The effects of dietary intervention and MAF supplementation on cognitive function in elderly users of outpatient rehabilitation

The effects of dietary intervention and MAF supplementation on cognitive function in elderly users of outpatient rehabilitation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effects of dietary intervention and MAF supplementation on cognitive function in elderly users of outpatient rehabilitation Yoko Uchiyama-Tanaka, Hajime Yamakage, Toshio Inui This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4272286/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Backgroud: Age, genetic and environmental factors are noted to contribute to dementia risk. Neuroplasticity, protection from degeneration and cell death, and early intervention are desirable for preventing dementia. The linkage between neurons and microglia has been a research focus. In this study, we examined the effects of dietary modification (a reduction in advanced glycation end products [AGEs]) and macrophage activating factor (MAF; a macrophage regulator) supplementation on cognitive function in elderly participants undergoing rehabilitation. Methods: Forty-three rehabilitation facility users aged over 60 years were randomly divided into three groups: a control group receiving placebo, a group receiving dietary guidance, and a group receiving dietary guidance and MAF supplementation. The amyloid-β40/42 ratio, dietary AGE intake, plasma AGE levels, dietary calorie intake and MCI screen as cognitive functions of participants were evaluated. Results: Four participants withdrew from the study. MCI screen scores significantly improved in MAF supplementation group especially after 6 months. Dietary modulation was also effective for improving cognitive function after 12 months compared to placebo. Only control group significantly increased plasma AGE and worsened, dietary modulation and MAF supplementation group showed no change after 12 months. Conclusions: MAF supplementation is effect for improvement of cognitive function especially after 6 months in elderly people with rehabilitation. Dietary modulation was also effective for cognitive function after 12 months compared to control group. Dietary guidance in day-care center rehabilitation was difficult due to conflicts with family members and the use of facilities. However, enthusiastic users showed improvement in cognitive function. In addition to exercise and dietary improvement, social involvement was found to be important again. Trial registration: UMIN 000050155, 2023/02/14 Dementia Cognitive function Macrophage AGEs Amyloid beta Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Multiple factors have b een identified to be associated with dementia risk, including age, genetic factors, and environmental factors (lifestyle, exercise, toxin exposure, diet, nutrition, social involvement, hearing, and educational history) 1-4 . These factors are believed to trigger protein misfolding, synaptic dysfunction, reactive oxygen species, mitochondrial dysfunction, impaired calcium regulation in the cytoplasm, and decreased cell number, resulting in neurodegeneration 1,5,6 . With the ageing of the population and the increase in the prevalence of diabetes and atherosclerosis, the prevalence of dementia is on the rise. The GBD Dementia Forecasting Collaborators indicate that the prevalence of dementia will reach 150 million by 2050 7 . If mild cognitive impairment is included in this estimation, the number will be even higher. On the other hand, dementia was once thought to be a progressive disease in which cognitive function could not be improved or recovered. There are also emerging reports that improvements in the causes of brain inflammation and amyloid-β accumulation may improve symptoms even after a diagnosis of dementia 1,8,9 . However, once dementia is diagnosed, organic changes in the brain progress, and recovery is difficult. Therefore, prevention of the onset of dementia is highly important. Exercise, a healthy diet, social stimulation, intestinal environment improvement, lifestyle modification, optimal sleep, stress care, hearing assistance, nutritional supplementation and supplements have been reported to be effective in dementia prevention 1,8,10 . Brain inflammation has been noted to be involved in cognitive dysfunction. The linkage between neurons and microglia has been noted in brain synapse loss, the removal of waste products such as amyloid-β, the control of infection and inflammation, synapse germination, and neurogenesis and pruning 5,6,11-17 . Microglia were previously thought to be structural factors in the brain but have been shown to have macrophage functions 5,14 . Microglial dysfunction is a problem in degenerative brain diseases 5,6,12,13 . Group-specific component macrophage activation factor (GcMAF) is a protein that results from the sequential deglycosylation of its precursor, vitamin binding protein (VDBP) 18,19 . The Gc protein VDBP is produced in the liver and is present in the majority of biological fluids. VDBP has multifunctional properties as a transporter of serum vitamin D3 and its metabolites, functions as an actin scavenger during cellular injury, acts as a chemotaxin for phagocytic cells, and plays a role in macrophage activation as a precursor for GcMAF. This Gc protein has a triple-domain modular structure, where domain III (the C-terminal end) harbours a single glycosylation site. The terminal N-acetylgalactosamine (GalNAc) moiety in domain III is the region involved in the GcMAF-mediated macrophage activation cascade. During inflammation, lysophosphatidylcholine is released from tissue, which induces the expression of beta-galactosidase in B cells and sialidase in T cells. These enzymes hydrolyse the terminal galactose and sialic acid saccharides of the Gc protein to convert it into GcMAF with an N-acetylgalactosamine moiety 18,20 . One of the cell types targeted is resident intestinal macrophages, which exhibit great phagocytic activity without initiating an inflammatory response due to their low, or even absent, expression of innate response receptors, including receptors for LPS (CD14), Fcα (CD89), Fcγ (CD64, CD16), and CR3 (CD11b/CD18). Resident intestinal macrophages constitute the largest pool of macrophages in the body. These cells are able to downregulate an excessive systemic inflammatory response by driving the resolution of inflammation and by contributing to the mechanism of oral tolerance to foreign antigens, as well as autoantigens. MAF was discovered to be a macrophage activator but has also been shown to regulate macrophage function, improve allergies, and optimize immune function, for example, providing adjuvant therapy against cancer and many other diseases 18 . In addition, MAF has been reported to be related to life span through, for example, telomere extension (in press). Furthermore, in animal experiments with MAF, recovery from brain damage (embolization model 21 , trauma model 22 ) and a reduction in amyloid-β have been observed, and clinically, the effectiveness of MAF has been shown in autism spectrum disorder 23 and multiple sclerosis 24 , where brain inflammation is suggested. However, the effects of MAF on cognitive function have not yet been studied. Healthy food consumption is very important for preventing dementia. Advanced glycation end products (AGEs) are formed by nonenzymatic reactions between sugars and amino groups of macromolecules, such as proteins, lipids, and nucleic acids 25 . Because glycation occurs constantly during normal ageing and the rate of degradation of glycated macromolecule derivatives is very slow, AGEs accumulate with increasing age. Accumulating evidence shows that AGEs play important roles in the development of age-related disorders, including diabetic vascular complications, osteoporosis, and Alzheimer’s disease 25-28 . It is estimated that 6-7% of AGEs are taken up by the body from exogenous sources (diet, tobacco, etc.) 29 . In this study, we examined the effects of nutritional guidance (reducing the amount of AGEs in the diet as much as possible) and MAF supplementation on cognitive function in a group of elderly individuals attending a day rehabilitation facility (that is, elderly individuals who were able to exercise regularly). This study was double-blind with respect to drug intervention but open with respect to the presence or absence of dietary guidance. Methods Study design and participants This was a single-centre, randomized controlled, open-label, parallel-arm trial. Participants without a diagnosis of dementia who were older than 60 years of age; had been attending Soushinkai, a daycare rehabilitation facility in Okayama, for at least three months; and were in stable condition were eligible for inclusion. The procedures were in accordance with the guidelines of the Declaration of Helsinki (2000) for human experimentation and informed consent was obtained from all subjects. At the time of entry, interviews, evaluations, blood tests, and medical examinations were conducted. Patients with cognitive dysfunction, severe anaemia, terminal cancer, or brain degenerative diseases such as Parkinson's disease were excluded. Soushinkai rehabilitation facilities provide not only passive rehabilitation but also voluntary rehabilitation, visitation, and assistance so that rehabilitation can be performed at home. The facility also has a daycare centre and exercise machines. People who consented to participate the study were randomly divided into three groups. Group C, a normal rehabilitation-only group as control group; Group D, a dietary guidance group, who received dietary guidance and rehabilitation by the same physician; and Group M, who received one capsule of MAF triple in the morning upon waking and one capsule before sleep and the same dietary guidance as Group D. Groups C and D received placebo in the same manner, with one capsule upon waking and one capsule before sleep. MAF triple capsules are dietary supplements produced by Saisei Pharma, Japan, that are designed to modulate the mucosal immunity of the intestine. Before assessing the Mild Cognitive Impairment Screening (MCIS) score, AGE levels were measured with an AGE reader. The plasma amyloid-β 40/42 ratio, general blood parameters (peripheral blood, GOT, GPT, gamma GPT, ALP, HbA1C, BUN, Cr, uric acid, total cholesterol, HDL cholesterol, triglycerides, ferritin, 25OH vitamin D, CRP, free T4, TSH, albumin, zinc, copper, sodium, potassium, chloride, folic acid, vitamin B12, vitamin B1), and dietary AGE intake were measured. The same procedure was used after 6 and 12 months. The study was approved by SaiseiMirai Ethics Comiittee (No. 2022-001). Randomization After screening, the data of each participant were linked to the participant identification code provided and anonymized. Next, the participants were randomized to Groups M, D and C at a ratio of 1:1:1. Randomized allocation was performed via the simple randomization method. The allocation table was generated and maintained by a third party at the facility not involved in the study. Dietary guidance Dietary guidance was provided to reduce the amount of AGEs in the diet as much as possible. It is generally known that AGEs are produced in large amounts when meat products and fat-rich foods are fried or baked at high temperatures. On the other hand, cooking methods such as slow steaming or boiling of foods with a high water content are less likely to produce AGEs, which have long been known to be produced in Maillard reactions or browning reactions. The browning of foods is a rough indication of their AGE content. Fructose is approximately 10 times more likely to form AGEs than glucose. It is thought that avoiding drinking carbonated beverages that contain a large amount of fructose corn syrup, avoiding excessive consumption of fructose, and avoiding consuming foods with significant browning can reduce the amount of exogenous AGE intake 30 . Lemon and vinegar can also reduce the formation of AGEs during the cooking process. A well-balanced diet rich in vegetables, seaweed, and mushrooms is also recommended 31 . First, all groups were asked to describe their meals for one week, or if they were unable to do so, they were asked to do so with the help of their family members, who were interviewed in more detail by a nutritionist. Calorie calculations were then performed. AGE calculations were performed with the exAGE formula devised by the AGE Research Association. These calculations were performed before the study and at 6 months. For Group D and Group M, at the start of the study, materials were first distributed to the group, and dietary guidance was given by the same physician in the form of a lecture. The same doctor showed them pictures and instructed them to eat less processed meat (sausage, bacon, etc.), packaged foods, deep fried foods, sugary sweets, and snacks, and more steamed foods, fresh vegetables, and fruits. Afterwards, during the individual interviews, we provided advice on what to maintain and what to add to the diet of each person based on the dietary chart. Individual interviews were held at the start of the study, at 6 months, and at 12 months. Calculation of AGEs in the diet The CML (carboxymethyllysine; a type of AGE) coefficient is determined by dividing foodstuffs into 18 categories, including grains, meats, fats, oils, and vegetables, and multiplying the coefficient of cooking (1 for raw foodstuffs and 1 for boiled or baked foodstuffs) by the coefficient of each category. The following original formula is used to estimate the CML (AGE) content of food products. CML content (in kilograms) = total protein and fat content (g) per 100 g of food material × processing factor × cooking factor × CML factor. This formula was derived by determining the protein and fat contents of ingredients from the Japanese Food Composition Table. There was a strong positive correlation (p<0.0001) between the measured CML content in foods reported by Uribarri et al. and the estimates obtained in the four factors described above, with a correlation coefficient of 0.52. The average CML intake for the American population is reported to be approximately 15,000 KU 30 . Cognitive function assessment The MCIS was used because it is applicable for those with dementia or mild dementia. The MCIS, derived from the Word List Memory test, differentiates cognitive changes associated with normal ageing from mild cognitive impairment as well as dementia 32 . The MCIS is a brief, electronically scored, verbally administered test that uses correspondence analysis to calculate an individual’s memory capabilities, which is then reported as the Memory Performance Index 33-35 . The MCIS has been validated in both academic and community clinical settings and in multiple languages 36,37 . Testing was performed at before the start of the study and at 6 and 12 months. Since large social fluctuations in participants have a direct impact on the score, this index is best for use in studies of populations without large social fluctuations. AGE measurement Glycation levels were measured on the dominant volar forearm using an AGE Reader mu (Diagnoptics Technologies B. V., Groningen, Netherlands) 38, 39 . Pentosidine and crossline have structural properties that cause them to emit fluorescent light across a specific range of wavelengths upon excitation by ultraviolet light. This unique characteristic has been used to develop technology that quantifies the accumulated AGEs within human skin. Although several confounding factors exist, such as other fluorophores, skincare cream use, and skin pigmentation, skin autofluorescence (SAF) is a prominent biomarker that may reflect tissue accumulation of AGEs 29,40,41 . Certain types of AGEs autofluoresce when exposed to ultraviolet light. The AGE Reader illuminates skin with ultraviolet light (excitation range= 300-420 nm) and then detects the resulting fluorescent light (emission range = 420-600 nm) while simultaneously detecting light reflected from the skin in the 300- to 420-nm range. SAF, reported in arbitrary units, is defined as the ratio of the intensity of the emitted fluorescent light to that of the reflected light 42-44 . Plasma ratio of amyloid- β40 to amyloid-β42 Recent technological advancements in mass spectrometry have led to improvements in instrument sensitivity and precision, resulting in the development of improved plasma Aβ assays. Many studies have reported encouraging results for plasma Aβ as a biomarker for Alzheimer’s disease. Tests for the risk of developing dementia were conducted at the starting, 6-month, and 12-month time points 45 . Sample size The study protocol was designed to detect a large effect size (effect size = 0.8) between groups for the change in endpoint over the 12-month study period. Based on that assumption and for a power of 80% and a 5% significance level, the sample size was calculated to be 13 participants per group. Statistical methods All data were analysed based on the intention-to-treat principle. The primary analysis was performed on the full analysis set (FAS), while the MCIS score, which is heavily influenced by social variables, was evaluated in the pre-protocol set (PPS). The absolute standard difference (ASD) was used to assess the balance of patient backgrounds by random assignment, and the ASD was considered in balance if the 95% confidence interval in this population was less than 0.755 as a threshold value that did not cross zero. The repeated-measures endpoints were analysed with linear mixed models that included intervention, dummy variables for time, intervention-by-time interactions and baseline parameters of endpoints as covariates and participants as a random effect. The covariance structure was a completely general covariance matrix. The results are reported as the least squares means with 95% confidence intervals (CIs) at each time point. A P value < 0.05 was considered to indicate statistical significance, and all P values were two-sided with multiplicity adjustment by the Bonferroni method. All the statistical analyses were performed using SPSS version 24.0 (IBM Japan, Ltd.). Results Between May 2022 and July 2022, a total of 43 people (mean age 79.0 ± 8.8 years, 17 males and 26 females, care level of support to care level 3) who consented to participate in the study were randomly divided into three groups. Of those, 15 were allocated to Group C, 14 were allocated to Group D, and 14 were allocated to Group M (Fig. 1). In Group D, it was revealed that one participant had taken donepezil hydrochloride after randomization, and this participant was subsequently excluded from FAS. In Group C, one participant had a myocardial infarction and discontinued use of the facility, and in Group D, two participants voluntarily withdrew from the study. In Group C, three participants experienced major social changes during the study period. Thus, the resultant PPS included 12 participants in Group C, 13 participants in Group D and 14 participants in Group M. The clinical characteristics of the participants are shown in Table 1. The ASD was less than 0.755 (the threshold for which the 95% CI for the ASD did not cross 0 in this study), indicating that the baseline characteristics (age, sex, level of care, presence of diabetes, cognitive function according to MCIS score, AGE, amyloid-β 40/42 ratio, AGE levels and calories) of the three groups were similar. The results of the analysis of outcomes for the FAS are shown in Table 2. Dietary caloric intake did not change before or after the intervention in any group, and there were no significant group differences in dietary calorie intake during the intervention (Fig. 2). The amount of change in dietary AGEs was unchanged in Group C but decreased significantly in Group D (-2378 [95% CI: -4724 to -32] KU). The amount of change in dietary AGEs was unchanged in Group M despite dietary guidance, and there were no significant group differences in intervention effects (Fig. 3). Only Group M had significantly improved MCIS scores after 6 months compared to before the study (from 46.65 [43.51 to 49.79] to 55.79 [52.65 to 58.93], change of +9.14 [4.70 to 13.58]) in the PPS. The MCIS score of Group M also improved significantly compared to that of both Group C and Group D ( P = 0.035 and 0.008, respectively). Even after 12 months, Group M maintained cognitive function (55.71 [52.45 to 58.97], change of +9.06 [4.53 to 13.59]). Compared with before the study, Group D exhibited significant improvements in the MCIS score at 12 months (from 46.73 [43.47 to 49.99] to 54.09 [50.37 to 57.81], change of +7.36 [2.42 to 12.3]). Compared with those in Group C, the MCIS score in Group M and Group D improved significantly at 12 months ( P = 0.010 and 0.0044, respectively) (Fig. 4). The AGE level measured by an AGE reader did not change significantly in Groups M or D at 6 months or at 12 months in the FAS. Only the AGE level of Group C significantly increased at 12 months (from 2.71 [2.53 to 2.88] to 3.08 [2.90 to 3.25], a change of +0.37 [0.17 to 0.57]). The AGE level in Group C at 12 months increased significantly compared to those in Group M and Group D ( P < 0.001 and 0.005, respectively) (Fig. 5). The serum amyloid-β 40/42 ratio showed no significant difference at 6 months, but at 12 months, that of all groups had decreased significantly compared to before the study (Group C, change of - 1.41 [-2.28 to -0.54]; Group D, change of - 1.39 [-2.34 to -0.44]; Group M, change of - 1.28 [-2.18 to -0.38]). There were no significant differences in serum amyloid beta levels between the intervention groups (Fig. 6). Discussion In this study, the administration of MAF supplements improved cognitive function. Microglia play complex roles that are both beneficial and detrimental to disease pathogenesis, including engulfing or degrading toxic entities such as amyloid plaques and promoting neurotoxicity through excessive inflammatory cytokine release 5,11 . Aberrations in the normal homeostatic functions of microglia, such as surveillance, synaptic pruning, and plasticity, may also contribute to excessive synapse loss and cognitive dysfunction in patients with Alzheimer’s disease and other diseases 6,17 . Failure to clear apoptotic cells, cellular debris, and toxic proteins, such as amyloid-β, can contribute to inflammation and neurodegeneration 15-17 . Synapse loss is an early hallmark of Alzheimer’s disease and other neurodegenerative disorders and is considered a strong correlate of cognitive decline. Numerous studies have demonstrated that microglia have many physiological, noninflammatory functions that are crucial for the central nervous system and for regulating neuroplasticity, such as driving neural programmed cell death and synaptic plasticity in adults. Microglia have highly dynamic processes and continually survey their local environment. It is estimated that resident microglia scan the entire volume of the brain as one of their homeostatic functions 16,17 . Other possible functions of resident microglia include trauma site reduction in posttrauma model mice observed in animal experiments, amyloid-β plaque and phospho-tau tangle reduction, the repair of infarction in models, macrophage activation, and VEGF-increasing effects 21 . Macrophages work in both inflammatory and anti-inflammatory directions, but according to the research of Uto et al., 21 the activation of anti-inflammatory macrophages increases when inflammation is high, suggesting that macrophage function is not regulated in one direction but rather changes according to the situation. Siniscalco et al. 23 also reported that GcMAF affects the endocannabinoid system, which controls cell-to-cell communication in, for example, greed, pain, immune regulation, emotional regulation, motor function, development and ageing, neuroprotection, cognitive function and memory. It is recognized that a high degree of glycation is associated with cognitive function 27,28 . The glycation level is related to exercise, smoking status, and age. AGEs essentially increase with age. Therefore, the fact that only the control group showed a worsening of AGE levels may be attributed to the effects of MAF and dietary guidance. However, only Group D showed a decrease in dietary AGEs, while Group M did not. This finding may due to the fact that the meals of many participants in Group M were cooked by day service users or family members, and many participants did not cook for themselves. Unintentionally, this study was conducted with Group C participants receiving an exercise-only intervention, Group D receiving an exercise and dietary modification intervention, and Group M receiving an exercise and MAF intervention. An improvement in cognitive function in the dietary guidance group was not observed until 12 months, and although there was no difference between Group M and Group C in terms of AGE levels, we believe that reducing AGEs in the diet may be helpful in improving cognitive function in the long term. The amyloid-β40/42 ratio improved in all three groups after 12 months. All three groups underwent rehabilitation, including an exercise program, so there were no significant differences in the amyloid-β40/42 ratio among the three groups after 12 months, but all three groups showed a decreasing trend in the amyloid-β40/42 ratio compared to the prestudy period. Physical exercise in combination with other interventions, including vascular risk management, diet, and cognitive training, has been found to be associated with improved cognitive performance 2,46,47 . Among the largest improvements were those seen in cognitive functions, overall health, and mood status. Limitations: It is important to note that we originally planned to continue providing dietary guidance after 12 months; however, cooperation on this guidance was difficult for participants and their family members, and following the guidance involved too much work and time. Since dietary guidance was provided throughout the 12-month period, the AGE levels after 12 months were unknown. The fact that the participants were in a daycare rehabilitation facility and therefore did not follow a uniform diet was also a factor in the ambiguous results. In addition, the advanced age of the participants made it difficult for them to continue the study. In this study, we did not determine genotypes such as the APOE type. The number of participants was originally small, but it decreased further due to withdrawal from the study due to infections and a worsening of underlying diseases. In the future, we hope to conduct a large-scale study with determinations of APOE type at residential facilities where meals can be provided under dietary controlled conditions. According to the individual results of this study, there were also cases of significant improvement in the MCIS score in the control group. One thing all participants had in common was that they felt motivated to come to this rehabilitation facility and looked forward to communicating with friends and staff at the facility. We once again recognized that social involvement is very important for cognitive function. This study showed that cognitive dysfunction is multifactorial but that earlier intervention can prevent its worsening or even improve cognitive function sooner. The importance of macrophages, the effectiveness yet challenges of dietary guidance, and the importance of social involvement were recognized. Conclusion Administration of MAF supplements not only prevented but also improved cognitive decline after 6 months, and the effect was maintained after 12 months. However, Group D, in which participants received dietary guidance, showed improvements in cognitive function after 12 months. The significant differences between Groups M and D disappeared after 12 months. However, compared to the control group, the dietary guidance and MAF-treated groups showed significant differences in cognitive function. Glycation levels tended to decrease in the MAF-treated group, but no significant pre- or posttreatment differences were observed. The control group showed a worsening (i.e., increase in) of AGE levels, with a significant difference between the dietary guidance group and the MAF-treated group. The amyloid-β 40/42 ratio decreased significantly in all three groups after 12 months compared to that at the start of the study. No adverse events occurred as a result of taking MAF supplements or receiving dietary guidance. Declarations Ethics approval and consent to participate The trial was reviewed and approved by the SaiseiMirai Ethics Comiittee (No. 2022-001). As part of the consent process, clinical study participants are informed about the risks and benefits of participating in the study. Written Informed consent for investigational treatment, study data collection, analysis, and publication were obtained from all study participants and their family members. Consent for publication Consent for publication is not applicable. Availability of data and material The datasets generated and /or analyzed during the current study are not publicly available because we have not obtained consent from the subjects to provide data to a third party currently, and we have not obtained approval from the Ethics Review Committee to do so but are available from the corresponding author on reasonable request. Competing interests YU-T and HY have no competing interests. TI is a director of Saisei Immunotherapy Clinic which is same group with Saisei Pharma. Funding The trial was no funding. Author contriutions YU-T conceived the study, collected the data, and wrote the manuscript with contributions from TI. HY performed the final statistical analysis. All the authors contributed to the refinement of the study protocol and approved the final manuscript. 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Isami F, West BJ, Nakajima S, Yamagishi S-I. Association of advanced glycation end products, evaluated by skin autofluorescence, with lifestyle habits in a general Japanese population. J Int Med Res. 2018; 46, 1043–1051. Yamagishi S-I, Matsui T. Pathologic role of dietary advanced glycation end products in cardiometabolic disorders, and therapeutic intervention. Nutrition. 2016; 32, 157–165. van Waateringe RP, Fokkens BT, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, Graaf R, Paterson AD, Smit AJ, Lutgers HL, Wolffenbuttel BHR. Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population. Diabetologia. 2019; 62, 269–280. Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon BA, Holtzman DM, Morris JC, Benzinger TLS, Xiong C, Fagan AM, Bateman RJ. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019; 93, e1647–e1659. Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015; 385, 2255–2263. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009; 302, 627–637. Tables Table 1. Baseline characteristics in the study Group M Group D Group C ASD n (in FAS) 14 13 15 Gender [n, %] 0.224 Male 5, 35.7% 5, 38.5% 7, 46.7% Female 9, 64.3% 8, 61.5% 8, 53.3% Age [years] mean±SD 80.8±10.3 78.5±10.1 77.8±6.8 0.342 Nursing care level [n, %] 0.411 Support Needed 11, 78.6% 10, 76.9% 9, 60.0% Care Needed 3, 21.4% 3, 23.1% 6, 40.0% Support: level 1 3, 21.4% 0, 0.0% 2, 13.3% Support: level 2 8, 57.1% 10, 76.9% 7, 46.7% Care: level 1 0, 0.0% 1, 7.7% 0, 0.0% Care: level 2 1, 7.1% 2, 15.4% 3, 20.0% Care: level 3 2, 14.3% 0, 0.0% 2, 13.3% Care: level 4 0, 0.0% 0, 0.0% 1, 6.7% Diabetes mellitus yes 2, 14.3% 5, 38.5% 6, 42.9% 0.667 Baseline parameter MCIS mean±SD 46.4±16.5 47.2±12.2 44.2±13.9 0.230 AGE mean±SD 2.7±0.6 2.5±0.5 2.7±0.5 0.269 Ab40/42 mean±SD 10.1±2.0 9.7±1.7 10.5±1.7 0.483 dietary AGEs mean±SD 11914±4632 12287±7108 11530±3513 0.135 Calories in diet mean±SD 1564±272 1626±297 1550±272 0.266 Group M (M): the MAT triple group, Group D (D): the diet group, Group C (C): the control group. SD: standard deviation, ASD: Absolute standardized difference, FAS: Full analysis set, MCIS: The mild cognitive impairment screen, AGE: Advanced glycation end products, Aβ40/42: plasma amyloid beta 40/42 ratio. Table 2. End points Analysis using Mixed Models Group M Group D Group C P ** LSM 95%CI P* LSM 95%CI P* LSM 95%CI P* M vs. C D vs. C M vs. D MCIS Baseline 46.65 43.51 to 49.79 46.73 43.47 to 49.99 46.62 43.22 to 50.01 At 6-month 55.79 52.65 to 58.93 46.52 42.98 to 50.06 48.61 45.06 to 52.15 Change at 6-month 9.14 4.70 to 13.58 <0.001 -0.21 -5.03 to 4.60 0.933 1.99 -2.91 to 6.90 0.422 0.035 0.526 0.008 At 12-month 55.71 52.45 to 58.97 54.09 50.37 to 57.81 46.71 42.99 to 50.44 Change at 12-month 9.06 4.53 to 13.59 <0.001 7.36 2.42 to 12.30 0.005 0.10 -4.93 to 5.13 0.969 0.010 0.044 0.624 AGE Baseline 2.70 2.54 to 2.86 2.69 2.51 to 2.86 2.71 2.53 to 2.88 At 6-month 2.62 2.47 to 2.78 2.72 2.55 to 2.90 2.81 2.64 to 2.98 Change at 6-month -0.08 -0.26 to 0.10 0.391 0.03 -0.17 to 0.23 0.740 0.10 -0.10 to 0.31 0.300 0.181 0.616 0.410 At 12-month 2.57 2.42 to 2.73 2.64 2.47 to 2.82 3.08 2.90 to 3.25 Change at 12-month -0.13 -0.31 to 0.05 0.164 -0.05 -0.25 to 0.16 0.656 0.37 0.17 to 0.57 <0.001 <0.001 0.005 0.538 Ab40/42 Baseline 10.12 9.55 to 10.69 9.89 9.29 to 10.49 10.36 9.81 to 10.92 At 6-month 9.50 8.92 to 10.07 9.39 8.68 to 10.09 9.65 9.08 to 10.22 Change at 6-month -0.63 -1.51 to 0.26 0.163 -0.50 -1.50 to 0.49 0.316 -0.71 -1.58 to 0.15 0.106 0.889 0.754 0.856 At 12-month 8.84 8.25 to 9.43 8.50 7.85 to 9.15 8.95 8.38 to 9.53 Change at 12-month -1.28 -2.18 to -0.38 0.006 -1.39 -2.34 to -0.44 0.005 -1.41 -2.28 to -0.54 0.002 0.839 0.975 0.871 dietary AGEs Baseline 12003 10775 to 13232 12043 10717 to 13370 11821 10592 to 13050 At 6-month 10975 9747 to 12203 9665 8062 to 11268 10893 9620 to 12166 Change at 12-month -1029 -3044 to 986 0.307 -2378 -4724 to -32 0.047 -928 -2968 to 1112 0.363 0.944 0.352 0.383 Calories in diet Baseline 1580 1490 to 1670 1600 1503 to 1698 1574 1486 to 1661 At 6-month 1581 1492 to 1672 1669 1548 to 1790 1605 1514 to 1695 Change at 6-month 1 -138 to 142 0.980 69 -97 to 235 0.410 31 -168 to 106 0.651 0.765 0.726 0.538 Group M (M): the MAT triple group, Group D (D): the diet group, Group C (C): the control group. MCIS: The mild cognitive impairment screen, AGE: Advanced glycation end products, Aβ40/42: plasma amyloid beta 40/42 ratio, LSM: least square mean; 95%CI: 95% confidence interval. Analysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates]. P *: Pairwise comparison with baseline values. P **: Pairwise comparison between intervention groups for change from baseline value. Additional Declarations Competing interest reported. Y. U-T and H.Y. have no competing interests. T.I. is a director of Saisei Immunotherapy Clinic which is same group with Saisei Pharma. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4272286","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292226264,"identity":"7c1e71ec-bf0e-483f-a8de-220a4df575ef","order_by":0,"name":"Yoko Uchiyama-Tanaka","email":"data:image/png;base64,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","orcid":"","institution":"Yoko Clinic","correspondingAuthor":true,"prefix":"","firstName":"Yoko","middleName":"","lastName":"Uchiyama-Tanaka","suffix":""},{"id":292226265,"identity":"6a8c31b7-ef72-4ed1-951c-0980f6d50a0b","order_by":1,"name":"Hajime Yamakage","email":"","orcid":"","institution":"Satista Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Hajime","middleName":"","lastName":"Yamakage","suffix":""},{"id":292226266,"identity":"5f2ae656-5afa-4d2d-8425-a99282268582","order_by":2,"name":"Toshio Inui","email":"","orcid":"","institution":"Saisei Immunotherapy Clinic","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Inui","suffix":""}],"badges":[],"createdAt":"2024-04-16 00:59:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4272286/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4272286/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55329589,"identity":"bd7f758f-e549-41f0-b7e7-5df36dd09c6f","added_by":"auto","created_at":"2024-04-25 18:59:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43133,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of this study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group, FAS: Full analysis set, PPS: per protocol set, MI: myocardial infarction.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/507a9a90a85ae37b0612497e.png"},{"id":55330096,"identity":"e015085a-dd0b-4869-8520-8a980fc1d3a4","added_by":"auto","created_at":"2024-04-25 19:07:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46804,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine and bar graphs of intervention effects on the calories in diet.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graphs: Least square (LS) mean and 95% confidence interval (CI) of calories in diet measurements at each measurement point for each group are shown. The results of the comparison test between measurement points for each group are shown.\u003c/p\u003e\n\u003cp\u003eBar graphs: LS means and 95% CIs of calories in diet change from baseline at each measurement point in each group are shown. Results of comparison tests between intervention groups are shown.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group, n.s.: not significant.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/a243a1c56e26fbf51678bac3.png"},{"id":55329588,"identity":"21b53a6e-bb76-4b3f-ae30-45bf722f5f4f","added_by":"auto","created_at":"2024-04-25 18:59:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":47094,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine and bar graphs of intervention effects on the dietary AGEs.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graphs: Least square (LS) mean and 95% confidence interval (CI) of dietary AGEs measurements at each measurement point for each group are shown. The results of the comparison test between measurement points for each group are shown.\u003c/p\u003e\n\u003cp\u003eBar graphs: LS means and 95% CIs of dietary AGEs change from baseline at each measurement point in each group are shown. Results of comparison tests between intervention groups are shown.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group, n.s.: not significant.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/f0346d0004a53e971299896d.png"},{"id":55329592,"identity":"7ed10ac2-3baa-49c9-b70b-f5749168b79d","added_by":"auto","created_at":"2024-04-25 18:59:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44683,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine and bar graphs of intervention effects on the mild cognitive impairment screen (MCIS).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graphs: Least square (LS) mean and 95% confidence interval (CI) of MCIS measurements at each measurement point for each group are shown. The results of the comparison test between measurement points for each group are shown.\u003c/p\u003e\n\u003cp\u003eBar graphs: LS means and 95% CIs of MCIS change from baseline at each measurement point in each group are shown. Results of comparison tests between intervention groups are shown.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/7eed6b3d4a7a7ac96fc80ae6.png"},{"id":55329591,"identity":"643dc5bf-ad87-476f-b972-5e2b63dfce27","added_by":"auto","created_at":"2024-04-25 18:59:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":50051,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine and bar graphs of intervention effects on the advanced glycation end products (AGE).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graphs: Least square (LS) mean and 95% confidence interval (CI) of AGE measurements at each measurement point for each group are shown. The results of the comparison test between measurement points for each group are shown.\u003c/p\u003e\n\u003cp\u003eBar graphs: LS means and 95% CIs of AGE change from baseline at each measurement point in each group are shown. Results of comparison tests between intervention groups are shown.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group, n.s.: not significant.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/23e59462c86b0c9801fdcdc6.png"},{"id":55329593,"identity":"fadc0c4b-5081-491e-8817-9a16430e6e10","added_by":"auto","created_at":"2024-04-25 18:59:57","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":49455,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLine and bar graphs of intervention effects on the plasma amyloid beta 40/42 ratio (Aβ40/42).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLine graphs: Least square (LS) mean and 95% confidence interval (CI) of Aβ40/42 measurements at each measurement point for each group are shown. The results of the comparison test between measurement points for each group are shown.\u003c/p\u003e\n\u003cp\u003eBar graphs: LS means and 95% CIs of Aβ40/42 change from baseline at each measurement point in each group are shown. Results of comparison tests between intervention groups are shown.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003eGroup M: the MAF triple group, Group D: the diet group, Group C: the control group, n.s.: not significant.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/1092277fe4d7898a82878222.png"},{"id":57242735,"identity":"728cc176-08c2-4aa7-9efa-919dc8ce9d5d","added_by":"auto","created_at":"2024-05-28 04:25:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1074249,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4272286/v1/5ea2ad2d-e996-40e4-be88-04bfe5b6ea14.pdf"}],"financialInterests":"Competing interest reported. Y. U-T and H.Y. have no competing interests. T.I. is a director of Saisei Immunotherapy Clinic which is same group with Saisei Pharma.","formattedTitle":"\u003cp\u003eThe effects of dietary intervention and MAF supplementation on cognitive function in elderly users of outpatient rehabilitation\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eMultiple factors have b een identified to be associated with dementia risk, including age, genetic factors, and environmental factors (lifestyle, exercise, toxin exposure, diet, nutrition, social involvement, hearing, and educational history)\u003csup\u003e1-4\u003c/sup\u003e. These factors are believed to trigger protein misfolding, synaptic dysfunction, reactive oxygen species, mitochondrial dysfunction, impaired calcium regulation in the cytoplasm, and decreased cell number, resulting in neurodegeneration\u003csup\u003e1,5,6\u003c/sup\u003e. With the ageing of the population and the increase in the prevalence of diabetes and atherosclerosis, the prevalence of dementia is on the rise. The GBD Dementia Forecasting Collaborators indicate that the prevalence of dementia will reach 150 million by 2050\u003csup\u003e7\u003c/sup\u003e. If mild cognitive impairment is included in this estimation, the number will be even higher. On the other hand, dementia was once thought to be a progressive disease in which cognitive function could not be improved or recovered. There are also emerging reports that improvements in the causes of brain inflammation and amyloid-\u0026beta; accumulation may improve symptoms even after a diagnosis of dementia\u003csup\u003e1,8,9\u003c/sup\u003e. However, once dementia is diagnosed, organic changes in the brain progress, and recovery is difficult. Therefore, prevention of the onset of dementia is highly important. Exercise, a healthy diet, social stimulation, intestinal environment improvement, lifestyle modification, optimal sleep, stress care, hearing assistance, nutritional supplementation and supplements have been reported to be effective in dementia prevention\u003csup\u003e1,8,10\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBrain inflammation has been noted to be involved in cognitive dysfunction. The linkage between neurons and microglia has been noted in brain synapse loss, the removal of waste products such as amyloid-\u0026beta;, the control of infection and inflammation, synapse germination, and neurogenesis and pruning\u003csup\u003e5,6,11-17\u003c/sup\u003e. Microglia were previously thought to be structural factors in the brain but have been shown to have macrophage functions\u003csup\u003e5,14\u003c/sup\u003e. Microglial dysfunction is a problem in degenerative brain diseases\u003csup\u003e5,6,12,13\u003c/sup\u003e. Group-specific component macrophage activation factor (GcMAF) is a protein that results from the sequential deglycosylation of its precursor, vitamin binding protein (VDBP)\u003csup\u003e18,19\u003c/sup\u003e. The Gc protein VDBP is produced in the liver and is present in the majority of biological fluids. VDBP has multifunctional properties as a transporter of serum vitamin D3 and its metabolites, functions as an actin scavenger during cellular injury, acts as a chemotaxin for phagocytic cells, and plays a role in macrophage activation as a precursor for GcMAF. This Gc protein has a triple-domain modular structure, where domain III (the C-terminal end) harbours a single glycosylation site. The terminal N-acetylgalactosamine (GalNAc) moiety in domain III is the region involved in the GcMAF-mediated macrophage activation cascade. During inflammation, lysophosphatidylcholine is released from tissue, which induces the expression of beta-galactosidase in B cells and sialidase in T cells. These enzymes hydrolyse the terminal galactose and sialic acid saccharides of the Gc protein to convert it into GcMAF with an N-acetylgalactosamine moiety\u003csup\u003e18,20\u003c/sup\u003e. One of the cell types targeted is resident intestinal macrophages, which exhibit great phagocytic activity without initiating an inflammatory response due to their low, or even absent, expression of innate response receptors, including receptors for LPS (CD14), Fc\u0026alpha; (CD89), Fc\u0026gamma; (CD64, CD16), and CR3 (CD11b/CD18). Resident intestinal macrophages constitute the largest pool of macrophages in the body. These cells are able to downregulate an excessive systemic inflammatory response by driving the resolution of inflammation and by contributing to the mechanism of oral tolerance to foreign antigens, as well as autoantigens.\u0026nbsp;MAF was discovered to be a macrophage activator but has also been shown to regulate macrophage function, improve allergies, and optimize immune function, for example, providing adjuvant therapy against cancer and many other diseases\u003csup\u003e18\u003c/sup\u003e. In addition, MAF has been reported to be related to life span through, for example, telomere extension (in press). Furthermore, in animal experiments with MAF, recovery from brain damage (embolization model\u003csup\u003e21\u003c/sup\u003e, trauma model\u003csup\u003e22\u003c/sup\u003e) and a reduction in amyloid-\u0026beta; have been observed, and clinically, the effectiveness of MAF has been shown in autism spectrum disorder\u003csup\u003e23\u003c/sup\u003e and multiple sclerosis\u003csup\u003e24\u003c/sup\u003e, where brain inflammation is suggested. However, the effects of MAF on cognitive function have not yet been studied.\u003c/p\u003e\n\u003cp\u003eHealthy food consumption is very important for preventing dementia. Advanced glycation end products (AGEs) are formed by nonenzymatic reactions between sugars and amino groups of macromolecules, such as proteins, lipids, and nucleic acids\u003csup\u003e25\u003c/sup\u003e. Because glycation occurs constantly during normal ageing and the rate of degradation of glycated macromolecule derivatives is very slow, AGEs accumulate with increasing age. Accumulating evidence shows that AGEs play important roles in the development of age-related disorders, including diabetic vascular complications, osteoporosis, and Alzheimer\u0026rsquo;s disease\u003csup\u003e25-28\u003c/sup\u003e. It is estimated that 6-7% of AGEs are taken up by the body from exogenous sources (diet, tobacco, etc.)\u003csup\u003e29\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn this study, we examined the effects of nutritional guidance (reducing the amount of AGEs in the diet as much as possible) and MAF supplementation on cognitive function in a group of elderly individuals attending a day rehabilitation facility (that is, elderly individuals who were able to exercise regularly). This study was double-blind with respect to drug intervention but open with respect to the presence or absence of dietary guidance.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design and participants\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single-centre, randomized controlled, open-label, parallel-arm trial. Participants without a diagnosis of dementia who were older than 60 years of age; had been attending Soushinkai, a daycare rehabilitation facility in Okayama, for at least three months; and were in stable condition were eligible for inclusion. The procedures were in accordance with the guidelines of the Declaration of Helsinki (2000) for human experimentation and informed consent was obtained from all subjects.\u003c/p\u003e\n\u003cp\u003eAt the time of entry, interviews, evaluations, blood tests, and medical examinations were conducted. Patients with cognitive dysfunction, severe anaemia, terminal cancer, or brain degenerative diseases such as Parkinson's disease were excluded. Soushinkai rehabilitation facilities provide not only passive rehabilitation but also voluntary rehabilitation, visitation, and assistance so that rehabilitation can be performed at home. The facility also has a daycare centre and exercise machines.\u003c/p\u003e\n\u003cp\u003ePeople who consented to participate the study were randomly divided into three groups. Group C, a normal rehabilitation-only group as control group; Group D, a dietary guidance group, who received dietary guidance and rehabilitation by the same physician; and Group M, who received one capsule of MAF triple in the morning upon waking and one capsule before sleep and the same dietary guidance as Group D. Groups C and D received placebo in the same manner, with one capsule upon waking and one capsule before sleep.\u0026nbsp;MAF triple capsules are dietary supplements produced by Saisei Pharma, Japan, that are designed to modulate the mucosal immunity of the intestine.\u003c/p\u003e\n\u003cp\u003eBefore assessing the Mild Cognitive Impairment Screening (MCIS) score, AGE levels were measured with an AGE reader. The plasma amyloid-β 40/42 ratio, general blood parameters (peripheral blood, GOT, GPT, gamma GPT, ALP, HbA1C, BUN, Cr, uric acid, total cholesterol, HDL cholesterol, triglycerides, ferritin, 25OH vitamin D, CRP, free T4, TSH, albumin, zinc, copper, sodium, potassium, chloride, folic acid, vitamin B12, vitamin B1), and dietary AGE intake were measured. The same procedure was used after 6 and 12 months. The study was approved by SaiseiMirai Ethics Comiittee (No.\u0026nbsp;2022-001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRandomization\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter screening, the data of each participant were linked to the participant identification code provided and anonymized. Next, the participants were randomized to Groups M, D and C at a ratio of 1:1:1. Randomized allocation was performed via the simple randomization method. The allocation table was generated and maintained by a third party at the facility not involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDietary guidance\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDietary guidance was provided to reduce the amount of AGEs in the diet as much as possible. It is generally known that AGEs are produced in large amounts when meat products and fat-rich foods are fried or baked at high temperatures. On the other hand, cooking methods such as slow steaming or boiling of foods with a high water content are less likely to produce AGEs, which have long been known to be produced in Maillard reactions or browning reactions. The browning of foods is a rough indication of their AGE content. Fructose is approximately 10 times more likely to form AGEs than glucose. It is thought that avoiding drinking carbonated beverages that contain a large amount of fructose corn syrup, avoiding excessive consumption of fructose, and avoiding consuming foods with significant browning can reduce the amount of exogenous AGE intake\u003csup\u003e30\u003c/sup\u003e.\u0026nbsp;Lemon and vinegar can also reduce the formation of AGEs during the cooking process. A well-balanced diet rich in vegetables, seaweed, and mushrooms is also recommended\u003csup\u003e31\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFirst, all groups were asked to describe their meals for one week, or if they were unable to do so, they were asked to do so with the help of their family members, who were interviewed in more detail by a nutritionist. Calorie calculations were then performed. AGE calculations were performed with the exAGE formula\u0026nbsp;devised\u0026nbsp;by the AGE Research Association. These calculations were performed before the study and at 6 months. For Group D and Group M, at the start of the study, materials were first distributed to the group, and dietary guidance was given by the same physician in the form of a lecture. The same doctor showed them pictures and instructed them to eat less processed meat (sausage, bacon, etc.), packaged foods, deep fried foods, sugary sweets, and snacks, and more steamed foods, fresh vegetables, and fruits. Afterwards, during the individual interviews, we provided advice on what to maintain and what to add to the diet of each person based on the dietary chart. Individual interviews were held at the start of the study, at 6 months, and at 12 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCalculation of AGEs in the diet\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CML (carboxymethyllysine; a type of AGE) coefficient is determined by dividing foodstuffs into 18 categories, including grains, meats, fats, oils, and vegetables, and multiplying the coefficient of cooking (1 for raw foodstuffs and 1 for boiled or baked foodstuffs) by the coefficient of each category. The following original formula is used to estimate the CML (AGE) content of food products.\u003c/p\u003e\n\u003cp\u003eCML content (in kilograms) = total protein and fat content (g) per 100 g of food material × processing factor × cooking factor × CML factor. This formula was derived by determining the protein and fat contents of ingredients from the Japanese Food Composition Table.\u0026nbsp;There was a strong positive correlation (p\u0026lt;0.0001) between the measured CML content in foods reported by Uribarri et al. and the estimates obtained in the four factors described above, with a correlation coefficient of 0.52. The average CML intake for the American population is reported to be approximately 15,000 KU\u003csup\u003e30\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCognitive function assessment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MCIS was used because it is applicable for those with dementia or mild dementia.\u0026nbsp;The MCIS,\u0026nbsp;derived from the Word List Memory test, differentiates cognitive changes associated with normal ageing from mild cognitive impairment as well as dementia\u003csup\u003e32\u003c/sup\u003e. The MCIS is a brief, electronically scored, verbally administered test that uses correspondence analysis\u0026nbsp;to calculate\u0026nbsp;an individual’s memory capabilities, which is then reported as the Memory Performance Index\u003csup\u003e33-35\u003c/sup\u003e. The MCIS has been validated in both academic and community clinical settings and in multiple languages\u003csup\u003e36,37\u003c/sup\u003e.\u0026nbsp;Testing was performed at before the start of the study and at 6 and 12 months. Since large social fluctuations in participants have a direct impact on the score, this index is best for use in studies of populations without large social fluctuations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAGE measurement\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGlycation levels were measured on the dominant volar forearm using an AGE Reader mu (Diagnoptics Technologies B. V., Groningen, Netherlands)\u003csup\u003e38,\u0026nbsp;39\u003c/sup\u003e. Pentosidine and crossline have structural properties that cause them to emit fluorescent light across a specific range of wavelengths upon excitation by ultraviolet light. This unique characteristic has been used to develop technology that quantifies the accumulated AGEs within human skin. Although several confounding factors exist, such as other fluorophores, skincare cream use, and skin pigmentation, skin autofluorescence (SAF) is a prominent biomarker that may reflect tissue accumulation of AGEs\u003csup\u003e29,40,41\u003c/sup\u003e. Certain types of AGEs autofluoresce when exposed to ultraviolet light. The AGE Reader illuminates skin with ultraviolet light (excitation range= 300-420 nm) and then detects the resulting fluorescent light (emission range = 420-600 nm) while simultaneously detecting light reflected from the skin in the 300- to 420-nm range. SAF, reported in arbitrary units, is defined as the ratio of the intensity of the emitted fluorescent light to that of the reflected light\u003csup\u003e42-44\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlasma ratio of amyloid-\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eβ40 to amyloid-β42\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecent technological advancements in mass spectrometry have led to improvements in instrument sensitivity and precision,\u0026nbsp;resulting in the development of improved plasma Aβ assays. Many studies\u0026nbsp;have reported encouraging results for plasma Aβ as a biomarker for\u0026nbsp;Alzheimer’s\u0026nbsp;disease.\u0026nbsp;Tests for the risk of developing dementia were conducted at the starting, 6-month, and 12-month time points\u003csup\u003e45\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSample size\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was designed to detect a large effect size (effect size = 0.8) between groups for the change in endpoint over the 12-month study period. Based on that assumption and for a power of 80% and a 5% significance level, the sample size was calculated to be 13 participants per group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical methods\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data were analysed based on the intention-to-treat principle. The primary analysis was performed on the full analysis set (FAS), while the MCIS score, which is heavily influenced by social variables, was evaluated in the pre-protocol set (PPS). The absolute standard difference (ASD) was used to assess the balance of patient backgrounds by random assignment, and the ASD was considered in balance if the 95% confidence interval in this population was less than 0.755 as a threshold value that did not cross zero.\u003c/p\u003e\n\u003cp\u003eThe repeated-measures endpoints were analysed with linear mixed models that included intervention, dummy variables for time, intervention-by-time interactions and baseline parameters of endpoints as covariates and participants as a random effect. The covariance structure was a completely general covariance matrix. The results are reported as the least squares means with 95% confidence intervals (CIs) at each time point. A \u003cem\u003eP\u003c/em\u003e value \u0026lt; 0.05 was considered to indicate statistical significance, and all \u003cem\u003eP\u003c/em\u003e values were two-sided with multiplicity adjustment by the Bonferroni method. All the statistical analyses were performed using SPSS version 24.0 (IBM Japan, Ltd.).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween May 2022 and July 2022, a total of 43 people (mean age 79.0 \u0026plusmn; 8.8 years, 17 males and 26 females, care level of support to care level 3) who consented to participate in the study were randomly divided into three groups. Of those, 15 were allocated to Group C, 14 were allocated to Group D, and 14 were allocated to Group M (Fig. 1). In Group D, it was revealed that one participant had taken donepezil hydrochloride after randomization, and this participant was subsequently excluded from FAS. In Group C, one participant had a myocardial infarction and discontinued use of the facility, and in Group D, two participants voluntarily withdrew from the study. In Group C, three participants experienced major social changes during the study period. Thus, the resultant PPS included 12 participants in Group C, 13 participants in Group D and 14 participants in Group M.\u003c/p\u003e\n\u003cp\u003eThe clinical characteristics of the participants are shown in Table 1. The ASD was less than 0.755 (the threshold for which the 95% CI for the ASD did not cross 0 in this study), indicating that the baseline characteristics (age, sex, level of care, presence of diabetes, cognitive function according to MCIS score, AGE, amyloid-\u0026beta; 40/42 ratio, AGE levels and calories) of the three groups were similar.\u003c/p\u003e\n\u003cp\u003eThe results of the analysis of outcomes for the FAS are shown in Table 2. Dietary caloric intake did not change before or after the intervention in any group, and there were no significant group differences in dietary calorie intake during the intervention (Fig. 2). The amount of change in dietary AGEs was unchanged in Group C but decreased significantly in Group D (-2378 [95% CI: -4724 to -32] KU). The amount of change in dietary AGEs was unchanged in Group M despite dietary guidance, and there were no significant group differences in intervention effects (Fig. 3).\u003c/p\u003e\n\u003cp\u003eOnly Group M had significantly improved MCIS scores after 6 months compared to before the study (from 46.65 [43.51 to 49.79] to 55.79 [52.65 to 58.93], change of +9.14 [4.70 to 13.58]) in the PPS. The MCIS score of Group M also improved significantly compared to that of both Group C and Group D (\u003cem\u003eP\u003c/em\u003e = 0.035 and 0.008, respectively). Even after 12 months, Group M maintained cognitive function (55.71 [52.45 to 58.97], change of +9.06 [4.53 to 13.59]). Compared with before the study, Group D exhibited significant improvements in the MCIS score at 12 months (from 46.73 [43.47 to 49.99] to 54.09 [50.37 to 57.81], change of +7.36 [2.42 to 12.3]). Compared with those in Group C, the MCIS score in Group M and Group D improved significantly at 12 months (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.010 and 0.0044, respectively) (Fig. 4).\u003c/p\u003e\n\u003cp\u003eThe AGE level measured by an AGE reader did not change significantly in Groups M or D at 6 months or at 12 months in the FAS. Only the AGE level of Group C significantly increased at 12 months (from 2.71 [2.53 to 2.88] to 3.08 [2.90 to 3.25], a change of +0.37 [0.17 to 0.57]). The AGE level in Group C at 12 months increased significantly compared to those in Group M and Group D (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001 and 0.005, respectively) (Fig. 5).\u003c/p\u003e\n\u003cp\u003eThe serum amyloid-\u0026beta; 40/42 ratio showed no significant difference at 6 months, but at 12 months, that of all groups had decreased significantly compared to before the study (Group C, change of - 1.41 [-2.28 to -0.54]; Group D, change of - 1.39 [-2.34 to -0.44]; Group M, change of - 1.28 [-2.18 to -0.38]). There were no significant differences in serum amyloid beta levels between the intervention groups (Fig. 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, the administration of MAF supplements improved cognitive function. Microglia play complex roles that are both beneficial and detrimental to disease pathogenesis, including engulfing or degrading toxic entities such as amyloid plaques and promoting neurotoxicity through excessive inflammatory cytokine release\u003csup\u003e5,11\u003c/sup\u003e. Aberrations in the normal homeostatic functions of microglia, such as surveillance, synaptic pruning, and plasticity, may also contribute to excessive synapse loss and cognitive dysfunction in patients with Alzheimer\u0026rsquo;s disease and other diseases\u003csup\u003e6,17\u003c/sup\u003e. Failure to clear apoptotic cells, cellular debris, and toxic proteins, such as amyloid-\u0026beta;, can contribute to inflammation and neurodegeneration\u003csup\u003e15-17\u003c/sup\u003e. Synapse loss is an early hallmark of Alzheimer\u0026rsquo;s disease and other neurodegenerative disorders and is considered a strong correlate of cognitive decline. Numerous studies have demonstrated that microglia have many physiological, noninflammatory functions that are crucial for the central nervous system and for regulating neuroplasticity, such as driving neural programmed cell death and synaptic plasticity in adults. Microglia have highly dynamic processes and continually survey their local environment. It is estimated that resident microglia scan the entire volume of the brain as one of their homeostatic functions\u003csup\u003e16,17\u003c/sup\u003e. Other possible functions of resident microglia include trauma site reduction in posttrauma model mice observed in animal experiments, amyloid-\u0026beta; plaque and phospho-tau tangle reduction, the repair of infarction in models, macrophage activation, and VEGF-increasing effects\u003csup\u003e21\u003c/sup\u003e. Macrophages work in both inflammatory and anti-inflammatory directions, but according to the research of Uto et al.,\u003csup\u003e21\u003c/sup\u003e the activation of anti-inflammatory macrophages increases when inflammation is high, suggesting that macrophage function is not regulated in one direction but rather changes according to the situation. Siniscalco et al.\u003csup\u003e23\u003c/sup\u003e also reported that GcMAF affects the endocannabinoid system, which controls cell-to-cell communication in, for example, greed, pain, immune regulation, emotional regulation, motor function, development and ageing, neuroprotection, cognitive function and memory.\u003c/p\u003e\n\u003cp\u003eIt is recognized that a high degree of glycation is associated with cognitive function\u003csup\u003e27,28\u003c/sup\u003e. The glycation level is related to exercise, smoking status, and age. AGEs essentially increase with age. Therefore, the fact that only the control group showed a worsening of AGE levels may be attributed to the effects of MAF and dietary guidance. However, only Group D showed a decrease in dietary AGEs, while Group M did not. This finding may due to the fact that the meals of many participants in Group M were cooked by day service users or family members, and many participants did not cook for themselves. Unintentionally, this study was conducted with Group C participants receiving an exercise-only intervention, Group D receiving an exercise and dietary modification intervention, and Group M receiving an exercise and MAF intervention. An improvement in cognitive function in the dietary guidance group was not observed until 12 months, and although there was no difference between Group M and Group C in terms of AGE levels, we believe that reducing AGEs in the diet may be helpful in improving cognitive function in the long term.\u003c/p\u003e\n\u003cp\u003eThe amyloid-\u0026beta;40/42 ratio improved in all three groups after 12 months. All three groups underwent rehabilitation, including an exercise program, so there were no significant differences\u0026nbsp;in the\u0026nbsp;amyloid-\u0026beta;40/42 ratio among the three groups after 12 months, but all three groups showed a decreasing trend in the amyloid-\u0026beta;40/42 ratio compared to the prestudy period. Physical exercise in combination with other interventions, including vascular risk management, diet, and cognitive training, has been found to be associated with improved cognitive performance\u003csup\u003e2,46,47\u003c/sup\u003e. Among the largest improvements were those seen in cognitive functions, overall health, and mood status.\u003c/p\u003e\n\u003cp\u003eLimitations: It is important to note that we originally planned to continue providing dietary guidance after 12 months; however, cooperation on this guidance was difficult for participants and their family members, and following the guidance involved too much work and time. Since dietary guidance was provided throughout the 12-month period, the AGE levels after 12 months were unknown. The fact that the participants were in a daycare rehabilitation facility and therefore did not follow a uniform diet was also a factor in the ambiguous results. In addition, the advanced age of the participants made it difficult for them to continue the study. In this study, we did not determine genotypes such as the APOE type. The number of participants was originally small, but it decreased further due to withdrawal from the study due to infections and a worsening of underlying diseases. In the future, we hope to conduct a large-scale study with determinations of APOE type at residential facilities where meals can be provided under dietary controlled conditions.\u003c/p\u003e\n\u003cp\u003eAccording to the individual results of this study, there were also cases of significant improvement in the MCIS score in the control group. One thing all participants had in common was that they felt motivated to come to this rehabilitation facility and looked forward to communicating with friends and staff at the facility. We once again recognized that social involvement is very important for cognitive function.\u003c/p\u003e\n\u003cp\u003eThis study showed that cognitive dysfunction is multifactorial but that earlier intervention can prevent its worsening or even improve cognitive function sooner. The importance of macrophages, the effectiveness yet challenges of dietary guidance, and the importance of social involvement were recognized.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAdministration of MAF supplements not only prevented but also improved cognitive decline after 6 months, and the effect was maintained after 12 months. However, Group D, in which participants received dietary guidance, showed improvements in cognitive function after 12 months. The significant differences between Groups M and D disappeared after 12 months. However, compared to the control group, the dietary guidance and MAF-treated groups showed significant differences in cognitive function. Glycation levels tended to decrease in the MAF-treated group, but no significant pre- or posttreatment differences were observed. The control group showed a worsening (i.e., increase in) of AGE levels, with a significant difference between the dietary guidance group and the MAF-treated group. The amyloid-\u0026beta; 40/42 ratio decreased significantly in all three groups after 12 months compared to that at the start of the study. No adverse events occurred as a result of taking MAF supplements or receiving dietary guidance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was reviewed and approved by the\u0026nbsp;SaiseiMirai Ethics Comiittee (No.\u0026nbsp;2022-001). As part of the consent process, clinical study participants are informed about the risks and benefits of participating in the study. Written Informed consent for investigational treatment, study data collection, analysis, and publication were obtained from all study participants and their family members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication is not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and /or analyzed during the current study are not publicly available because we have not obtained consent from the subjects to provide data to a third party currently, and we have not obtained approval from the Ethics Review Committee to do so but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYU-T and HY have no competing interests. TI is a director of Saisei Immunotherapy Clinic which is same group with Saisei Pharma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contriutions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYU-T conceived the study, collected the data, and wrote the manuscript with contributions from TI. HY performed the final statistical analysis. All the authors contributed to the refinement of the study protocol and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Masahiko Futagami, the president of Soushinkai, and the staff who helped collect blood and data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRao RV, Subramaniam VKG, Gregory J, Bredesen A, Coward C, Okada S, Kelly L, Bredesen DE. Rationale for a multi-factorial approach for the reversal of cognitive decline in Alzheimer\u0026apos;s disease and MCI: a review. Int J Mol Sci. 2023; 24(2):1659.\u003c/li\u003e\n\u003cli\u003eTroups K, Hathaway A, Gordon D, Chung H, Raji C, Boyd A, Hill BD, Hausman-Cohen S, Attarha M, Chwa WJ.et al. Precision medicine approach to Alzheimer\u0026apos;s disease: successful pilot project. J Alzheimer\u0026apos;s Dis. 2022;88:1411-1421.\u003c/li\u003e\n\u003cli\u003eSingh A, Ansari VA, Mahmood T, Ahsan F, Rufaida W, Shariq M, Parveen S, Maheshwari S. Receptor for advanced glycation end products: dementia and cognitive impairment. Drug Res (Stuttg). 2023; 73(5): 247-250.\u003c/li\u003e\n\u003cli\u003eTakeuchi M,Yamagishi, S. Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimers disease. Curr Pharm Des. 2008; 14: 973-978.\u003c/li\u003e\n\u003cli\u003eSalter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017; 23, 1018\u0026ndash;1027.\u003c/li\u003e\n\u003cli\u003eSalter M W, Beggs S. Sublime microglia: expanding roles for the guardians of the CNS. Cell. 2014; 158, 15\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eGBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022; 2, e105\u0026ndash;e125.\u003c/li\u003e\n\u003cli\u003eBredesen DE, Amos EC,\u003csup\u003e \u003c/sup\u003e Canick J,\u003csup\u003e \u003c/sup\u003e Ackerley M,\u003csup\u003e \u003c/sup\u003e Raji C, Fiala M\u003csup\u003e \u003c/sup\u003e, Ahdidan J. Reversal of cognitive decline in Alzheimer\u0026apos;s disease. Aging. 2016; 8, 1250\u0026ndash;1258.\u003c/li\u003e\n\u003cli\u003eTobin MK, Musaraca K, Disouky A, Bennett DA, Arfanakis K, Lazarov O. Human hippocampal neurogenesis persists in aged adults and Alzheimer\u0026apos;s disease patients. Cell Stem Cell. 2019; 24, 974\u0026ndash;982.e3.\u003c/li\u003e\n\u003cli\u003eLivingston G, Hutley J, Sommerlad A, Ames D, Ballard C, Banerjee S. Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimaki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL Samus Q, Schneider LS, Selbek G, Teri L, Mukadam N. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020; 396, 413\u0026ndash;446.\u003c/li\u003e\n\u003cli\u003eMcNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J, Miron VE. Microglia regulate central nervous system myelin growth and integrity. 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Nat Rev Neurosci. 2015; 15, 209\u0026ndash;216.\u003c/li\u003e\n\u003cli\u003eSierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010; 7, 483\u0026ndash;495.\u003c/li\u003e\n\u003cli\u003eNagasawa H, Uto Y, Sasaki H, Okamura N, Murakami A, Kubo S, Kirk KL, Hori H. Gc protein (vitamin D-binding protein): Gc genotyping and GcMAF precursor activity. Anticancer Res. 2005; 25, 3689\u0026ndash;3695.\u003c/li\u003e\n\u003cli\u003eThyer L\u003csup\u003e \u003c/sup\u003e, Ward E, Smith R, Fiore MG, Magherini S, Branca JJV, Morucci G, Gulisano M, Ruggiero M, Pacini S. A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages. 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J Chem Neuroanat. 2023; 130, 102258 .\u003c/li\u003e\n\u003cli\u003eSiniscalco D, Bradstreet JJ, Cirillo A, Antonucci N. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J Neuroinflammation. 2014; 11, 78.\u003c/li\u003e\n\u003cli\u003eInui T, Katuura G, Kubo K, Kuchiike D, Chenery L, Uto Y, Nishikata T, Mette M. Case report: GcMAF treatment in a patient with multiple sclerosis. Anticancer Res. 2016;36, 3771\u0026ndash;3774.\u003c/li\u003e\n\u003cli\u003eMonnier VM. Nonenzymatic glycosylation, the Maillard reaction and the aging process. J Gerontol. 1990; 45, B105\u0026ndash;B111.\u003c/li\u003e\n\u003cli\u003eYamagishi S-i, Fukami K, Matsui T. Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: a novel marker of vascular complications in high-risk patients for cardiovascular disease. Int J Cardiol. 2015;185, 263\u0026ndash;268.\u003c/li\u003e\n\u003cli\u003eYamagishi S-i. Role of advanced glycation end products (AGEs) in osteoporosis in diabetes. Curr. Drug Targets. 2011; 12, 2096\u0026ndash;2102.\u003c/li\u003e\n\u003cli\u003eYamagishi S-I. Potential clinical utility of advanced glycation end product cross-link breakers in age- and diabetes-associated disorders. Rejuvenation Res. 2012;15, 564\u0026ndash;572.\u003c/li\u003e\n\u003cli\u003eYamagishi S-i, Ueda S, Okuda S. Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. Curr Pharm Des. 2007;13, 2832\u0026ndash;2836. \u003c/li\u003e\n\u003cli\u003eUribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc.2010; 110, 911\u0026ndash;916.e12.\u003c/li\u003e\n\u003cli\u003eWest BJ, Uwaya A, Isami F, Deng S, Nakajima S, Jensen CJ. Antiglycation activity of iridoids and their food sources. Int J Food Sci. 2014, 276950.\u003c/li\u003e\n\u003cli\u003eShankle WR, Mangrola T, Chan T, Hara J. Development and validation of the memory performance index: reducing measurement error in recall tests. Alzheimer\u0026apos;s Dement. 2009;5, 295\u0026ndash;306.\u003c/li\u003e\n\u003cli\u003eRafii MS, Taylor C, Coutinho A, Kim,K, Galasko D. Comparison of the memory performance index with standard neuropsychological measures of cognition. Am J Alzheimer\u0026apos;s Dis Other Dement. 2011; 26, 235\u0026ndash;239.\u003c/li\u003e\n\u003cli\u003eSnyder PJ, Jackson CE, Petersen RC, Khachaturian AR, Kaye J, Albeeert MS, Weintraub S. Assessment of cognition in mild cognitive impairment: a comparative study. Alzheimer\u0026apos;s Dement. 2011;7, 338\u0026ndash;355.\u003c/li\u003e\n\u003cli\u003eShankle WR, Romney AK, Hara J, Fortier D, Dick MB, Chen JM, Chan T, Sun X. Methods to improve the detection of mild cognitive impairment. Proc Natl Acad Sci U S A. 2005;102, 4919\u0026ndash;4924.\u003c/li\u003e\n\u003cli\u003eTrenkle DL, Shankle WR, Azen SP. Detecting cognitive impairment in primary care: performance assessment of three screening instruments. J Alzheimer\u0026apos;s Dis. 2007; 11, 323\u0026ndash;335.\u003c/li\u003e\n\u003cli\u003eCho A, Sugimura M, Nakano S, Yamada T. The Japanese MCI screen for early detection of Alzheimer\u0026apos;s disease and related disorders. Am J Alzheimer\u0026apos;s Dis Other Dement. 2008;23, 162\u0026ndash;166.\u003c/li\u003e\n\u003cli\u003eMeerwaldt R, Graaf R, Oomen PHN, Links TP, Japer JJ, Alderson NL, Thorpe SR, Baynes JW, Gans ROB, Smit AJ. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004; 47, 1324\u0026ndash;1330.\u003c/li\u003e\n\u003cli\u003eBos DC, de Ranitz-GrevenWL, de Valk HW. Advanced glycation end products, measured as skin autofluorescence and diabetes complications: a systematic review. Diabetes Technol Ther. 2011; 13, 773\u0026ndash;779.\u003c/li\u003e\n\u003cli\u003eCorstjens H, Dicanio D, Muizzuddin N, Neven A, Sparacio R, Declercq L. Maes D. Glycation associated skin autofluorescence and skin elasticity are related to chronological age and body mass index of healthy subjects. Exp Gerontol. 2008; 43, 663\u0026ndash;667.\u003c/li\u003e\n\u003cli\u003eObayashi H, Nakano K, Shigeta H, Yamaguchi M, Yoshimori K, Fukui M, Fujii M, Kitagawa Y, Nakamura N, Nakamura K, Ienaga K, Ohta M, Nishimura M, Fukui I, Kondo M. Formation of crossline as a fluorescent advanced glycation end product in vitro and in vivo. Biochem Biophys Res Commun. 1996; 226, 37\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eIsami F, West BJ, Nakajima S, Yamagishi S-I. Association of advanced glycation end products, evaluated by skin autofluorescence, with lifestyle habits in a general Japanese population. J Int Med Res. 2018; 46, 1043\u0026ndash;1051.\u003c/li\u003e\n\u003cli\u003eYamagishi S-I, Matsui T. Pathologic role of dietary advanced glycation end products in cardiometabolic disorders, and therapeutic intervention. Nutrition. 2016; 32, 157\u0026ndash;165.\u003c/li\u003e\n\u003cli\u003evan Waateringe RP, Fokkens BT, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, Graaf R, Paterson AD, Smit AJ, Lutgers HL, Wolffenbuttel BHR. Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population. Diabetologia. 2019; 62, 269\u0026ndash;280.\u003c/li\u003e\n\u003cli\u003eSchindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon BA, Holtzman DM, Morris JC, Benzinger TLS, Xiong C, Fagan AM, Bateman RJ. High-precision plasma \u0026beta;-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019; 93, e1647\u0026ndash;e1659.\u003c/li\u003e\n\u003cli\u003eNgandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015; 385, 2255\u0026ndash;2263.\u003c/li\u003e\n\u003cli\u003eScarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009; 302, 627\u0026ndash;637.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Baseline characteristics in the study\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003eGroup M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003eGroup D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003eASD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003en (in FAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003eGender [n, %]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.224\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e5, 35.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e5, 38.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e7, 46.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e9, 64.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e8, 61.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e8, 53.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003eAge [years]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e80.8\u0026plusmn;10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e78.5\u0026plusmn;10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e77.8\u0026plusmn;6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.342\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003eNursing care level [n, %]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.411\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eSupport Needed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e11, 78.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e10, 76.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e9, 60.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eCare Needed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e3, 21.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e3, 23.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e6, 40.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eSupport: level 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e3, 21.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2, 13.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eSupport: level 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e8, 57.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e10, 76.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e7, 46.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eCare: level 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1, 7.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eCare: level 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1, 7.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2, 15.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e3, 20.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eCare: level 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2, 14.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2, 13.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eCare: level 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e0, 0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1, 6.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2, 14.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e5, 38.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e6, 42.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003eBaseline parameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; MCIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e46.4\u0026plusmn;16.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e47.2\u0026plusmn;12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e44.2\u0026plusmn;13.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.230\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; AGE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2.7\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2.5\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e2.7\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Ab40/42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e10.1\u0026plusmn;2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e9.7\u0026plusmn;1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e10.5\u0026plusmn;1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003edietary AGEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e11914\u0026plusmn;4632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e12287\u0026plusmn;7108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e11530\u0026plusmn;3513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.19869706840391%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Calories in diet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.241042345276874%\" valign=\"top\"\u003e\n \u003cp\u003emean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1564\u0026plusmn;272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1626\u0026plusmn;297\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.146579804560261%\" valign=\"top\"\u003e\n \u003cp\u003e1550\u0026plusmn;272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.120521172638437%\" valign=\"top\"\u003e\n \u003cp\u003e0.266\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGroup M (M):\u0026nbsp;the MAT triple group, Group D (D): the diet group, Group C (C):\u0026nbsp;the control group.\u003c/p\u003e\n\u003cp\u003eSD: standard deviation, ASD: Absolute standardized difference, FAS: Full analysis set, MCIS: The mild cognitive impairment screen, AGE: Advanced glycation end products, A\u0026beta;40/42: plasma amyloid beta 40/42 ratio.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. End points Analysis using Mixed Models\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"936\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.17094017094017%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eGroup M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eGroup D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eGroup C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003e**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003eLSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003eLSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003eLSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eP*\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003eM vs. C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003eD vs. C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003eM vs. D\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003eMCIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e46.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e43.51 to 49.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e46.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e43.47 to 49.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e46.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e43.22 to 50.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e55.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e52.65 to 58.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e46.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e42.98 to 50.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e48.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e45.06 to 52.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e4.70 to 13.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-5.03 to 4.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.933\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-2.91 to 6.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.526\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e55.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e52.45 to 58.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e54.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e50.37 to 57.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e46.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e42.99 to 50.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e4.53 to 13.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e7.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.42 to 12.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-4.93 to 5.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.969\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003eAGE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.54 to 2.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.51 to 2.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.53 to 2.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.47 to 2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.55 to 2.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.64 to 2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-0.26 to 0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.391\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-0.17 to 0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-0.10 to 0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.616\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.410\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.42 to 2.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e2.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.47 to 2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e3.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e2.90 to 3.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-0.31 to 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-0.25 to 0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.656\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e0.17 to 0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003eAb40/42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e10.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9.55 to 10.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9.29 to 10.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e10.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9.81 to 10.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e8.92 to 10.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e8.68 to 10.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9.08 to 10.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-1.51 to 0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-1.50 to 0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-1.58 to 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.754\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e8.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e8.25 to 9.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e8.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e7.85 to 9.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e8.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e8.38 to 9.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-2.18 to -0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-1.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-2.34 to -0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e-1.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-2.28 to -0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.839\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.975\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e0.871\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003edietary AGEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e12003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e10775 to 13232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e12043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e10717 to 13370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e11821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e10592 to 13050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e10975\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9747 to 12203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e9665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e8062 to 11268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e10893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e9620 to 12166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 12-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e-1029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e-3044 to 986\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e-2378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e-4724 to -32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e-928\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e-2968 to 1112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.944\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.383\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003eCalories in diet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1490 to 1670\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1503 to 1698\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1574\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1486 to 1661\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;At 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1492 to 1672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1669\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1548 to 1790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1605\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e1514 to 1695\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.154749199573105%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Change at 6-month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-138 to 142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-97 to 235\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.016008537886873%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.099252934898612%\"\u003e\n \u003cp\u003e-168 to 106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.651\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.726\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08324439701174%\" valign=\"top\"\u003e\n \u003cp\u003e0.538\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGroup M (M):\u0026nbsp;the MAT triple group, Group D (D): the diet group, Group C (C):\u0026nbsp;the control group.\u003c/p\u003e\n\u003cp\u003eMCIS: The mild cognitive impairment screen, AGE: Advanced glycation end products, A\u0026beta;40/42: plasma amyloid beta 40/42 ratio, LSM: least square mean; 95%CI: 95% confidence interval.\u003c/p\u003e\n\u003cp\u003eAnalysis method: Repeated measures linear mixed model with subjects as a variable [model including initial dependent values as covariates].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e*: Pairwise comparison with baseline values.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e**: Pairwise comparison between intervention groups for change from baseline value.\u003cstrong\u003e\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dementia, Cognitive function, Macrophage, AGEs, Amyloid beta","lastPublishedDoi":"10.21203/rs.3.rs-4272286/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4272286/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackgroud: Age, genetic and environmental factors are noted to contribute to dementia risk. Neuroplasticity, protection from degeneration and cell death, and early intervention are desirable for preventing dementia. The linkage between neurons and microglia has been a research focus. In this study, we examined the effects of dietary modification (a reduction in advanced glycation end products [AGEs]) and macrophage activating factor (MAF; a macrophage regulator) supplementation on cognitive function in elderly participants undergoing rehabilitation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: Forty-three rehabilitation facility users aged over 60 years were randomly divided into three groups: a control group receiving placebo, a group receiving dietary guidance, and a group receiving dietary guidance and MAF supplementation. The amyloid-β40/42 ratio, dietary AGE intake, plasma AGE levels, dietary calorie intake and MCI screen as cognitive functions of participants were evaluated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Four participants withdrew from the study. MCI screen scores significantly improved in MAF supplementation group especially after 6 months. Dietary modulation was also effective for improving cognitive function after 12 months compared to placebo. Only control group significantly increased plasma AGE and worsened, dietary modulation and MAF supplementation group showed no change after 12 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: MAF supplementation is effect for improvement of cognitive function especially after 6 months in elderly people with rehabilitation. Dietary modulation was also effective for cognitive function after 12 months compared to control group. Dietary guidance in day-care center rehabilitation was difficult due to conflicts with family members and the use of facilities. However, enthusiastic users showed improvement in cognitive function. In addition to exercise and dietary improvement, social involvement was found to be important again.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eUMIN 000050155, 2023/02/14\u003c/p\u003e","manuscriptTitle":"The effects of dietary intervention and MAF supplementation on cognitive function in elderly users of outpatient rehabilitation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-25 18:59:52","doi":"10.21203/rs.3.rs-4272286/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1a1ccaf-fe1d-4e41-9a2f-a183f88d5027","owner":[],"postedDate":"April 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-28T04:17:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-25 18:59:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4272286","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4272286","identity":"rs-4272286","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}