Background: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. Objective: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). Methods: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. Results: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. Conclusion: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

{{Introduction: Advanced glycation end products (AGEs) in diet and serum are positively correlated with chronic conditions such as type 2 diabetes and cognitive decline. Dietary reduction of AGEs was shown to reduce their level in serum and to have a beneficial effect on metabolic biomarkers. However, in part due to limitations of feasibility, clinical trials have not tested its effect on cognition in elderly. The current pilot study examines the feasibility of AGE reduction in elderly with diabetes in terms of recruitment and retention. Methods: The design is a randomized controlled pilot trial of dietary AGEs in elderly with type 2 diabetes (clinicaltrials.gov NCT02739971). Recruitment followed two stages: we first recruited participants with mild cognitive impairment (MCI), and after expanding inclusion criteria, we later recruited cognitively normal participants with subjective memory complaints (SMCs). Participants were randomized to two arms. Participants in the control arm received standard of care (SOC) guidelines for good glycemic control; those in the experimental arm, in addition to SOC guidelines, were instructed to lower their dietary AGE intake, primarily by changing their cooking methods. Participants were closely followed for dietary adherence over 6 months and evaluated before and after the intervention for adherence to the assigned diet, blood tests, cognitive performance, and brain MRI. Results: Seventy-five participants (52 with MCI and 23 cognitively normal with SMCs) were recruited primarily through mass mailing and advertising in social media websites. Seventy participants finished the study, and dropout was similar in both groups (7.5% in control vs. 5.7% in intervention

The Presenilin1 (PSEN1) gene encodes the catalytic peptide of the gamma-secretase complex, a key enzyme that cleaves the amyloid-beta protein precursor (A beta PP), to generate the amyloid-beta (A beta) peptides, involved in Alzheimer's Disease (AD). Other substrates of the gamma-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences PSEN1 expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the PSEN1 5MODIFIER LETTER PRIME-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. PSEN1 expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher PSEN1 expression during brain development and in disease progression. PSEN1 methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in PSEN1 CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of gamma-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that PSEN1 DNA methylation in peripheral blood may provide a biomarker for AD.

Introduction: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. Methods: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article (ClinicalTrials.gov Identifier: NCT02739971). Results: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. Conclusions: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia. © 2019 The Authors

Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline?deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet?induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ?-oxidation: fibroblast growth factor 21 and peroxisome proliferator?activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ?-oxidation in liver and the effects on PL metabolism in brain.?Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline?deficient rats.Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline?deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet?induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ?-oxidation: fibroblast growth factor 21 and peroxisome proliferator?activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ?-oxidation in liver and the effects on PL metabolism in brain.?Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline?deficient rats.

Background: Milk is a major source of iodine in human nutrition. Because both iodine content and the consumption of milk and dairy vary widely over time and populations, their contribution to iodine intake must be evaluated regularly. A recent national iodine survey found Israel's population to be mildly iodine deficient, possibly due to unmonitored changes in the food content of dietary iodine. Accounting for dairy iodine content can help guide efforts to prevent iodine deficiency. Objectives: This study aimed to determine the iodine concentration of dairy products typically consumed in the Israeli diet, and to estimate iodine intake from dairy products among Israeli adults. Methods: Iodine was analyzed in 33 selected dairy products that account for 89% of the total population's dairy intake according to the ?MABAT? Israeli National Health and Nutrition survey. Based on these data, the distribution of iodine intake from milk, dairy, and dairy-based foods in the adult population was calculated. Results: Israeli milk is rich in iodine, with a mean concentration of 22??g/100?g. However, due to low dairy consumption, the mean iodine intake from milk and dairy was only 34??g/day (median 23??g/day; range: 0?337??g/day) or 22% of the recommended daily allowance. Self-reported intake among poor, male, and Arab subgroups was even lower. Conclusions: Because Israeli milk and dairy products are iodine rich, their contribution to the population's iodine intake would increase if they were consumed in greater amounts, particularly by high-risk groups. Dairy's potential contribution to iodine nutrition should be considered in recommendations for dairy consumption and iodine prophylaxis.Background: Milk is a major source of iodine in human nutrition. Because both iodine content and the consumption of milk and dairy vary widely over time and populations, their contribution to iodine intake must be evaluated regularly. A recent national iodine survey found Israel's population to be mildly iodine deficient, possibly due to unmonitored changes in the food content of dietary iodine. Accounting for dairy iodine content can help guide efforts to prevent iodine deficiency. Objectives: This study aimed to determine the iodine concentration of dairy products typically consumed in the Israeli diet, and to estimate iodine intake from dairy products among Israeli adults. Methods: Iodine was analyzed in 33 selected dairy products that account for 89% of the total population's dairy intake according to the ?MABAT? Israeli National Health and Nutrition survey. Based on these data, the distribution of iodine intake from milk, dairy, and dairy-based foods in the adult population was calculated. Results: Israeli milk is rich in iodine, with a mean concentration of 22??g/100?g. However, due to low dairy consumption, the mean iodine intake from milk and dairy was only 34??g/day (median 23??g/day; range: 0?337??g/day) or 22% of the recommended daily allowance. Self-reported intake among poor, male, and Arab subgroups was even lower. Conclusions: Because Israeli milk and dairy products are iodine rich, their contribution to the population's iodine intake would increase if they were consumed in greater amounts, particularly by high-risk groups. Dairy's potential contribution to iodine nutrition should be considered in recommendations for dairy consumption and iodine prophylaxis.

{Introduction: In many affluent countries, including Israel, networks of food banks and pantries have increasing responsibility to alleviate endemic poverty and food insecurity. While they may relieve acute hunger, their long-term influence on health and well-being is poorly understood. Methods: An exploratory cross-sectional telephone survey assessed both adequacy and quality of food aid provided via food pantries in the Leket Israel food bank network, in relation to recipients’ dietary needs and health. The quality of food baskets and recipient diets were given a Healthy Portions Score (HPS) to measure compliance with Government guidelines for a “Basic Healthy Food Basket”, and a Nutrient Density Score (NDS) to capture how well the food achieved the recommended dietary allowance (RDA) for vital macro and micronutrients. A total of 105 pantry users were surveyed from 16 pantries around the country. Results: The basket HPS correlated positively and highly significantly with dietary quality (individual NDS) after adjusting for gender, marital status and country of birth (standardized β= 0.22

BACKGROUND: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients. DESIGN: The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy. PARTICIPANTS: 584 participants from 18 sites across North America. INTERVENTION: The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6). MEASUREMENTS: Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations. RESULTS: At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p≤0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes. CONCLUSIONS: High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.

Dementia and Alzheimer's disease (AD) pose one of the greatest social and economic burdens to public health. Dementia is a clinical syndrome characterized by the development of multiple cognitive deficits including memory, orientation in space and time, attention, and executive functions, leading to a substantial decline from functioning levels and causing significant loss in social and/or occupational functioning. The cognitive symptoms of dementia may arise due to different underlying pathologies, alone or in combination. Advanced glycation end products (AGEs) are a class of chemical compounds that are formed by the nonenzymatic reaction between reducing sugars and free amino groups. AGEs can affect cellular functions by acting as ligands for several receptors. The AGE receptor, receptor for AGEs, is a member of the immunoglobulin family, and its cellular signaling activates transcription factors such as nuclear factor kappaB, AP-1, and FOXO that regulate inflammation and oxidative stress by inducing the expression of cytokines, adhesion molecules, and prothrombotic and vasoconstrictive products.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required.

BACKGROUND: Food banks seeking to rescue and redistribute highly nutritious perishable foods to simultaneously alleviate food insecurity and reduce food waste often encounter practical, ethical, and political dilemmas. OBJECTIVES: We present a case study of "Leket Israel," an Israeli food bank that uses an effective large-scale logistical model for the rescue and redistribution of perishable food and discuss the challenges and solutions it offers. RESULTS: The organization operates in a rich country plagued with poverty and inequality, where the government passively encourages nongovernmental organizations to respond to the serious and growing problem of food insecurity. Operating under a business-to-business model, Leket Israel distributes food via intermediary nonprofit organizations (NPOs), enriching the food they provide with fresh produce. Food is obtained through an Agricultural Gleaning project, Self-Growing Farm project, and Meal Rescue project. The partnering NPOs then distribute the food to people in need. Although the rescue and redistribution of highly perishable food is more costly and complex than acquiring, storing, and distributing dried and staple foods and it requires specialized knowledge and infrastructure in order to maintain rigorous safety standards, it improves the nutritional quality of the aid. In 2015, Leket Israel distributed 15 217 389 kg of food, 90% of which was fruit and vegetables, to 180 partnering NPOs nationwide, reaching an estimated 175 000 recipients. CONCLUSION: "Leket Israel" offers a valuable model that can be studied and emulated by international nutrition scientists, practitioners, and policy makers who are seeking to reduce food insecurity and food waste in other countries.

BACKGROUND: National data on iodine status in Israel are lacking. Reliance on iodine-depleted desalinated water, the absence of a salt iodization program, and reports of increased use of thyroid medication in Israel suggest that the population's iodine intake is likely inadequate. The aims of this study were therefore to determine the iodine status of Israeli school-age children (SAC) and pregnant women (PW) in a nationally representative sample obtained by a novel approach of using pre-discard urinalysis samples collected from a centralized national laboratory. METHODS: Spot urine samples from 1023 SAC and 1074 PW, representing all regions and major sectors in Israel, were collected during 2016 at the Maccabi Healthcare Services central laboratory. Urinary iodine concentration (UIC) was measured, and the results were analyzed by trimester, sex, region, and sector. RESULTS: SAC were iodine deficient, with a median (interquartile range [IQR]) UIC of 83 μg/L (52-127 μg/L); 62% of SAC UICs were below the World Health Organization adequacy range for SAC (100-199 μg/L). PW were also iodine deficient, with a median (IQR) UIC of 61 μg/L (36-97 μg/L); 85% of PW UICs were below the adequacy range for PW (150-249 μg/L). For both SAC and PW, the median UIC was below the World Health Organization's adequacy range across all sectors, sexes, and districts. Among SAC, the median (IQR) UIC was lower among females (75 μg/L; 48-119 μg/L) than males (92 μg/L; 59-133 μg/L; p < 0.05). Median UIC values of PW correlated significantly with the median UIC for SAC by sub-district (R = 0.3, p < 0.05). CONCLUSIONS: Urine sampling via a centralized national laboratory was efficient and cost-saving. Iodine deficiency in Israeli SAC and PW is a serious public-health concern. A national program of salt iodization and iodine supplementation of PW should be urgently considered.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B , B , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B (50 mg/day), and vitamin B (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B or B , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research.

Objective Over 300 million people rely on desalinated seawater and the numbers are growing. Desalination removes iodine from water and could increase the risk of iodine-deficiency disorders (IDD). The present study assessed the relationship between iodine intake and thyroid function in an area reliant on desalination. Design A case–control study was performed between March 2012 and March 2014. Thyroid function was rigorously assessed by clinical examination, ultrasound and blood tests, including serum thyroglobulin (Tg) and autoimmune antibodies. Iodine intake and the contribution made by unfiltered tap water were estimated by FFQ. The contribution of drinking-water to iodine intake was modelled using three iodine concentrations: likely, worst-case and best-case scenario. Setting The setting for the study was a hospital located on the southern Israeli Mediterranean coast. Subjects Adult volunteers (n 102), 21–80 years old, prospectively recruited. Results After screening, seventy-four participants met the inclusion criteria. Thirty-seven were euthyroid controls. Among those with thyroid dysfunction, twenty-nine were classified with non-autoimmune thyroid disease (NATD) after excluding eight cases with autoimmunity. Seventy per cent of all participants had iodine intake below the Estimated Average Requirement (EAR) of 95 µg/d. Participants with NATD were significantly more likely to have probable IDD with intake below the EAR (OR=5·2; 95 % CI 1·8, 15·2) and abnormal serum Tg>40 ng/ml (OR=5·8; 95 % CI 1·6, 20·8). Conclusions Evidence of prevalent probable IDD in a population reliant on desalinated seawater supports the urgent need to probe the impact of desalinated water on thyroid health in Israel and elsewhere.

Passion fruit is a commercially important crop. The neuroprotective activity of fruit extracts from two hybrid lines of antioxidant ester thiol-rich Passiflora edulis Sims, the commercial “Passion Dream” and novel cultivar 428 (“Dena”) line were studied. Crude extracts from line 428 displayed the strongest dose-dependent neuroprotective activity, preventing glutamate induced cell-death, mitochondrial depolarization and glutathione depletion, when added to the medium of cultured HT4 neurons (p < 0.05). Supplementing diet of mice with the 428 fruit-extract improved survival of dopaminergic neurons by 60% in mice injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT) compared to control-fed MPTP-injected mice (p < 0.05). The neuroprotection conferred by passion fruit extracts in vivo and in vitro shows promise for further research into their bioactive potential for medical exploitation.