Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer’s Disease: A Narrative Review

Cognitive impairment and Alzheimer’s Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer’s Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer’s Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings.     

Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials

New dietary approaches for the prevention of cognitive impairment are being investigated. However, evidence from dietary interventions is mainly from food and nutrient supplement interventions, with inconsistent results and high heterogeneity between trials. We conducted a comprehensive systematic search of randomized controlled trials (RCTs) published in MEDLINE-PubMed, from January 2018 to July 2021, investigating the impact of dietary counseling, as well as food-based and dietary supplement interventions on cognitive function in adults with or without cognitive impairment. Based on the search strategy, 197 eligible publications were used for data abstraction. Finally, 61 articles were included in the analysis. There was reasonable evidence that dietary patterns, as well as food and dietary supplements improved cognitive domains or measures of brain integrity. The Mediterranean diet showed promising results, whereas the role of the DASH diet was not clear. Healthy food consumption improved cognitive function, although the quality of these studies was relatively low. The role of dietary supplements was mixed, with strong evidence of the benefits of polyphenols and combinations of nutrients, but with low evidence for PUFAs, vitamin D, specific protein, amino acids, and other types of supplements. Further well-designed RCTs are needed to guide the development of dietary approaches for the prevention of cognitive impairment.     

Validation of the Neurobehavioral Cognitive Status Examination and the Rivermead Behavioural Memory Test in investigations of dementia

Abstract

The aim of this retrospective study was to validate two commonly used instruments, Cognistat and the Rivermead Behavioural Memory Test, RBMT, for detection of MCI and mild dementia. Two different diagnosis groups, mild cognitive impairment (MCI) and Alzheimer's disease combined with mixed dementia representing mild dementia (MD), were compared with a group of patients who did not receive a diagnosis of dementia. All patients were assessed at a specialized outpatient memory clinic in a university hospital in Sweden using the Mini Mental State Examination (MMSE), Cognistat, and RBMT. Sensitivity, specificity, predictive value, and likelihood ratio were calculated for the tests. The Cognistat and RBMT have moderate validity in the detection of MCI and mild dementia. On their own, none of the tests used is sufficient for diagnosing MCI or mild dementia. A combination of the Cognistat and RBMT provides additional information in early stage dementia; in this regard the RBMT is better than the Cognistat, which also has other limitations. The RBMT can be helpful for distinguishing between MCI and mild dementia. There is a need for a more sensitive screening test to capture early cognitive impairment related to patients' occupational performance and problems in daily life.     

Extra-Virgin Olive Oil Enhances the Blood–Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial

Mild cognitive impairment (MCI) and early Alzheimer’s disease (AD) are characterized by blood–brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-β (Aβ) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aβ₄₂/Aβ₄₀ and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aβ. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil’s protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.     

A Critical Review of the Study of Neuroprotective Diets to Reduce Cognitive Decline

Alzheimer’s disease (AD) and other dementias are now the seventh leading cause of death in the world and are projected to affect 115.4 million people by 2050. Delaying the onset of AD by just five years is estimated to reduce the cost and prevalence of the disease by half. There is no cure for AD nor any drug therapies to halt its progression once the disease begins. Lifestyle choices including diet are being seen as a viable complementary therapy to reduce cognitive decline, the hallmark of AD. Mediterranean, DASH (Dietary Approaches to Stop Hypertension), and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diets have biological mechanisms supporting their potential neuroprotective benefits, but the findings of study outcomes about these benefits have been inconsistent. This paper analyzed five Randomized Clinical Trials (RCTs) (from 2000 to 2021) and 27 observational studies (from 2010 to 2021) focused on the link between cognitive health and the Mediterranean/DASH/MIND diets to identify gaps and challenges that could lead to inconsistent results. These include a lack of accuracy in assessing food intake, multiple dietary pattern scoring systems, a shifting metric among studies focused on the Mediterranean diet, a lack of standards in the tools used to assess cognitive decline, and studies that were underpowered or had follow-up periods too short to detect cognitive change. Insights from these gaps and challenges are summarized in recommendations for future RCTs, including both pragmatic and explanatory RCTs.     

Moringa Oleifera Alleviates Aβ Burden and Improves Synaptic Plasticity and Cognitive Impairments in APP/PS1 Mice

Alzheimer’s disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Moringa oleifera (MO) that have strong anti-oxidative, anti-inflammatory, anticholinesterase, and neuroprotective virtues. In this study, we treated APP/PS1 mice with a methanolic extract of MO for four months and evaluated its effect on AD-related pathology in these mice using a multitude of behavioral, biochemical, and histochemical tests. Our data revealed that MO improved behavioral deficits such as anxiety-like behavior and hyperactivity and cognitive, learning, and memory impairments. MO treatment abrogated the Aβ burden to wild-type control mice levels via decreasing BACE1 and AEP and upregulating IDE, NEP, and LRP1 protein levels. Moreover, MO improved synaptic plasticity by improving the decreased GluN2B phosphorylation, the synapse-related proteins PSD95 and synapsin1 levels, the quantity and quality of dendritic spines, and neurodegeneration in the treated mice. MO is a nutraceutical agent with promising therapeutic potential that can be used in the management of AD and other neurodegenerative diseases.     

Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

Alzheimer’s disease (AD) is the most common type of dementia leading to progressive memory loss and cognitive impairment. Considering that pharmacological treatment options for AD are few and not satisfactory, increasing attention is being paid to dietary components that may affect the development of the disease. Such a dietary component may be caffeine contained in coffee, tea or energy drinks. Although epidemiological data suggest that caffeine intake may counteract the development of cognitive impairment, results of those studies are not conclusive. The aim of the present study is to review the existing experimental studies on the efficacy of caffeine against AD and AD-related cognitive impairment, focusing on the proposed protective mechanisms of action. In conclusion, the reports of studies on experimental AD models generally supported the notion that caffeine may exert some beneficial effects in AD. However, further studies are necessary to elucidate the role of caffeine in the effects of its sources on cognition and possibly AD risk.     

Metabolic Syndrome,Cognitive Impairment and the Role of Diet: A Narrative Review

Background: This narrative review presents the association between metabolic syndrome (MetS), along with its components, and cognition-related disorders, as well as the potential reversal role of diet against cognitive impairment by modulating MetS. Methods: An electronic research in Medline (Pubmed) and Scopus was conducted. Results: MetS and cognitive decline share common cardiometabolic pathways as MetS components can trigger cognitive impairment. On the other side, the risk factors for both MetS and cognitive impairment can be reduced by optimizing the nutritional intake. Clinical manifestations such as dyslipidemia, hypertension, diabetes and increased central body adiposity are nutrition-related risk factors present during the prodromal period before cognitive impairment. The Mediterranean dietary pattern stands among the most discussed predominantly plant-based diets in relation to cardiometabolic disorders that may prevent dementia, Alzheimer’s disease and other cognition-related disorders. In addition, accumulating evidence suggests that the consumption of specific dietary food groups as a part of the overall diet can improve cognitive outcomes, maybe due to their involvement in cardiometabolic paths. Conclusions: Early MetS detection may be helpful to prevent or delay cognitive decline. Moreover, this review highlights the importance of healthy nutritional habits to reverse such conditions and the urgency of early lifestyle interventions.     

Discovery of Natural Inhibitors of Cholinesterases from Hydrangea: In Vitro and In Silico Approaches

Alzheimer’s disease (AD) is a neurodegenerative disease conceptualized as a clinical-biological neurodegenerative construct where amyloid-beta pathophysiology is supposed to play a role. The loss of cognitive functions is mostly characterized by the rapid hydrolysis of acetylcholine by cholinesterases including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, both enzymes are responsible for non-catalytic actions such as interacting with amyloid β peptide (Aβ) which further leads to promote senile plaque formation. In searching for a natural cholinesterase inhibitor, the present study focused on two isocoumarines from hydrangea, thunberginol C (TC) and hydrangenol 8-O-glucoside pentaacetate (HGP). Hydrangea-derived compounds were demonstrated to act as dual inhibitors of both AChE and BChE. Furthermore, the compounds exerted selective and non-competitive mode of inhibition via hydrophobic interaction with peripheral anionic site (PAS) of the enzymes. Overall results demonstrated that these natural hydrangea-derived compounds acted as selective dual inhibitors of AChE and BChE, which provides the possibility of potential source of new type of anti-cholinesterases with non-competitive binding property with PAS.     

Decision-Making in People With Dementia or Mild Cognitive Impairment: A Narrative Review of Decision-Making Tools

ObjectivesThis review summarized the applicability of various decision-making tools for helping people with dementia or mild cognitive impairment (MCI) and their families make decisions.DesignThis study was a narrative literature review. The protocol of this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020182259).Setting and ParticipantsPeople with dementia or MCI and their families were included in this study.MethodsThis review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched the Cochrane Library, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Chinese Electronic Periodical Services databases from inception to May 2021. The Joanna Briggs Institute Critical Appraisal Checklists for a variety of study designs were used.ResultsTopics related to decision-making were categorized as everyday activity decisions or medical treatment decisions. Various types of decision-making tools were identified, and we observed that decision aids can be modified and used for both everyday activity decisions and medical treatment decisions. In addition to highlighting decision aids for specific decisional issues and topics, we also elucidated other validated tools that can be used to facilitate the decision-making process.Conclusions and ImplicationsThis study highlighted the topics involved in decision-making and using decision-making tools. The current review provides information that can help individuals and health care professionals choose optimal decision-making tools. On the basis of our findings, future studies can determine the most appropriate tools for intervention or outcome measures.     

Comparison of Computerized and Paper-and-Pencil Memory Tests in Detection of Mild Cognitive Impairment and Dementia: A Systematic Review and Meta-analysis of Diagnostic Studies

Objectives

To compare the diagnostic performance of computerized and paper-and-pencil memory tests in detection of mild cognitive impairment (MCI) and dementia.

Metabolic Syndrome: Is It Time to Add the Central Nervous System?

Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias. The syndrome affects 25% of adults worldwide. The definition of MS has evolved over the last 80 years, with various classification systems and criteria, whose limitations and benefits are currently the subject of some controversy. Likewise, hypotheses regarding the etiology of MS add more confusion from clinical and epidemiological points of view. The leading suggestion for the pathophysiology of MS is insulin resistance (IR). IR can affect multiple tissues and organs, from the classic “triumvirate” (myocyte, adipocyte, and hepatocyte) to possible effects on organs considered more recently, such as the central nervous system (CNS). Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) may be clinical expressions of CNS involvement. However, the association between MCI and MS is not understood. The bidirectional relationship that seems to exist between these factors raises the questions of which phenomenon occurs first and whether MCI can be a precursor of MS. This review explores shared pathophysiological mechanisms between MCI and MS and establishes a hypothesis of a possible MCI role in the development of IR and the appearance of MS.     

Synergistic Neuroprotective Effects of a Natural Product Mixture against AD Hallmarks and Cognitive Decline in Caenorhabditis elegans and an SAMP8 Mice Model

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer’s disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aβ plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aβ C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies.     

Administration of Bifidobacterium breve Improves the Brain Function of Aβ1-42-Treated Mice via the Modulation of the Gut Microbiome

Psychobiotics are used to treat neurological disorders, including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the mechanisms underlying their neuroprotective effects remain unclear. Herein, we report that the administration of bifidobacteria in an AD mouse model improved behavioral abnormalities and modulated gut dysbiosis. Bifidobacterium breve CCFM1025 and WX treatment significantly improved synaptic plasticity and increased the concentrations of brain-derived neurotrophic factor (BDNF), fibronectin type III domain-containing protein 5 (FNDC5), and postsynaptic density protein 95 (PSD-95). Furthermore, the microbiome and metabolomic profiles of mice indicate that specific bacterial taxa and their metabolites correlate with AD-associated behaviors, suggesting that the gut–brain axis contributes to the pathophysiology of AD. Overall, these findings reveal that B. breve CCFM1025 and WX have beneficial effects on cognition via the modulation of the gut microbiome, and thus represent a novel probiotic dietary intervention for delaying the progression of AD.     

The Effects of Spirulina maxima Extract on Memory Improvement in Those with Mild Cognitive Impairment: A Randomized,Double-Blind,Placebo-Controlled Clinical Trial

Spirulina maxima is a marine microalga that has been promoted worldwide as a super food. This study was conducted to evaluate its ability to improve memory in the older adults using Spirulina maxima 70% ethanol extract (SM70EE). This randomized, double-blind, placebo-controlled clinical trial comprised 80 volunteers recruited from Jeonbuk National University Hospital in Jeonju, Republic of Korea, who were randomly assigned to two groups. The participants received either 1 g/day of SM70EE or a placebo without otherwise changing their diet or physical activity. The participants were examined at baseline and after a 12-week interval to determine whether there were changes in their results for visual learning, visual working memory, and verbal learning tests from the Korean version of the Montreal Cognitive Assessment, brain-derived neurotrophic factor and beta-amyloid levels, and total antioxidant capacity. Compared to the placebo group, the treatment group showed a significant improvement in visual learning and visual working memory test results and enhanced vocabulary. SM70EE use was shown to improve memory, with no adverse effects. Its efficacy in alleviating Alzheimer’s disease symptoms was verified for the first time through this clinical trial. SM70EE could play a role in the management of patients with dementia. This trial is registered with registration number of clinical research information service (CRIS: KCT0006161).     

Cognitive Decline Related to Diet Pattern and Nutritional Adequacy in Alzheimer’s Disease Using Surface-Based Morphometry

Dietary pattern (DP) results in nutrition adequacy and may influence cognitive decline and cortical atrophy in Alzheimer’s disease (AD). The study explored DP in 248 patients with AD. Two neurobehavioral assessments (intervals 13.4 months) and two cortical thickness measurements derived from magnetic resonance images (intervals 26.5 months) were collected as outcome measures. Reduced rank regression was used to assess the groups of DPs and a linear mixed-effect model to explore the cortical neurodegenerative patterns. At screening, underweight body mass index (BMI) was related to significant higher lipid profile, impaired cognitive function, smaller cortical thickness, lower protein DP factor loading scores and the non-spouse caregiver status. Higher mini-mental state examination (MMSE) scores were related to the DP of coffee/tea, compared to the lipid/sugar or protein DP group. The underweighted-BMI group had faster cortical thickness atrophy in the pregenual and lateral temporal cortex, while the correlations between cortical thickness degeneration and high HbA1C or low B12 and folate levels were localized in the medial and lateral prefrontal cortex. The predictive model suggested that factors related to MMSE score were related to the caregiver status. In conclusion, normal or overweight BMI, coffee/tea DP group and living with a spouse were considered as protective factors for better cognitive outcomes in patients with AD. The influence of glucose, B12 and folate on the cortical degeneration was spatially distinct from the pattern of AD degeneration.     

Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration.     

Consumption of Oleic Acid on the Preservation of Cognitive Functions in Japanese Elderly Individuals

We recruited 154 community-dwelling elderly individuals and conducted a cohort study to find out the nutrient intake that is suitable for maintaining cognitive function in Japanese elders. Cognitive function was evaluated by the two functional tests, the Montreal Cognitive Assessment (MoCA) and Wechsler Memory Scale-Delayed Recall (WMS-DR), and daily nutrient intake was estimated from a Brief-type Self-administered Diet History Questionnaire (BDHQ). By a multiple regression analysis, among the four major nutrients (protein, fat, carbohydrate and ash), we detected a significant correlation between the score of cognitive functions assessed by both MoCA and WMS-DR and daily consumption of fat (p = 0.0317 and p = 0.0111, respectively). Among categories of fatty acid, we found a significant correlation between the score of both MoCA and WMS-DR and consumption of monounsaturated fatty acid (MUFA) (p = 0.0157 and p = 0.0136, respectively). Finally, among MUFAs, we observed a significant correlation between the score of both MoCA and WMS-DR and consumption of oleic acid (p = 0.0405 and p = 0.0165, respectively). From these observations, we can propose that daily consumption of fat, especially in oleic acid, has a beneficial effect against cognitive decline in community-dwelling Japanese elderly individuals.     

Evaluation of Available Cognitive Tools Used to Measure Mild Cognitive Decline: A Scoping Review

Cognitive decline is a broad syndrome ranging from non-pathological/age-associated cognitive decline to pathological dementia. Mild cognitive impairment MCI) is defined as the stage of cognition that falls between normal ageing and dementia. Studies have found that early lifestyle interventions for MCI may delay its pathological progression. Hence, this review aims to determine the most efficient cognitive tools to discriminate mild cognitive decline in its early stages. After a systematic search of five online databases, a total of 52 different cognitive tools were identified. The performance of each tool was assessed by its psychometric properties, administration time and delivery method. The Montreal Cognitive Assessment (MoCA, n = 15), the Mini-Mental State Examination (MMSE, n = 14) and the Clock Drawing Test (CDT, n = 4) were most frequently cited in the literature. The preferable tools with all-round performance are the Six-item Cognitive Impairment Test (6CIT), MoCA (with the cut-offs of ≤24/22/19/15.5), MMSE (with the cut-off of ≤26) and the Hong Kong Brief Cognitive Test (HKBC). In addition, SAGE is recommended for a self-completed survey setting whilst a 4-point CDT is quick and easy to be added into other cognitive assessments. However, most tools were affected by age and education levels. Furthermore, optimal cut-off points need to be cautiously chosen while screening for MCI among different populations.