-matched placebo across several measures of cognition, including verbal recall, executive function, and lateral tracking.114 Similarly, individuals aged 68–90 years with mild cognitive impairment showed improvement in memory performance, together with greater activation in the anterior and posterior right hemisphere on functional neuroimaging.115 In a randomized, placebo-controlled trial in adults aged 60–85 years, 1-month of curcumin supplementation improved working memory and mood.97 In 23 healthy but overweight individuals aged 50–80 years, 26 weeks of resveratrol supplementation resulted in better verbal memory performance, increased hippocampal functional connectivity, higher leptin, reduced body fat, and decreased HbA1c, a long-term marker of glucose control.98 Other neurological conditions Animal studies In terms of use of polyphenols to prevent or remediate cognitive function in neurological conditions, several studies have investigated polyphenols. Resveratrol, found in grapes, red and white wine, dark berries, and cocoa, has been shown to prevent impaired memory induced by chronic stress,116 diabetes,117 traumatic brain injury,118 and ischemic stroke119 in rats. Pretreatment of orally administered curcumin at doses of 50–300 mg/kg has been demonstrated to improve learning and memory in experimental animal models of epilepsy.120–126 Curcumin, found in the yellow spice turmeric, administered prior to127–129 or following130,131 traumatic brain injury in rats, counteracts impairments in learning and memory. In animal models, curcumin also confers protection against cognitive impairments induced by diabetes,132 human immunodeficiency virus,133 stress,134 and cigarette smoke.135,136 These effects were associated with normalization of hippocampal levels of brain-derived neurotrophic factor, synaptic plasticity, and markers of inflammation and oxidative stress. In an animal model of multiple sclerosis, curcumin also reduced the severity and duration of symptoms, the number of inflammatory cells, and T-cell proliferation, although no investigation of cognition was reported.137,138 Learning and memory deficits in young mice with experimentally induced autism were attenuated by green tea consumption.139 Randomized controlled trials Despite the promise exhibited in animal studies, only 1 human study has examined polyphenol supplementation to remediate cognitive function in a neurological condition other than age-related cognitive decline. Postoperative cognitive dysfunction following surgery with general anesthesia is commonly observed, presumably due to ischemic hippocampal damage suffered during the surgery.140 Pomegranate extract, high in several polyphenols, including punicalagins, anthocyanins, and ellagic acid, was administered in a small pilot study (n = 10) twice per day for 1 week prior to and 6 weeks following surgery. Whereas the placebo group had memory deficits after surgery, the pomegranate extract group actually had improved memory performance compared with baseline.141 MEDITERRANEAN DIET The Mediterranean diet encompasses many of the beneficial dietary factors described above. Although there is some heterogeneity in the definition across studies, the general consensus is that it incorporates high intake of fish, fruits, vegetables, legumes, whole grains, olive oil, and nuts and minimal intake of processed foods, including hydrogenated or trans-fats, refined grains, and added sugar. The diet is so named because it is representative of the diet consumed by the populations of Greece, Italy, and Yugoslavia, which, relative to Western countries, have been observed to have greater longevity and lower rates of cardiovascular disease, cancer, and other chronic health conditions.142,143 The initial interest in the Mediterranean diet was sparked by the 7 Countries study,143 which has been criticized for failing to include several countries that did not fit the pattern of results. Further, as the study was epidemiological, the effects of diet are difficult to tease apart from other factors such as climate and physical activity. Nevertheless, many experimental studies have now shown that this traditional dietary pattern has favorable effects in cardiovascular disease, diabetes, cancer, and other conditions (eg, see Serra-Majem et al.144). Age-related cognitive decline Many studies have now shown beneficial associations between the Mediterranean diet and cognition. Three systematic reviews16,30,145 and 2 meta-analyses146,147 have been conducted on this topic since 2016; thus there is substantial information on this topic available elsewhere, and it is summarized only briefly herein. Meta-analyses A meta-analysis of 5 cohort studies found that the Mediterranean diet was associated with a decrease in incidence of dementia (risk ratio, 0.69).146 Another meta-analysis published subsequently that included 4 additional studies showed that in the 9 cohort studies with a total of 34 168 participants, higher Mediterranean diet intake was associated with a lower risk of developing mild cognitive impairment or Alzheimer’s disease (risk ratio, 0.79).147 Systematic reviews Although the meta-analyses were focused on risk of mild cognitive impairment or Alzheimer’s disease (according to Mini Mental State Examination [MMSE] score or Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria), the systematic reviews provide greater information regarding specific cognitive domains. Regarding the Mediterranean diet and cognition in normal aging, the most recent systematic review concluded that for the 4 studies that assessed specific cognitive domains (as opposed to basic cognitive screening), higher Mediterranean diet intake was associated with slower decline in episodic and semantic memory in 1 study and with improved verbal memory in 1 study; however, the other studiess showed no relationship with these cognitive domains, nor with verbal fluency, speed of production, visuospatial memory, or working memory. Regarding Mediterranean diet and cognition in individuals with dementia, a systematic review145 described that in 3 cross-sectional studies, higher Mediterranean diet intake was associated with a higher cognitive score combining memory, language, processing speed, and visuospatial function. Of 18 longitudinal studies, lower Mediterranean diet intake was associated with poorer working memory and verbal fluency, processing speed, verbal memory, and immediate and delayed recall. Five RCTs were also identified, with 4 of the 5 showing improved cognition, specifically reduced confusion,148 improved global cognition on basic screening,149,150 and better visuospatial working memory. Cross-sectional studies Since the publication of the most recent review, 3 cross-sectional studies have been published. Greater adherence to the Mediterranean diet was shown to be associated with better global cognitive function using screening measures in 3 different aging populations—Spain, the United States, and France.151–153 Overall, with respect to the Mediterranean diet and cognition in aging and neurodegenerative conditions, the results of meta-analyses show the Mediterranean diet is protective against development of MCI or Alzheimer’s disease using brief cognitive screening (MMSE) or DSM criteria. Studies investigating specific cognitive domains in more depth are very heterogenous, with improvement or slowing of decline most commonly shown in episodic or verbal memory, although even this is not consistent across studies. Other neurological conditions The ability of the Mediterranean diet to reduce inflammatory responses, increase serum polyphenols, reduce oxidative stress, and improve cellular energy metabolism154 should in theory also confer benefit in the treatment of other neurological diseases. Indeed, studies suggest that the Mediterranean diet lowers risk of and level of disability in multiple sclerosis.155,156 One recent study of 2087 individuals with multiple sclerosis showed a diet pattern with many components of the Mediterranean diet (high fish, fruit, vegetable, and legume intake) was associated with better self-reported mental and cognitive quality of life.157 The previously described RCT in 20 individuals with multiple sclerosis showed a combination of 10 days of caloric restriction followed by 6 months of the Mediterranean diet improved subjective attention, concentration, and memory.78 However, the design makes it impossible to attribute effects to either diet. To the authors’ knowledge, no other studies directly investigate the ability of the Mediterranean diet to remediate cognition in neurological conditions such as multiple sclerosis, traumatic brain injury, and epilepsy. DISCUSSION The present review provides a summary of the scientific research available regarding the potential for diet to be used as an intervention to improve cognition. This literature is still emerging; therefore in most instances, a background regarding the mechanisms through which such diets may exert their effects, the animal literature to date (which tends to precede human studies), and the results of any human epidemiological or intervention studies where extant have been provided. Although the literature is still emerging, the evidence taken as a whole does seem to suggest that diet can be used as an intervention to improve cognition in several neurological disorders, with the most commonly investigated disorders being traumatic brain injury, epilepsy, and multiple sclerosis (a brief overview is provided in Table 3). The types of diet that appear to have the most support in the scientific literature are those with the potential for diet to reduce oxidative stress, inflammation, and mitochondrial function, which is why they have been chosen for review: ketogenic diet, use of polyphenols, fasting and fast-mimicking diet, and the Mediterranean diet. There is some overlap in these diets; for example, the Mediterranean diet tends to be high in polyphenols, and all of the diets described result in reduced intake of refined carbohydrates and sugar, which are known to have an adverse effect on cognition.158 Table 3 Summary of key findings regarding the impact of each diet on cognition in various neurological conditions Neurological disorder  Ketogenic  Calorie restriction  Polyphenolic  Mediterranean  Epilepsy  Several single-case studies and quasi-experimental studies are suggestive of improved processing speed, attention, and executive function. One RCT showed improved receptive vocabulary and reaction time  No studies available  Curcumin counteracts effect of seizures on learning and memory in rats  No studies available  Traumatic brain injury  Improves memory function in rats. No human studies  Two animal studies have shown improved recovery of memory function. No human studies  Animal studies have shown attenuation of memory impairments following resveratrol and curcumin  No studies available  Multiple sclerosis  Improves memory in rats. One RCT found subjective improvement in cognition (attention, concentration, and memory)  One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  No studies available  One cross-sectional study showed association with better subjective cognitive function. One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  Autism  One prospective study found improvement on rating scale with several cognitive items, but no control group  No studies available  Green tea remediated memory deficits in young mice with experimentally induced autism  No studies available  Aging and neurodegenerative conditions  Improves memory in aged rats, and in 2 RCTs, higher blood ketone levels achieved through diet, improved memory in MCI and AD  Several studies have shown beneficial effects on learning and memory. One RCT showed improved verbal memory  Two systematic reviews showed benefits to memory and executive function  Five RCTs have shown reduced risk of MCI, reduced confusion, improved global function on cognitive screening, and better reaction time  Neurological disorder  Ketogenic  Calorie restriction  Polyphenolic  Mediterranean  Epilepsy  Several single-case studies and quasi-experimental studies are suggestive of improved processing speed, attention, and executive function. One RCT showed improved receptive vocabulary and reaction time  No studies available  Curcumin counteracts effect of seizures on learning and memory in rats  No studies available  Traumatic brain injury  Improves memory function in rats. No human studies  Two animal studies have shown improved recovery of memory function. No human studies  Animal studies have shown attenuation of memory impairments following resveratrol and curcumin  No studies available  Multiple sclerosis  Improves memory in rats. One RCT found subjective improvement in cognition (attention, concentration, and memory)  One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  No studies available  One cross-sectional study showed association with better subjective cognitive function. One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  Autism  One prospective study found improvement on rating scale with several cognitive items, but no control group  No studies available  Green tea remediated memory deficits in young mice with experimentally induced autism  No studies available  Aging and neurodegenerative conditions  Improves memory in aged rats, and in 2 RCTs, higher blood ketone levels achieved through diet, improved memory in MCI and AD  Several studies have shown beneficial effects on learning and memory. One RCT showed improved verbal memory  Two systematic reviews showed benefits to memory and executive function  Five RCTs have shown reduced risk of MCI, reduced confusion, improved global function on cognitive screening, and better reaction time  Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; RCT, randomized controlled trial. It should be noted that it is not proposed that diet should be used instead of pharmacological and other medical treatments, but rather as an adjunct. A crucial advantage of these dietary interventions is that they are noninvasive and relatively low risk because they are typically devoid of side effects and sometimes consistent with dietary recommendations (eg, Mediterranean diet) aimed at improving other aspects of physical health. Caveats are however necessary for more extreme diets such as the ketogenic diet or fasting, which could, theoretically, cause ketoacidosis (unrestrained, abnormally excessive levels of ketone bodies) in individuals predisposed to the condition. Nevertheless, these diets are in popular use in the community to assist in weight loss (eg, the Atkins Diet, popular in the 1970s159), and even in clinical populations, such diets seem generally well-tolerated.78 Dietary intervention is not without its disadvantages. When compared with pharmaceutical intervention, adherence to a prescribed diet can be difficult to achieve. For example, the ketogenic diet was originally developed as an alternative to fasting, which was considered hard to implement. However, adherence to the ketogenic diet is also often reported as difficult, with reported side effects such as gastrointestinal disorders, loss of weight, and fatigue.58 There are intermittent fasting protocols that do appear potentially easier to adhere to, but given the varied nature of the duration and extent of the fasting, a lot more work needs to be done to understand the degree of restriction that is necessary, for how long, and at what age/severity of neurological disorder the benefits are seen. Similar to the above point, as opposed to pharmaceutical-based interventions, evaluating the effects of diet interventions proves more difficult. The features of RCTs in evidence-based medicine, although appropriate for measuring drug effects, may not be appropriate in the nutritional context. There are difficulties in obtaining a true “placebo” group because, of course, a nutrient-deficient group is unethical and impractical to consider. As such, baseline levels of nutrient intake should be obtained, ideally using biomarkers rather than self-report. However, this greatly increases costs of research, and additionally, controlling for baseline levels can reduce the statistical power to detect significant effects. In a similar vein, evaluation of whole diet changes cannot be performed under blinded circumstances because the participants will be aware they are making the diet changes and indeed will likely need to be motivated to adhere to the diet changes. As such, again, it is necessary to evaluate compliance with the intervention, preferably using biomarkers rather than self-report, which is subject to social desirability effects. CONCLUSION The current review aims to address some of the more prominent diets in the literature, those with a scientific basis and evidence of effects on cognition. There are, of course, numerous other diets and diet factors that are in common use—for example, low-fat diet or high polyunsaturated fat diet. However, the focus of the low-fat diet has traditionally been on weight loss, and sufficient data were not available to discuss the diet with respect to cognition. Data regarding polyunsaturated fatty acids and cognition tended to be in respect to supplementation rather than whole diet change, and the effects of increased polyunsaturated fats were encompassed by the Mediterranean diet literature. Nevertheless, the present review provides a summary of promising work in the field to support the use of diet to prevent and remediate cognitive deficits in neurological conditions. Although there are now a greater number of studies investigating whole-diet change on physical features in these conditions (eg, level of disability), it is hoped that this review provides the impetus to include evaluation of cognition in the outcome measures of future research. Acknowledgments The authors thank the Australian Research Council for their continued support. Author contributions. H.M.F. and R.J.S. performed the literature review, drafted the manuscript, and approved the final manuscript. Funding. This work was supported by a grant from The Australian Research Council (http://www.arc.gov.au/; grant DP150100105 to R.J.S.). Declaration of interest. The authors have no relevant interests to declare. References 1 Francis HM, Mirzaei M, Pardey MC, et al.   Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet. Proteomics . 2013; 13: 3076– 3091. 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Potential for diet to prevent and remediate cognitive deficits in neurological disorders

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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0029-6643
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1753-4887
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10.1093/nutrit/nux073
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Abstract

Abstract The pathophysiology of many neurological disorders involves oxidative stress, neuroinflammation, and mitochondrial dysfunction. There is now substantial evidence that diet can decrease these forms of pathophysiology, and an emerging body of literature relatedly suggests that diet can also prevent or even remediate the cognitive deficits observed in neurological disorders that exhibit such pathology (eg, Alzheimer’s disease, multiple sclerosis, age-related cognitive decline, epilepsy). The current review summarizes the emerging evidence in relation to whole diets prominent in the scientific literature—ketogenic, caloric restriction, high polyphenol, and Mediterranean diets—and provides a discussion of the possible underlying neurophysiological mechanisms. caloric restriction, cognition, fasting, ketogenic, Mediterranean, polyphenol INTRODUCTION Diet is increasingly understood to impact on neurological function. Animal studies show that consumption of a Western diet, high in saturated fat, refined sugar, and processed foods, impairs learning and memory and is associated with oxidative stress, inflammation, and mitochondrial dysfunction.1,2 On the other hand, various aspects of diet (eg, polyphenols) and diet patterns (eg, Mediterranean diet) have antioxidant and anti-inflammatory properties.3,4 Although neurological conditions, such as epilepsy, multiple sclerosis, and traumatic brain injury, have distinct disease processes, each exhibit increased oxidative stress, neuroinflammation, and disrupted energy metabolism, and reducing this pathology has the potential to improve neuronal function, repair, and growth (eg, for reviews see Halaris5 and Mattson et al.6). In light of the fact that these pathophysiological factors can be influenced by dietary means, it is reasonable that diet could alter the course and outcomes of these neurological conditions. Although the effects of diet on physical symptoms and pathology have been explored in many studies and reviews and the literature regarding the effect of diet on cognition in aging and neurodegeneration is becoming well-established, there has not as yet been a review of the evidence regarding the effect of diet on cognition in neurological disorders. This is surprising because preservation of cognition is often a predominant concern for patients with neurological disorders, perhaps due to the substantial impact on occupation, social relationships, activities of daily living, and quality of life.7 Perhaps more important still, diet is something patients can exert control over; therefore it is an appealing target for change. There is increasing public awareness of the potential link between diet and cognition; for example, a recent review showed that healthy diet was identified as a protective factor for cognitive health by respondents in 10 of 17 studies examined.8 This awareness appears to be manifesting in changed patient behavior; for instance, 64.7% of 428 people with multiple sclerosis surveyed in South Australia reported using dietary intervention, with approximately 30% of those citing improved memory as a reason.9 There is then a need to effectively review and summarize the objective scientific findings to date. There are several papers that provide an analysis of the ability for diet to remediate specific disease mechanisms and physiological symptoms (eg, seizures, mobility), and these are provided in Table 110–27 for the interested reader. However, none provide a summary of the ability for diet to ameliorate cognition specifically in neurological conditions. Although this has been done in terms of the relationship between diet and cognition in aging and dementia, there is no review that combines this literature with a wider range of neurological conditions. This article therefore aims to provide a summary of and draw attention to the links between these niche literatures, which to date have remained relatively separate. Improved understanding of the aspects of diet that the scientific literature has demonstrated to have therapeutic benefit in either preventing or remediating cognitive deficits will be useful for patients seeking self-efficacy in improving cognition, for clinicians in providing evidence-based recommendations for their patients, and to guide the direction of future research. Table 1 Reviews addressing the relationship between diet and cognition in various conditions, and diet as a treatment for neurological conditions more generally Diet type  Cognition in mental health  Cognition in aging and neurodegenerative conditions  Cognition in other neurological conditions  Diet as a treatment for various neurological conditions  Ketogenic  Not available  Baranano and Hartman (2008)10,a  Hallböök et al. (2012)15,b  Strafstrom and Rho (2012)13,c,d Baranano and Hartman (2008)c,d,10  Caloric restriction/fasting  Not available  Wahl et al. (2016)17,a  Not available  Maalouf et al. (2009)11,c,d  Polyphenolic  Trebaticka and Durackova (2015)26,a Zainuddin and Thuret (2012)27,a  Macready et al. (2009)12 Lamport et al. (2012)14  Not available  Pathak et al. (2013)21,e Riccio et al. (2011)22,d Bhullar et al. (2013)18,c,d Grosso et al. (2013)19,c,d  Mediterranean  Not available  Hardman et al. (2016)16 Lourida et al. (2013)20  Not available  Psaltopoulou et al. (2013)24,c,d,e Lai et al. (2014)23,e  Dietary Approach to Stop Hypertension (DASH)f  Not available  Tangney (2014)25  Not available  Tangney (2014)25,c  Very low sugar  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Gluten-free  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Paleolithic  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Diet type  Cognition in mental health  Cognition in aging and neurodegenerative conditions  Cognition in other neurological conditions  Diet as a treatment for various neurological conditions  Ketogenic  Not available  Baranano and Hartman (2008)10,a  Hallböök et al. (2012)15,b  Strafstrom and Rho (2012)13,c,d Baranano and Hartman (2008)c,d,10  Caloric restriction/fasting  Not available  Wahl et al. (2016)17,a  Not available  Maalouf et al. (2009)11,c,d  Polyphenolic  Trebaticka and Durackova (2015)26,a Zainuddin and Thuret (2012)27,a  Macready et al. (2009)12 Lamport et al. (2012)14  Not available  Pathak et al. (2013)21,e Riccio et al. (2011)22,d Bhullar et al. (2013)18,c,d Grosso et al. (2013)19,c,d  Mediterranean  Not available  Hardman et al. (2016)16 Lourida et al. (2013)20  Not available  Psaltopoulou et al. (2013)24,c,d,e Lai et al. (2014)23,e  Dietary Approach to Stop Hypertension (DASH)f  Not available  Tangney (2014)25  Not available  Tangney (2014)25,c  Very low sugar  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Gluten-free  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Paleolithic  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  Few, if any, individual studies  The shaded columns indicate those included in this review. a Cognition not main focus but mentioned when relevant. b Focus mainly on epilepsy. c Aging and neurodegenerative conditions. d Other neurological conditions. e Mental health. f Not sufficient literature to warrant review in this manuscript but mentioned because evidence is emerging or diet is in popular use. This article aims to summarize the available evidence for the ability of diet to prevent or remediate cognition in neurological disorders and the putative underlying mechanisms. Because there have been systematic reviews conducted within the specialized areas, a narrative review approach was undertaken, with the aim of providing an overview of the emerging and exciting findings in this field together. As such, broader inclusion criteria (as outlined further below) for studies were allowed. This approach allowed for the provision of description of the epidemiological basis for thinking the selected diets (ketogenic, fasting, polyphenolic, and Mediterranean) should improve cognition, as well as inclusion of studies to describe the underlying mechanisms that suggest there is a causal basis for their effects. So as to be as inclusive as possible in the search for relevant studies, searches using combinations of diet-related terms (ketogenic, caloric restriction, polyphenol*, flavon*) and cognition-related terms (cognit*, neuropsy*, memory) were performed. Databases searched included PubMed and PsychINFO. The * or $ was used (dependent on database) for truncation to ensure all possible suffixes were covered (eg, cognition, cognitive). Reference lists of the included studies were also searched. The number of papers identified using these search terms is provided in Table 2, together with the final number of papers deemed relevant through search of the titles and abstracts with papers excluded for 1) repetition or 2) because the content was not relevant, largely for the following reasons: i) no focus on diet; ii) no assessment of cognition or cognitive domains; and iii) no focus on the searched neurological condition. The review is not limited to only these studies because inclusion of background studies and those dealing with the role of diet in specific disease mechanisms and the mechanisms thought to underlie improvements in cognition was desired. Table 2 Number of papers obtained using the listed search terms for each diet type and neurological disorder, as well as the final number of papers selected for review in the current manuscript (in brackets) Diet type  Epilepsy  Traumatic brain injury  Multiple sclerosis  Autism  Aging and neurodegenerative conditions  Ketogenic  64 (25)  1 (1)  2 (2)  4 (1)  23 (4)  Caloric restriction  1 (0)  2 (2)  1 (1)  0 (0)  4 (2)a  Polyphenolic  8 (7)  10 (6)  1 (0)  1 (1)  155 (16)b  Mediterranean  0 (0)  1 (0)  4 (4)  0 (0)  5 (3)c  Diet type  Epilepsy  Traumatic brain injury  Multiple sclerosis  Autism  Aging and neurodegenerative conditions  Ketogenic  64 (25)  1 (1)  2 (2)  4 (1)  23 (4)  Caloric restriction  1 (0)  2 (2)  1 (1)  0 (0)  4 (2)a  Polyphenolic  8 (7)  10 (6)  1 (0)  1 (1)  155 (16)b  Mediterranean  0 (0)  1 (0)  4 (4)  0 (0)  5 (3)c  a Search results since most recent review published January 2016.28 b Search results since most recent review published January 2012.29 c Search results since most recent review published May 2017.30 In sum, the present article is aimed at providing an overview of the literature suggesting that diet has the ability to ameliorate cognition in a wide range of neurological conditions. The diets selected as the focus of the article were driven by the literature (ie, prominence and level of evidence available); the other diets that were considered but not reviewed are detailed in Table 1.10–27 Note that the aim was to examine whole diet pattern, rather than specific nutrients. This distinction becomes blurry when considering polyphenols; however, it seemed reasonable to include epidemiological studies that examined diets rich in polyphenols or supplement studies where the supplement was a dietary source (eg, juice or cocoa). Neurological conditions that were searched were based on those for which there was evidence in the literature that diet could alter the course or outcome of those disorders (see Table 1 for reviews that provide this information). Thus, epilepsy, multiple sclerosis, traumatic brain injury, stroke, autism, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis were included. The reader will observe that many of these are not mentioned at all in the article because, although there may be evidence that diet can attenuate the neuropathology or physical outcomes, no studies specifically investigating cognition—the focus here—were found. Where the cognition-related literature had recently been reviewed (typically in relation to age-related or neurodegenerative disorders), only summaries of past reviews are provided, along with an update on any subsequent studies. Psychiatric conditions were not included. Although the authors recognize that these also involve neurological pathology, it was felt that their exclusion was reasonable considering the generally accepted distinction between psychiatry and neurology, as illustrated by the existence of 2 separate medical specialties. Nevertheless, any review papers in relation to diet and mental health have been included in Table 1 as an additional resource for the interested reader. KETOGENIC DIET The ketogenic diet has been used for treatment of drug-resistant epilepsy for a number of decades and is also being studied for its therapeutic effect in other neurological disorders. The ketogenic diet is high in fat and low in carbohydratea, typically at a ratio of 3–4:1. Fat type or chain length is not specified, but typically a ketogenic diet includes mostly saturated fats, often obtained from cream, butter, or oils.31 Variations of this diet include the modified Atkins diet, low glycemic index treatment, and medium-chain triglyceride diet. The primary mechanism through which these diets are thought to exert their effects is a reduction in glycolysis and a promotion of ketone body formation. The brain is able to use ketones to generate cellular energy. This shift in energy metabolism appears to reset cellular metabolic dysfunction and neuronal activity,32,33 although the exact mechanisms remain unclear and are currently the subject of further research. Various theories propose that ketone body generation alters metabolism of neurotransmitters such as glutamate and gamma-amino butyric acid (GABA), improves mitochondrial function, decreases oxidative stress, and activates energy-sensing signaling pathways such as the peroxisome proliferator-activated receptor (PPAR), mammalian target of rapamycin (mTOR), and AMP-activated kinase (AMPK) pathways. The beneficial effects of these diets for enhancing cellular metabolism and mitochondrial function have been described in more detail previously,32,33 whereas the effects specific to cognition have not been subject to the same extensive review. This article aims to summarize the current knowledge specific to the effects of ketogenic diet on cognition. Epilepsy The original ketogenic diet was described by Wilder in 1921 and proposed to treat epilepsy.34 There is now considerable evidence that the diet results in seizure reduction in up to three-quarters of drug-resistant epilepsy patients. Importantly, these findings include randomized controlled trials (RCTs).35 Although the seizure-reducing effects are quite well-established, studies that claim improvements in cognition have not been as rigorous. Animal studies In some animal studies, ketogenic diet has actually been proposed to impair learning and memory. For example, although ketogenic diet reduced seizure frequency in weanling rats with induced status epilepticus, rats on the ketogenic diet had impaired spatial learning and memory compared with rats on the control diet.36 Similarly, following kainic acid induced status epilepticus, rats on a ketogenic diet had fewer spontaneous seizures but poorer spatial learning than rats on a control diet.37 However, in both of these studies, the ratio of fat to protein/carbohydrate was far higher than is typically used clinically (≈8–9:1), and rats in the ketogenic diet groups failed to gain weight at the same rate as rats fed the control diet. Thus, rats in the ketogenic diet group were gaining weight at a reduced rate, indicating they may have been undernourished, without the adequate nutrient levels for normal growth and development of both body and brain. In contrast, animal studies where rats were placed on a 4:1 “classic” ketogenic diet showed a reduction in seizures and no accompanying deficits in spatial learning and memory.38 Furthermore, 2 studies that investigated induced recurrent seizures showed that ketogenic diet attenuated spatial learning deficits, suggesting the diet actually has a beneficial effect on hippocampal-dependent aspects of cognition, which are presumed to be mediated by this structure.35,39 To investigate the underlying mechanism of these effects, Kim et al.40 showed that administration of ketone bodies alone was sufficient to reduce seizures and improve spatial memory deficits in epileptic mice. Children with epilepsy In children with epilepsy, improvements in cognition following ketogenic diet appear to fluctuate with seizure control41 and can occur prior to the reduction of antiepileptic drugs.42 This suggests that effects on cognition are not just due to the ability to withdraw from medication and are intimately tied to reduced pathology associated with seizure reduction. As such, in the discussion of the effects of diet, it has been noted where cognitive improvements are accompanied by seizure reduction. Single case studies. Several single case reports describe improvements in cognition following ketogenic diet in different conditions that cause epileptic seizures. Two single case reports on glucose transporter 1 (GLUT1) deficiency syndrome, which causes frequent seizures, document improved processing speed and executive functioning, as well as seizure control, following ketogenic diet in a child aged 10 years43 and modified Atkins diet in a child aged 6 years.44 Similarly, drug-resistant seizures were controlled following ketogenic diet in a 5-year-old girl with Landau-Kleffner syndrome, and the patient regained normal cognitive functioning on formal neuropsychological testing, compared with complete unresponsiveness prior to diet administration.45 Quasi-experimental studies. Parental reports of improvements in problematic behaviors, attention, alertness, concentration, language, and school performance have been described in several group studies of ketogenic46–49 and modified Atkins diet.50 Several studies have reported on neuropsychological data obtained before and after diet initiation, with some studies finding no improvement41 and others showing varying degrees of improvement.42,51–53 However, these studies are typically small in numbers (n = 3–11) and use a nonrandomized, pre/post-intervention design due to difficulties in defining a suitable control group. Further, given children who experience seizures from a young age typically experience developmental delay, it is difficult to discern whether a lack of change from baseline scores might actually represent normal developmental trajectories after starting on the diet. Randomized controlled trials. To the authors’ knowledge, only 1 RCT has assessed cognitive functioning following ketogenic diet to reduce seizures. Twenty-six children and adolescents between the ages of 1–18 years who received the ketogenic diet for 4 months showed reduced seizure frequency and severity, compared with the 22 patients in the care-as-usual group.54 Note that although there was a wide age range overall, groups were matched for age. Cognitively, the ketogenic diet groups had greater improvement in receptive vocabulary and simple reaction time but no improvements in tasks assessing motor activation or integration of visual and motor abilities.55 Although receptive vocabulary can be used as a predictor of general cognitive functioning, more comprehensive neuropsychological assessment, including measures of attention, working memory, memory, and executive functioning, are warranted. Adults with epilepsy Quasi-experimental studies. In adults with refractory epilepsy, there are subjective reports of improvements in alertness and concentration following ketogenic diet.56,57 However, studies of adults placed on a ketogenic diet for 6–12 months, which have used objective neuropsychological testing, have not shown any clear change in cognition despite reductions in seizure frequency.58,59 It may be the case that early intervention with ketogenic diet is necessary to prevent developmental delay from occurring. This interpretation is supported by studies that suggest improvements appear to be largest in the youngest children.52 Other neurological disorders There are 2 putative mechanisms that are proposed to underlie the beneficial effects of ketogenic diet on neurological function. First, ketogenic diet reduces oxidative stress by decreasing reactive oxygen species,60 increasing levels of antioxidant agents,61 increasing mitochondrial biogenesis,62 and reducing inflammation.63 Second, ketones offer an alternative to glucose as a source of fuel to the brain. Thus, ketogenic diet may improve neurological function in conditions such as multiple sclerosis, traumatic brain injury, and Alzheimer’s disease because these conditions demonstrate increased oxidative stress,64–66 neuroinflammation,67–69 and impaired glucose metabolism in the brain.70–72 Similarly, the ketogenic diet has been suggested as an additional therapy for individuals with autism in light of observed disturbances in mitochondrial energy production in this condition.73 The focus in previous reviews10,13 has typically been on reducing pathology in these conditions (eg, demyelinating lesions in multiple sclerosis or axonal cell death in traumatic brain injury) and resultant effects on level of physical disability, with these papers referenced in Table 1. In contrast, there have been no papers summarizing the effects on cognition. Here what is known regarding the effects of ketogenic diet on cognition in traumatic brain injury, multiple sclerosis, age-related cognitive decline, and autism is discussed. Traumatic brain injury Ketogenic diet administered for 7 days after traumatic brain injury in adolescent rats improved recovery of memory function,74 with several studies suggesting the underlying mechanism to be reduced alterations in cell metabolism and cell death.75–77 However, there are no human studies to our knowledge that investigate ketogenic diet and cognition in traumatic brain injury. Multiple sclerosis In an animal model of multiple sclerosis, ketogenic diet reduced neuroinflammation, with corresponding attenuation of memory dysfunction.63 One RCT has been carried out in 20 patients with multiple sclerosis. Ketogenic diet (<50 g of carbohydrates, >160 g of fat, and <100 g of protein intake daily) for 6 months improved self-rated mental and cognitive health, compared with 20 patients maintained on diet as usual.78 The scale used was self-report and included ratings of concentration, attention, and memory. However, it is difficult to establish a blinded control condition in such trials due to the nature of the intervention; therefore, future studies would benefit from objective neuropsychological testing rather than subjective report of cognitive improvement. Autism In a prospective study examining 30 children with autistic behavior who were placed on a ketogenic diet for 6 months, 23 of the patients adhered to the diet, with the other 7 reporting gastrointestinal symptoms or dislike of the diet. Improvement on the Childhood Autism Rating Scale was noted in all 18 patients who were able to adhere to the diet.73 The rating scale contains several items that assess cognitive and behavioral characteristics, although specific item scores were not reported. The mechanism of action was hypothesized to be an increase in ketone bodies attenuating disturbed mitochondrial function and improving the synthesis of γ-aminobutyric acid (GABA). Age-related cognitive decline Animal studies In aged rats, ketogenic diet administered for 3 weeks improved learning and memory.79 This was associated with increased angiogenesis and capillary density, suggesting the ketogenic diet may support cognitive function through improved vascular function. Randomized controlled trials In 20 older adults with Alzheimer’s disease or mild cognitive impairment, consumption of a drink containing medium-chain triglycerides to elevate serum ketone body levels improved performance on a brief screening tool covering several cognitive domains, including attention, memory, language, and praxis.80 However, this effect was observed only for those individuals without the Apolipoprotein-E (APOE) e4 allele, suggesting these individuals are better able to use ketones than APOE e4 carriers. In 23 older adults with mild cognitive impairment, ketosis was induced using a very low carbohydrate diet (5%–10%) and was shown to improve verbal memory performance compared with a high carbohydrate diet (50%), with improved memory positively correlated with ketone levels.81 One other RCT in 152 individuals with Alzheimer’s disease administered an agent to increase serum ketone bodies, finding improved performance on cognitive screening (Alzheimer’s Disease Assessment Scale–Cognitive Subscale) compared with placebo. Although this is a pharmacologic intervention, it lends further support for increasing ketone bodies via dietary means to improve cognition in Alzheimer’s disease.82 Conclusion In sum, the findings regarding the effect of ketogenic diet on cognition in neurological conditions are limited but interestingly suggestive at this stage. Although animal models do provide some evidence for a causal role, they do not always accurately represent the underlying pathogenesis of neurological conditions. Most of the human studies to date have been quasi-experimental, using a pre/post-intervention design but without randomization or an adequate control group. However, the RCTs that have been conducted have demonstrated a beneficial effect of ketogenic diet on verbal receptive vocabulary and reaction time in children with epilepsy and self-rated attention, concentration, and memory in adults with multiple sclerosis. Although neuropsychological testing could have been more comprehensive in both of these studies, the results do provide causal evidence and suggest that further studies are warranted to document the cognitive effects of the 4:1 ketogenic diet, both in epilepsy and other neurological conditions. FASTING/CALORIC RESTRICTION Prior to ketogenic diet, calorie restriction was recognized as an effective treatment for epileptic seizures and, more recently, has been recognized as a potential means for increasing lifespan and reducing the incidence of age- and lifestyle-related disorders such as diabetes, cancer, and cardiovascular disease.83,84 Protocols for implementing dietary restriction are varied. Restriction can be achieved through an overall reduction in daily calorie intake, with reductions typically between 30% and 40%.85 Alternatively, intermittent fasting can be implemented, with periods of reduced or no calorie intake interspersed with ad libitum feeding. Similar mechanisms appear to underlie the neuroprotective mechanisms of caloric restriction and ketogenic diet. As with the ketogenic diet, a central feature is a reduction in glycolysis and an increase in the body’s production of ketone bodies, resulting in reductions in inflammatory mediators, proapoptotic factors, and oxidative stress, as well as improved mitochondrial function.11 These mechanisms are proposed to underlie the ability for caloric restriction to reduce neuronal pathology in Alzheimer’s disease, Parkinson’s disease, ischemic stroke, and multiple sclerosis.78,86,87 A few studies have additionally examined the effects of caloric restriction on cognition in neurological disorders. A brief discussion of the findings in relation to age-related cognitive decline has been included herein because previous reviews have a greater focus on protection and repair at the neuronal level,88 but the authors are not aware of any review focusing on cognition. Age-related cognitive decline The most recent review of the literature on this topic was conducted in 2016 and evaluates the literature regarding the beneficial effects of caloric restriction on brain aging and Alzheimer’s disease.28 In the summary below, the findings from this review that are related to cognition have been included, and a brief review of papers published since the review has been provided. Animal studies In terms of cognition, several studies have shown that dietary restriction reduces age-related learning and memory impairments in rats.89–91 Dietary restriction does not appear to require lifelong adherence to obtain benefit. Rats that were fasted every second day for a period of 3 months in late life showed improvement in learning and memory, accompanied by improved mitochondrial function and synaptic protein expression.92 Since the publication of Cauwenberge et al.’s 2016 review, there have been 2 animal studies published that have investigated the effects of caloric restriction on cognition in rodent models of aging or neurodegeneration. In aged mice, caloric restriction preserved memory performance and reduced the rate of decline in cerebral blood flow usually associated with age. Caloric restriction in ApoE-deficient mice resulted in better memory performance, which was associated with decreased tau-phosphorylation and increased synaptic plasticity. Randomized controlled trials Consistent with the animal literature, dietary restriction for 3 months was shown to improve verbal memory compared with controls in normal-to-overweight older individuals (mean age, 60.5).93 In obese elderly individuals with symptoms of mild cognitive impairment, caloric restriction–induced weight loss was associated with improvements in verbal memory, verbal fluency, executive function, and global cognition.94 The 2016 review noted no other trials in aging or neurodegenerative diseases that have investigated cognition, and a search did not reveal any articles that have been published since then. Other neurological disorders Traumatic brain injury Animal studies. In a rat model of traumatic brain injury, fasting animals for 24 hours following moderate injury improved recovery of memory function, which was associated with improved mitochondrial function and reduced cell death at the site of the injury.95 Maintaining rats on a calorie-restricted diet (70% normal food intake) for 3 months prior to head injury substantially attenuated memory deficits, increased brain-derived neurotrophic factor, and reduced the size of the cortical contusion.96 Multiple sclerosis Animal studies. Three cycles of fasting (3 days of fasting out of 7 days) stimulated remyelination and ameliorated both disease severity and clinical symptoms in experimental autoimmune encephalitis, a mouse model of multiple sclerosis.78 Randomized controlled trials. Following success of the mouse model, the same researchers investigated a potential “fasting-mimicking diet” in humans. Considering the innately undesirable nature of fasting, they aimed to design a diet that would be tolerable, involving consuming only 800 kcal on day 1, followed by 200–250 kcal of vegetable broth or juice plus 3 tablespoons of linseed oil on days 2–7 and reintroduction of solid foods on days 8–10. Twenty individuals with multiple sclerosis were placed on the fasting-mimicking diet for 10 days, then the Mediterranean diet for the remainder of the 6 months. Compared with a regular diet group, a clinically meaningful improvement was demonstrated in mental health–related quality-of-life scores, which include a self-rated improvement in general cognition (attention, concentration, and memory).78 The diet group had lower lymphocyte counts and higher white blood cell counts, as well as improved estimated disability status scale scores. Because the fasting-mimicking diet and Mediterranean diet were administered to the same group, it cannot be stated definitively that effects were due to fasting-mimicking diet or the following period of Mediterranean diet; however, there is at least now evidence of safety and tolerability of cycles of caloric restriction in multiple sclerosis. Conclusion In sum, the animal data strongly suggest a causal role for caloric restriction in reducing the effects of aging on memory function. The results of 2 RCTs in older individuals and overweight individuals with mild cognitive impairment support the animal data. In traumatic brain injury, animal models show improved memory function, although there have been no human trials. In a rodent model of multiple sclerosis, intermittent fasting reduced clinical symptoms, and the same diet improved self-reported attention and memory. Overall, there is mounting evidence that caloric restriction can improve longevity and health span, although fewer studies have investigated effects on cognition. The research summarized above is promising; however there are few human clinical trials, perhaps due to difficulty recruiting individuals who will commit themselves to such stringent diets as implemented in the animal studies. Therefore, research may instead focus on biochemical compounds that mimic the physiological effects of caloric restriction. POLYPHENOLS Polyphenols are natural compounds found in plant-based foods, which are proposed to be beneficial to cognition due to their antioxidant and anti-inflammatory properties.3 They are classed into subgroups, including flavonoids, lignans, phenolic acids, and stilbenes. This aspect of diet is included in the review because the polyphenolic compounds are also readily obtained through dietary sources. Although many of the supplement studies are at concentrations that would be difficult to obtain solely through diet,97,98 the epidemiological studies discussed herein do suggest that dietary consumption of polyphenols at levels that could be achieved through diet (eg, >600 mg/d of polyphenols or > 495 mg/d of flavonoids have been used as cutoffs14,99) is associated with improved cognition. This would be achievable through diet, with 200–300 mg of polyphenols per 100 g of various fruits (eg, grapes, apples, dark berries) or 100 mg of polyphenols per cup of tea or large coffee.100 Further, the supplement literature can guide which diet sources should be sought out. Age-related cognitive decline Two relatively recent systematic reviews have summarized the evidence for the beneficial effects of flavonoids12 and all polyphenol groups on cognition.29 Briefly, Lamport et al.29 found that across 28 epidemiological and intervention studies consumption of added polyphenols in the diet in healthy or mildly cognitively impaired older adults had beneficial effects on cognition, in particular for declarative and spatial memory. The most beneficial polyphenol sources appeared to be berry fruit juices and isoflavone sources such as soy protein or soy isoflavone supplements. Across 15 RCTs that examined the effects of flavonoids on cognition, Macready et al.12 found a positive association between flavonoid consumption and cognitive function, with all but 3 studies showing improvements in cognition. The greatest benefit appeared to be conferred to memory and executive function, with some increases also seen in general cognition and processing speed. Both reviews noted a lack of consistency among cognitive tests used, dose, and duration of interventions, making study comparisons difficult. Since the publication of these reviews, a few studies that examined the effect of dietary polyphenol intake and cognition in aging and neurodegenerative conditions have been published. They are reviewed below. Animal studies In rat models of Alzheimer’s disease, grape seed,101 curcumin,102 lychee,103 dark chocolate,104 green tea,105 red wine,106 and cinnamon 107 have been shown to improve learning and memory performance. Observational studies In a cross-sectional study, urinary biomarkers of polyphenol intake were associated with better scores in immediate memory in individuals aged 55–80 years.108 In 652 individuals aged 65 years or greater, higher urinary biomarkers of polyphenol intake over 3 years were associated with lower risk of cognitive decline on a brief cognitive screening tool and in processing speed on Trail Making Test A.99 In a large-scale prospective study in 2574 middle-aged adults,109 high total polyphenol intake measured using dietary records was associated with better language and verbal memory assessed after a follow-up of 13 years. Randomized controlled trials Several studies investigating the effects of supplementation with various phenolic compounds to remediate cognitive decline in aging have been conducted. Cocoa is high in polyphenols, including epicatechin, catechin, and oligomeric procyanidins.110 In individuals aged 40–65 years, consumption of a cocoa-containing drink for 30 days enhanced positive mood compared with placebo, but no effects were observed for cognition.111 In another RCT, healthy elderly individuals who consumed a high cocoa diet for 3 months had improved memory function on a pattern separation task, which was accompanied by enhanced activity in the dentate gyrus, the area of the hippocampus responsible for neurogenesis.112 Grape juice is rich in polyphenols, including resveratrol, anthocyanins, and flavonoids.113 Healthy women aged 40–50 years who consumed grape juice for 12 weeks consistently showed benefits over a taste-matched placebo across several measures of cognition, including verbal recall, executive function, and lateral tracking.114 Similarly, individuals aged 68–90 years with mild cognitive impairment showed improvement in memory performance, together with greater activation in the anterior and posterior right hemisphere on functional neuroimaging.115 In a randomized, placebo-controlled trial in adults aged 60–85 years, 1-month of curcumin supplementation improved working memory and mood.97 In 23 healthy but overweight individuals aged 50–80 years, 26 weeks of resveratrol supplementation resulted in better verbal memory performance, increased hippocampal functional connectivity, higher leptin, reduced body fat, and decreased HbA1c, a long-term marker of glucose control.98 Other neurological conditions Animal studies In terms of use of polyphenols to prevent or remediate cognitive function in neurological conditions, several studies have investigated polyphenols. Resveratrol, found in grapes, red and white wine, dark berries, and cocoa, has been shown to prevent impaired memory induced by chronic stress,116 diabetes,117 traumatic brain injury,118 and ischemic stroke119 in rats. Pretreatment of orally administered curcumin at doses of 50–300 mg/kg has been demonstrated to improve learning and memory in experimental animal models of epilepsy.120–126 Curcumin, found in the yellow spice turmeric, administered prior to127–129 or following130,131 traumatic brain injury in rats, counteracts impairments in learning and memory. In animal models, curcumin also confers protection against cognitive impairments induced by diabetes,132 human immunodeficiency virus,133 stress,134 and cigarette smoke.135,136 These effects were associated with normalization of hippocampal levels of brain-derived neurotrophic factor, synaptic plasticity, and markers of inflammation and oxidative stress. In an animal model of multiple sclerosis, curcumin also reduced the severity and duration of symptoms, the number of inflammatory cells, and T-cell proliferation, although no investigation of cognition was reported.137,138 Learning and memory deficits in young mice with experimentally induced autism were attenuated by green tea consumption.139 Randomized controlled trials Despite the promise exhibited in animal studies, only 1 human study has examined polyphenol supplementation to remediate cognitive function in a neurological condition other than age-related cognitive decline. Postoperative cognitive dysfunction following surgery with general anesthesia is commonly observed, presumably due to ischemic hippocampal damage suffered during the surgery.140 Pomegranate extract, high in several polyphenols, including punicalagins, anthocyanins, and ellagic acid, was administered in a small pilot study (n = 10) twice per day for 1 week prior to and 6 weeks following surgery. Whereas the placebo group had memory deficits after surgery, the pomegranate extract group actually had improved memory performance compared with baseline.141 MEDITERRANEAN DIET The Mediterranean diet encompasses many of the beneficial dietary factors described above. Although there is some heterogeneity in the definition across studies, the general consensus is that it incorporates high intake of fish, fruits, vegetables, legumes, whole grains, olive oil, and nuts and minimal intake of processed foods, including hydrogenated or trans-fats, refined grains, and added sugar. The diet is so named because it is representative of the diet consumed by the populations of Greece, Italy, and Yugoslavia, which, relative to Western countries, have been observed to have greater longevity and lower rates of cardiovascular disease, cancer, and other chronic health conditions.142,143 The initial interest in the Mediterranean diet was sparked by the 7 Countries study,143 which has been criticized for failing to include several countries that did not fit the pattern of results. Further, as the study was epidemiological, the effects of diet are difficult to tease apart from other factors such as climate and physical activity. Nevertheless, many experimental studies have now shown that this traditional dietary pattern has favorable effects in cardiovascular disease, diabetes, cancer, and other conditions (eg, see Serra-Majem et al.144). Age-related cognitive decline Many studies have now shown beneficial associations between the Mediterranean diet and cognition. Three systematic reviews16,30,145 and 2 meta-analyses146,147 have been conducted on this topic since 2016; thus there is substantial information on this topic available elsewhere, and it is summarized only briefly herein. Meta-analyses A meta-analysis of 5 cohort studies found that the Mediterranean diet was associated with a decrease in incidence of dementia (risk ratio, 0.69).146 Another meta-analysis published subsequently that included 4 additional studies showed that in the 9 cohort studies with a total of 34 168 participants, higher Mediterranean diet intake was associated with a lower risk of developing mild cognitive impairment or Alzheimer’s disease (risk ratio, 0.79).147 Systematic reviews Although the meta-analyses were focused on risk of mild cognitive impairment or Alzheimer’s disease (according to Mini Mental State Examination [MMSE] score or Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria), the systematic reviews provide greater information regarding specific cognitive domains. Regarding the Mediterranean diet and cognition in normal aging, the most recent systematic review concluded that for the 4 studies that assessed specific cognitive domains (as opposed to basic cognitive screening), higher Mediterranean diet intake was associated with slower decline in episodic and semantic memory in 1 study and with improved verbal memory in 1 study; however, the other studiess showed no relationship with these cognitive domains, nor with verbal fluency, speed of production, visuospatial memory, or working memory. Regarding Mediterranean diet and cognition in individuals with dementia, a systematic review145 described that in 3 cross-sectional studies, higher Mediterranean diet intake was associated with a higher cognitive score combining memory, language, processing speed, and visuospatial function. Of 18 longitudinal studies, lower Mediterranean diet intake was associated with poorer working memory and verbal fluency, processing speed, verbal memory, and immediate and delayed recall. Five RCTs were also identified, with 4 of the 5 showing improved cognition, specifically reduced confusion,148 improved global cognition on basic screening,149,150 and better visuospatial working memory. Cross-sectional studies Since the publication of the most recent review, 3 cross-sectional studies have been published. Greater adherence to the Mediterranean diet was shown to be associated with better global cognitive function using screening measures in 3 different aging populations—Spain, the United States, and France.151–153 Overall, with respect to the Mediterranean diet and cognition in aging and neurodegenerative conditions, the results of meta-analyses show the Mediterranean diet is protective against development of MCI or Alzheimer’s disease using brief cognitive screening (MMSE) or DSM criteria. Studies investigating specific cognitive domains in more depth are very heterogenous, with improvement or slowing of decline most commonly shown in episodic or verbal memory, although even this is not consistent across studies. Other neurological conditions The ability of the Mediterranean diet to reduce inflammatory responses, increase serum polyphenols, reduce oxidative stress, and improve cellular energy metabolism154 should in theory also confer benefit in the treatment of other neurological diseases. Indeed, studies suggest that the Mediterranean diet lowers risk of and level of disability in multiple sclerosis.155,156 One recent study of 2087 individuals with multiple sclerosis showed a diet pattern with many components of the Mediterranean diet (high fish, fruit, vegetable, and legume intake) was associated with better self-reported mental and cognitive quality of life.157 The previously described RCT in 20 individuals with multiple sclerosis showed a combination of 10 days of caloric restriction followed by 6 months of the Mediterranean diet improved subjective attention, concentration, and memory.78 However, the design makes it impossible to attribute effects to either diet. To the authors’ knowledge, no other studies directly investigate the ability of the Mediterranean diet to remediate cognition in neurological conditions such as multiple sclerosis, traumatic brain injury, and epilepsy. DISCUSSION The present review provides a summary of the scientific research available regarding the potential for diet to be used as an intervention to improve cognition. This literature is still emerging; therefore in most instances, a background regarding the mechanisms through which such diets may exert their effects, the animal literature to date (which tends to precede human studies), and the results of any human epidemiological or intervention studies where extant have been provided. Although the literature is still emerging, the evidence taken as a whole does seem to suggest that diet can be used as an intervention to improve cognition in several neurological disorders, with the most commonly investigated disorders being traumatic brain injury, epilepsy, and multiple sclerosis (a brief overview is provided in Table 3). The types of diet that appear to have the most support in the scientific literature are those with the potential for diet to reduce oxidative stress, inflammation, and mitochondrial function, which is why they have been chosen for review: ketogenic diet, use of polyphenols, fasting and fast-mimicking diet, and the Mediterranean diet. There is some overlap in these diets; for example, the Mediterranean diet tends to be high in polyphenols, and all of the diets described result in reduced intake of refined carbohydrates and sugar, which are known to have an adverse effect on cognition.158 Table 3 Summary of key findings regarding the impact of each diet on cognition in various neurological conditions Neurological disorder  Ketogenic  Calorie restriction  Polyphenolic  Mediterranean  Epilepsy  Several single-case studies and quasi-experimental studies are suggestive of improved processing speed, attention, and executive function. One RCT showed improved receptive vocabulary and reaction time  No studies available  Curcumin counteracts effect of seizures on learning and memory in rats  No studies available  Traumatic brain injury  Improves memory function in rats. No human studies  Two animal studies have shown improved recovery of memory function. No human studies  Animal studies have shown attenuation of memory impairments following resveratrol and curcumin  No studies available  Multiple sclerosis  Improves memory in rats. One RCT found subjective improvement in cognition (attention, concentration, and memory)  One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  No studies available  One cross-sectional study showed association with better subjective cognitive function. One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  Autism  One prospective study found improvement on rating scale with several cognitive items, but no control group  No studies available  Green tea remediated memory deficits in young mice with experimentally induced autism  No studies available  Aging and neurodegenerative conditions  Improves memory in aged rats, and in 2 RCTs, higher blood ketone levels achieved through diet, improved memory in MCI and AD  Several studies have shown beneficial effects on learning and memory. One RCT showed improved verbal memory  Two systematic reviews showed benefits to memory and executive function  Five RCTs have shown reduced risk of MCI, reduced confusion, improved global function on cognitive screening, and better reaction time  Neurological disorder  Ketogenic  Calorie restriction  Polyphenolic  Mediterranean  Epilepsy  Several single-case studies and quasi-experimental studies are suggestive of improved processing speed, attention, and executive function. One RCT showed improved receptive vocabulary and reaction time  No studies available  Curcumin counteracts effect of seizures on learning and memory in rats  No studies available  Traumatic brain injury  Improves memory function in rats. No human studies  Two animal studies have shown improved recovery of memory function. No human studies  Animal studies have shown attenuation of memory impairments following resveratrol and curcumin  No studies available  Multiple sclerosis  Improves memory in rats. One RCT found subjective improvement in cognition (attention, concentration, and memory)  One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  No studies available  One cross-sectional study showed association with better subjective cognitive function. One RCT showed 10 d of calorie restriction followed by 6 mo of Mediterranean diet improved self-rated attention and memory  Autism  One prospective study found improvement on rating scale with several cognitive items, but no control group  No studies available  Green tea remediated memory deficits in young mice with experimentally induced autism  No studies available  Aging and neurodegenerative conditions  Improves memory in aged rats, and in 2 RCTs, higher blood ketone levels achieved through diet, improved memory in MCI and AD  Several studies have shown beneficial effects on learning and memory. One RCT showed improved verbal memory  Two systematic reviews showed benefits to memory and executive function  Five RCTs have shown reduced risk of MCI, reduced confusion, improved global function on cognitive screening, and better reaction time  Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment; RCT, randomized controlled trial. It should be noted that it is not proposed that diet should be used instead of pharmacological and other medical treatments, but rather as an adjunct. A crucial advantage of these dietary interventions is that they are noninvasive and relatively low risk because they are typically devoid of side effects and sometimes consistent with dietary recommendations (eg, Mediterranean diet) aimed at improving other aspects of physical health. Caveats are however necessary for more extreme diets such as the ketogenic diet or fasting, which could, theoretically, cause ketoacidosis (unrestrained, abnormally excessive levels of ketone bodies) in individuals predisposed to the condition. Nevertheless, these diets are in popular use in the community to assist in weight loss (eg, the Atkins Diet, popular in the 1970s159), and even in clinical populations, such diets seem generally well-tolerated.78 Dietary intervention is not without its disadvantages. When compared with pharmaceutical intervention, adherence to a prescribed diet can be difficult to achieve. For example, the ketogenic diet was originally developed as an alternative to fasting, which was considered hard to implement. However, adherence to the ketogenic diet is also often reported as difficult, with reported side effects such as gastrointestinal disorders, loss of weight, and fatigue.58 There are intermittent fasting protocols that do appear potentially easier to adhere to, but given the varied nature of the duration and extent of the fasting, a lot more work needs to be done to understand the degree of restriction that is necessary, for how long, and at what age/severity of neurological disorder the benefits are seen. Similar to the above point, as opposed to pharmaceutical-based interventions, evaluating the effects of diet interventions proves more difficult. The features of RCTs in evidence-based medicine, although appropriate for measuring drug effects, may not be appropriate in the nutritional context. There are difficulties in obtaining a true “placebo” group because, of course, a nutrient-deficient group is unethical and impractical to consider. As such, baseline levels of nutrient intake should be obtained, ideally using biomarkers rather than self-report. However, this greatly increases costs of research, and additionally, controlling for baseline levels can reduce the statistical power to detect significant effects. In a similar vein, evaluation of whole diet changes cannot be performed under blinded circumstances because the participants will be aware they are making the diet changes and indeed will likely need to be motivated to adhere to the diet changes. As such, again, it is necessary to evaluate compliance with the intervention, preferably using biomarkers rather than self-report, which is subject to social desirability effects. CONCLUSION The current review aims to address some of the more prominent diets in the literature, those with a scientific basis and evidence of effects on cognition. There are, of course, numerous other diets and diet factors that are in common use—for example, low-fat diet or high polyunsaturated fat diet. However, the focus of the low-fat diet has traditionally been on weight loss, and sufficient data were not available to discuss the diet with respect to cognition. Data regarding polyunsaturated fatty acids and cognition tended to be in respect to supplementation rather than whole diet change, and the effects of increased polyunsaturated fats were encompassed by the Mediterranean diet literature. Nevertheless, the present review provides a summary of promising work in the field to support the use of diet to prevent and remediate cognitive deficits in neurological conditions. Although there are now a greater number of studies investigating whole-diet change on physical features in these conditions (eg, level of disability), it is hoped that this review provides the impetus to include evaluation of cognition in the outcome measures of future research. Acknowledgments The authors thank the Australian Research Council for their continued support. Author contributions. H.M.F. and R.J.S. performed the literature review, drafted the manuscript, and approved the final manuscript. Funding. This work was supported by a grant from The Australian Research Council (http://www.arc.gov.au/; grant DP150100105 to R.J.S.). Declaration of interest. The authors have no relevant interests to declare. References 1 Francis HM, Mirzaei M, Pardey MC, et al.   Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet. Proteomics . 2013; 13: 3076– 3091. 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