Progress 05/01/09 to 04/30/14
Outputs
Progress Report Objectives (from AD-416): LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using other animal models of human cognitive decline. Approach (from AD-416): LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. The lab continues to analyze the rich data set from the NAME study examining the associations between nutritional factors, cognitive function and brain pathology. We have previously reported a number of important relationships between nutritional factors and the maintenance of cognitive function during aging. We are analyzing the final data on the large multi-center randomized clinical trial evaluating the effect of B vitamins in lowering blood homocystine to prevent cardiovascular complications and cognitive decline. We continue to analyze important data sets from human cohorts to examine further relationships between nutrition status and cognitive function. In the laboratory we proceed to use animal models and to examine the mechanism of the relationships between nutritional status and aging brain function. These explorations have identified relationships between markers of epigenetic status which may include micro RNA and their influence on brain metabolism and functioning. We also continue to use transgenic animal models of age- related cognitive impairment to examine the interaction of nutrient status including the nutrients choline and folic acid and the gene directed cognitive decline in these animals. Vitamin B6 is essential in many aspects of brain function such as neurotransmitter synthesis, receptor binding, macronutrient metabolism, and gene expression, and deficiencies have been associated with higher levels of inflammation and risk of atherosclerosis. ARS-funded researchers at the JM USDA HNRCA at Tufts University in Boston, MA assessed whether low plasma vitamin B6 concentration (< 30 nm/L) was a risk factor for cognitive decline in the Boston Puerto Rican Health Study cohort . Thirty percent of participants had low vitamin B6 status. Low vitamin B6 was associated with smoking, diabetes, and higher BMI, as well as higher plasma homocysteine (Hcy), C-reactive protein (CRP) and white blood-cell (WBC) count. Low vitamin B6 status was predictive of 2 year decline in executive cognitive function (= 1 SD decrease in cognitive testing composite score) and with a similar trend for memory , adjusting for baseline cognitive score, demographics, vitamins B9, B12, C, and D, and diabetes, hypertension, depression, Hcy, CRP, WBC and lifestyle variables. Vitamin B6 quintile was inversely related to depressive symptoms severity and perceived stress in similar full models. Our findings suggest that low vitamin B6 status remains a risk factor for cognitive decline and depression in at-risk populations. Calorie restriction (CR) extends lifespan in a range of animal models and potentially decreases disease risk factors in humans. It is unclear, however, how CR impacts cognition; a negative outcome could decrease the feasibility and practicality of CR for health improvement. Previous studies in both animal models and humans have provided inconsistent findings reporting either positive, negative, or no effects. ARS-funded researchers at the JM USDA HNRCA at Tufts University in Boston, MA studied the effect of CR on cognition during a 2-year, multi-center, randomized controlled trial. The analysis population was comprised of 218 healthy normal- and over-weight adult volunteers who were enrolled into the CALERIE study, were randomized 2:1 into a 25% CR or an Ad Libitum control group, and began intervention. Cognition was measured through a computerized battery of tests (reaction time, attention/vigilance, verbal and visual memory, working memory, and executive function) at baseline, and 6-, 12-, and 24-month follow-up. Analysis was on an intention-to- treat basis, with models adjusted for study site, sex, baseline BMI stratum, baseline scores, age and education. Our results showed no consistent main effect of study intervention for any of the cognitive tests, nor a significant interaction between intervention and BMI stratum. Our null findings suggest that cognitive outcome is not a limitation for the use of CR for health improvement. Vitamin D de�ciency and cognitive impairment are both prevalent in hemodialysis patients in the United States. This study tested the hypothesis that vitamin D de�ciency may be associated with cognitive impairment because of its vasculoprotective, neuroprotective, and immune- modulatory properties. In a cohort of 255 patients receiving hemodialysis, ARS-funded researchers from Tufts University in Boston, MA found that 69% of patients had plasma vitamin D concentrations in the deficient or insufficient ranges. Patients in the de�cient group were more likely to be women, African American, and diabetic and to have been on dialysis for longer periods of time. Higher vitamin D levels were independently associated with better performance on several tests of executive function (e.g. mental flexibility, organization, and planning). No association was seen with tests assessing memory. Accomplishments 01 NUTRITION AND NEUROCOGNITION LAB: Genetics of Diabetes and its modulation by diet. Scores of genetic studies have scrutinized the human genome looking for diabetes-related genes and many genes and genetic variants have been identified resulting from this effort, however, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, ARS funded researchers at JMUSDA-HNRCA at Tufts University in Boston, Massachusetts have used a novel tool for Genome-wide Complex Trait Analysis (GCTA) to examine GxE contribution of 15 macronutrients and lifestyle to the variability on the expression of diabetes-related traits in the entire genome. This research has brought us to the identification of two key environmental factors making significant contributions to the modulation of the expression of diabetes and diabetes-related factors: First, dietary carbohydrate influences fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), a method used to quantify how effective is insulin in the body; second, n-6 polyunsaturated fatty acid (PUFA) influences HOMA-�-cell-function, a similar method that measures the functioning of the beta-cell in the pancreas. In summary, we utilized a novel and sophisticated method that demonstrates the importance of genome-wide GxE interactions in explaining how dietary factors can drive some of the inter-individual variability in the expression of diabetes and diabetes related traits. This information will be used towards more personalized dietary guidelines and interventions aimed to the prevention of diabetes. 02 NUTRITION AND NEUROCOGNITION LAB: Genetics plays a role in the relationship between dairy consumption and obesity: Obesity and its associated diseases are becoming a major individual and societal health burden. The current global epidemic of obesity is driven by a combination of genetic and environmental factors and the current approaches to curtail the current upward trends for this disease have failed primarily because we don�t have ways to predict the risk and the appropriate therapeutic dietary approach for each individual. Among the genetic factors associated with obesity and response to dietary intervention we have repeatedly shown a significant interaction between a gene known as apolipoprotein A2 gene (APOA2) and saturated fatty acids (SFAs) for the outcome of body mass index (BMI). Therefore, in the current research we have extrapolated these findings to include widely consumed, generally recommended and controversial foods, namely dairy products. To investigate this issue, ARS funded researchers at JM-USDA-HNRCA at Tufts University, Boston Massachusetts evaluated interactions between dairy products and the common APOA2 -265 T>C (rs5082) gene variant for BMI in Hispanic and White populations. Dairy products were evaluated as total dairy, higher-fat dairy (>1%), and low- fat dairy (=1%) in servings per day as well as dichotomized into high and low. In both Hispanics and Whites individuals, those who were predisposed to obesity and more sensitive to the effects of saturated fat (CC genotype, 10-16% of the population) had a greater BMI when consuming a larger amount of higher-fat dairy foods compared to those consuming less higher-fat dairy. For individuals lacking the CC genotype (84-90% of the population), higher fat dairy consumption was not associated with BMI. In addition, low-fat dairy consumption was protective against high BMI in Whites that carried the CC genotype. 03 NUTRITION AND NEUROCOGNITION LAB: Mediterranean diet counteracts genetic predisposition to stroke: Epidemiological evidence supports a health-promoting effect of the Mediterranean Diet (MedDiet), especially in the prevention of cardiovascular disease which has been attributed to a number of components of the MedDiet Little is known about the underlying mechanisms and about the genes that define inter-individual variation in response to the MedDiet. ARS funded researchers at JMUSDA- HNRCA at Tufts University in Boston, Massachusetts investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. For this purpose we investigated such interaction in 7,018 participants in the PREvenci�n con DIetaMEDiterr�nea (PREDIMED) study we discovered that TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes. MedDiet interacted significantly with rs7903146 on fasting glucose at baseline. When adherence to the MedDiet was low, TT had higher fasting glucose concentrations than CC+CT individuals. Nevertheless, when adherence was high, this increase was not observed. Most relevant, TT subjects had a higher stroke incidence in the control group, whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes. In summary, our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence, and supports the concept that personalized dietary advice based on genetic testing may be a successful approach to prevent age-related diseases. 04 NUTRITION AND NEUROCOGNITION LAB: Discovery and refinement of genes associated with lipid levels. Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. In previous work we have identified dozens of genes associated with these risk factors; however, many more remain to be identified. Therefore, in order to identify new genes and refine known genes influencing these lipids, ARS funded researchers at JMUSDA- HNRCA at Tufts University in Boston, Massachusetts examined 188,577 individuals using genome-wide and custom genotyping arrays. We identified and annotated 157 loci associated with lipid levels, including 62 genes or regions not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrowed association signals in 12 genes or genomic regions. We found that regions associated with blood lipid levels were often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
Impacts
(N/A)
Publications
- Winer, D.E., Scott, T.M., Giang, L.M., Agganis, B.T., Sorensen, E.P., Tighiouart, H., Sarnak, M. 2011. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. American Journal of Kidney Diseases. 58(5):733-781.
- Shaffi, K., Tighiouart, H., Scott, T., Lou, K., Drew, D., Weiner, D., Sarnak, M. 2013. Low 25-hydroxyvitamin D levels and cognitive impairment in hemodialysis patients. Journal of the American Society of Nephrology. 8(6):979-986.
- Giang, L.M., Tighiouart, H., Loi, K., Agganis, B., Drew, D.A., Shaffi, K., Scott, T., Weiner, D.E., Sarnak, M. 2013. Measures of blood pressure and cognition in dialysis patients. Hemodialysis International. 17(1):24-31.
- Rodriguez, L., Tighiouart, H., Scott, T., Lou, K., Giang, L., Sorensen, E., Weiner, D.E., Sarnak, M.J. 2013. Association of sleep disturbances with cognitive impairment and depression in maintenance memodialysis patients. The American Journal of Nephrology. 26(01):101-110. DOI:10.5301/jn. 5000131.
- Ye, X., Scott, T., Gao, X., Maras, J.E., Bakun, P.J., Tucker, K.L. 2013. Mediterranean Diet, Healthy Eating Index-2005, and Cognitive Function in Middle-Aged and Older Puerto Rican Adults. Journal of the Academy of Nutrition and Dietetics. 113(2):276-281. e1-3. DOI:10.1016/j.jand.2012.10. 014.
- Rosenberg, I. 2012. A history of the isolation and identification of vitamin B(6). Annals of Nutrition and Metabolism. 61(3):239-238.
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Progress 10/01/12 to 09/30/13
Outputs
Progress Report Objectives (from AD-416): LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using other animal models of human cognitive decline. Approach (from AD-416): LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. The lab continues to analyze the rich dataset from the NAME study (Nutrition and Memory in Elders), examining the associations between nutritional factors, cognitive function and brain pathology. In addition to previously reported associations of vitamin D insufficiency and elevated homocysteine blood concentrations with cognitive dysfunction and cerebrovascular disease, scientists are now evaluating the relationship of dietary fish intake and omega-3 fatty acids with cognitive function and brain health. We are also now analyzing the remainder of the blood samples taken from a large multi-center randomized clinical trial evaluating the effect of B- vitamins in lowering blood homocysteine to prevent cardiovascular complications and cognitive decline in kidney transplant patients. These blood samples from the baseline are being looked at to see whether individuals with low B-vitamin blood concentrations prior to treatment benefited more from the intervention than did those who were B-vitamin sufficient. We continue to employ a Near Infrared Spectroscopy (NIRS) technique that measures the amount of blood supplied to the brain and oxygen availability. NIRS will allow scientists to further evaluate the effect of aging together using both human subjects and animal models, with nutritional manipulations (such as B-vitamins, choline deficiency, and hyperhomocysteinemia) and of hypertension on the brain�s vasculature integrity, and study the mechanisms leading to vascular dementia. The lab is also currently in the process of planning feeding studies that will examine the relationship between choline intake, B vitamin status, choline-contained phospholipids in blood and brain, and cognitive decline. An animal double transgenic mouse model of Alzheimer�s disease was used to study the relationship between long-term dietary vitamin B deficiency- induced hyperhomocysteinemia and neurocognitive degeneration. It was found that long-term dietary vitamin B deficiency accelerates Alzheimer�s disease-related pathology and thus contributes to cognitive dysfunction and brain degeneration. Our findings showed a robust disruption in learning and memory performance assessed by the novel object recognition test in vitamin B deficient group suggesting abnormalities in the cortex of vitamin B deficient mice. The novel object recognition behavior was also negatively correlated with the plaque burden and choline-containing lipids in the cortex but not in the hippocampus. Neither behavior controlled by the hippocampus nor hippocampal choline-containing lipid metabolisms were affected by the vitamin B deficiency. Our findings suggest a higher sensitivity of the cortex to long term dietary vitamin B deficiency-induced hyperhomocysteinemia and Alzheimer�s disease-related pathology as compared to the hippocampus in double transgenic mice. Accomplishments 01 Plasma homocysteine is associated with cognitive impairment and MRI indicators of cerebrovascular pathology in older adults. Elevated plasma homocysteine concentration has been implicated as a risk factor for cardiovascular disease, stroke, and dementia. ARS funded researchers at JMUSDA-HNRCA at Tufts University at Boston, Massachusetts evaluated the relationship between homocysteine, sub- types of cerebrovascular pathology on magnetic resonance imaging (MRI), and cognition in a subset of 340 community-dwelling elders from the Nutrition Aging and Memory (NAME) study through brain MRIs and neuropsychological tests. We observed that cerebrovascular pathology, particularly small vessel infarct and periventricular white matter hyperintensity (WMHI), was associated with elevated fasting Hcy independent of other risk factors. Hcy was associated with total brain atrophy in those participants with periventricular WMHI, and was inversely related to measures of executive function. The results of our study suggest cerebrovascular disease and associated cognitive impairment as a target for Hcy lowering treatment. 02 Hyperhomocysteinemia (Hcy) predicts small vessel MRI pathology and cognitive impairment with high amyloid-B-peptide degrading proteases in the NAME elderly cohort. ARS funded researchers at JMUSDA-HNRCA at Tufts University at Boston, Massachusetts studied 318 home bound multi- ethnic elderly- Nutrition Aging and Memory Study (NAME) with nutritional, cognitive, and magnetic resonance imaging (MRI) to assess the relationship of small vessel pathology (infarcts and white matter abnormalities) with high blood homocysteine and cognitive impairments while noticing the association of small vessel infarcts to elevated amyloid-beta-peptide degrading enzymes. Total cerebrovascular pathology, particularly small vessel infarcts and periventricular white matter hyperintensities was associated with elevated fasting Hcy which was inversely related to measures of executive cognitive function. Small vessel infarcts were related to elevated activities of amyloid-beta- peptide degrading enzyme activity. These observations of small vessel pathology in brain with high Hcy and cognitive impairment and now with beta-amyloid processing emphasize the importance of considering vascular elements of age-related dementia and even the relations of cerebrovascular and beta-amyloid pathogenesis in Alzheimer�s Dementia. 03 Homocysteine lowering with B-vitamin supplements and cognitive function in renal transplant recipients. There is a high prevalence of hyper- homocysteinemia in individuals with chronic kidney disease. Epidemiologic studies have shown that elevated plasma total homocysteine (tHcy) concentrations are associated with diminished cognitive function in the general population, and significantly increase the risk of cognitive impairment, cerebrovascular disease, stroke and dementia. In this study ARS-funded researchers at JMUSDA- HNRCA at Tufts University at Boston, Massachusetts assessed whether homocysteine-lowering B-vitamin therapy would prevent cognitive decline in kidney-transplant patients with hyper-homocysteinemia in both a North American and a Brazilian cohort. Almost none of the participants in either the high-dose-B-vitamin or control groups were B-vitamin deficient prior to intervention. Our results showed that while cognitive impairment was common, elevated tHcy was not associated with the degree of this impairment. Treatment with high-doses of B-vitamins was efficacious in lowering tHcy levels, but had modest and inconsistent effects on cognitive function, mostly in the executive function domain. While it�s possible that chronically high tHcy is a risk factor for cognitive impairment in this group, it may be that damage from long-term exposure cannot be reversed. It is also possible that individuals with poorer nutritional status would benefit more from B-vitamin supplementation. 04 Non-invasive assessment of age-related changes in cerebral tissue perfusion and vasoconstriction using Near Infrared Spectroscopy (NIRS) approach in animals. Age remains the strongest risk factor for developing cognitive decline and dementia. Since structural and functional disturbances in brain vasculature are prevalent in dementia, these vascular changes have been suggested to contribute to the development of and affect the severity of age-related neurodegeneration and cognitive decline. A Near Infrared Spectoscopy (NIRS) technique has been developed by ARS-funded researchers at JMUSDA-HNRCA at Tufts University at Boston, Massachusetts in order to measure non-invasively the amount cerebral blood volume. In order to assess the effect of age on cerebral tissue perfusion and vascular stiffness, we have measured cerebral blood volume and vasomotor reactivity on WKY rats during a year time frame, using NIRS instrumentation. By longitudinally following the rats from young to middle-age, we were able to record a significant age-related decrease in cerebral blood volume, suggesting a reduction in tissue perfusion. Vasomotor reactivity, on the other hand, did not appear to be significantly affected by age, as seen by the similar extent of vasodilatation following hypercapnic challenge at both age. A comprehensive understanding of the factors affecting brain vascular health together with the ability to detect the first signs of dysfunction will allow better and quicker treatments to age-related cognitive disorders. 05 Long-term hypertension affects cerebral vasomotor reactivity but does not aggravate age-related decrease in tissue perfusion in rats. Vascular dementia has been suggested to be a long term complication of hypertension. The reported changes in vascular morphology due to hypertension share many common features with those seen in age-related neurodegenerative disorders such as Alzheimer�s disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University at Boston, Massachusetts therefore hypothesized that hypertension drives a general decrease in blood supply to brain tissue and a reduction in vascular elasticity. We therefore submitted Spontaneous Hypertensive rats (SHRs) to NIRS at a young age (4 months), and then followed-up a year later at middle-age (16 months). Decreased cerebral blood volume was recorded in middle-aged hypertensive rats, but the magnitude of decrease occurring between young to middle-age appeared similar to the one seen in WKY (normotensive) strain (study described above). Therefore hypertension itself did not appear to aggravate the impact of age on cerebral tissue perfusion. On the other hand, the vasodilatory capacity (represented through the response to a hypercapnic challenge) appeared greatly reduced in the hypertensive animals from a young age and was further reduced at middle-age. These results emphasize the detrimental effect of hypertension, already apparent at the early stages of the disease. 06 Long-term Folate Deficiency and Homocysteine Findings. Long-term dietary vitamin B-induced deficiency results in hyperhomocysteinemia and dysregulation of choline metabolism in double transgenic mouse model of Alzheimer�s disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University at Boston, Massachusetts evaluated the impact of B- vitamin deficiency on behavior, Alzheimer�s disease-related pathology and choline metabolism in the brain regions of double transgenic mice. It was found that long-term dietary vitamin B deficiency resulted in hyperhomocysteinemia, diminished levels of choline-containing lipids in the cortex but not in the hippocampus. The size of the plaques was also significantly larger in the cortex of vitamin B deficient mice as compared to those in the control group; and it was negatively correlated with the cortical choline-containing lipids. Study results also showed that vitamin B deficiency significantly affected behavior controlled by the cortex whereas behavior controlled by the hippocampus was not affected. These findings are important because they reveal that the effects of long-term vitamin B deficiency on Alzheimer�s disease- related pathology are brain region-specific and mediated through dysregulation of choline-containing lipid metabolism.
Impacts
(N/A)
Publications
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Progress 10/01/11 to 09/30/12
Outputs
Progress Report Objectives (from AD-416): LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using other animal models of human cognitive decline. Approach (from AD-416): LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. The lab continues to analyze the rich dataset from the NAME study (Nutrition and Memory in Elders), examining the associations between nutritional factors, cognitive function and brain pathology. In addition to previously reported associations of vitamin D insufficiency and elevated homocysteine blood concentrations with cognitive dysfunction and cerebrovascular disease, scientists are now evaluating the relationship of dietary fish intake and omega-3 fatty acids with cognitive function and brain health. Findings are that regular fish consumption and higher intakes of omega-3s are associated with better memory in elderly men. They are also finding that lower dietary intake and lower blood concentrations of omega-3s are associated with brain atrophy (as measured by magnetic brain imaging�MRI), particularly in the hippocampus (a part of the brain that is involved in the processing of new memories). We are also now analyzing the remainder of the blood samples taken from a large multi-center randomized clinical trial evaluating the effect of B- vitamins in lowering blood homocysteine to prevent cardiovascular complications and cognitive decline in kidney transplant patients. These blood samples from the baseline are being looked at to see whether individuals with low B-vitamin blood concentrations prior to treatment benefited more from the intervention than did those who were B-vitamin sufficient. In addition to the studies described above, collaborations are continuing with colleagues at Tufts Medical Center and Northeastern University, on a longitudinal study of an at-risk population (the Boston Puerto Rican Health Study). Scientists are assessing the interactive effects of nutrition, genetics, and metabolic and psychosocial stress on cognitive function. Currently they are analyzing baseline and 2nd year follow-up data to ascertain factors that are predictive of cognitive decline. We continue to employ a Near Infrared Spectroscopy (NIRS) technique that measures the amount of blood supplied to the brain and oxygen availability. NIRS will allow scientists to further evaluate the effect of aging together using both human subjects and animal models, with nutritional manipulations (such as B-vitamins, choline deficiency, and hyperhomocysteinemia) on the brain�s vasculature integrity, and study the mechanisms leading to vascular dementia. Also currently in the process of planning future experiments utilizing animal models that will examine the relationship between long-term vitamin B deficiency and neurocognitive degeneration. Accomplishments 01 Near Infrared Spectroscopy approach for assessing cerebral vascular heal Disturbances in brain blood vessel�s� integrity and density have been suggested to precede and accompany age-related neurodegeneration and cognitive decline. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, have developed a Near Infrared Spectroscopy (NIRS) technique that measures non-invasively the amount of blood supplied to the brain and the availability of oxygen to neural cel They have applied this technique on human subjects as well as in animal models to evaluate the effect of multiple physiological conditions (such as aging or hypertension) or nutritional manipulation (B-vitamins or folate deficiency) on the integrity of the brain�s vasculature. The studies conducted demonstrated a clear decrease in blood supply resultin in lower oxygen delivery to the brain as a result of aging and/or hypertension. This technique will provide for faster response and better targeting of treatments for age-related cognitive disorders via a comprehensive understanding of the factors affecting brain vascular heal together with the ability to detect the first signs of dysfunction. 02 The methylenetetrahydrofolate reductase gene C677T polymorphism is not associated with cognitive dysfunction and depression in folate-sufficien adults. The C677T variant of the human methylene tetrahydrofolate reductase (MTHFR) gene results in a mild deficiency of an enzyme that regulates folate metabolism, causing an elevation of homocysteine concentration in the blood (a risk factor for cardiovascular disease). ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts in collaboration with researchers at Tufts Medical Center, Northeastern University, and the Mount Sinai School of Medicine evaluate whether this gene variant is also associated with poorer cognition and higher levels of depressive symptoms. They found that in a population with adequate folate intake, this variant in the MTHFR gene was not associated with cognitive dysfunction or depression. 03 Higher intakes of added sugars and sugar-sweetened beverages is associat with lower scores on cognitive tests. The consumption of added sugars, mainly fructose and sucrose, has been associated with obesity, the metabolic syndrome and type-2 diabetes. Since diabetes is a risk factor for cognitive impairment, ARS-funded researchers at JMUSDA-HNRCA at Tuft University, Boston, Massachusetts in collaboration with researchers at Northeastern University evaluated whether habitual consumption of these sweeteners was associated with impaired cognition. They found that great intakes of total sugars, added sugars, and sugar-sweetened beverages, bu not of sugar-sweetened solid foods, were associated with lower scores on cognitive tests. These findings suggest that a high consumption of added sugars may negatively impact cognitive function. 04 Brain imaging patterns can predict risk of falling in the elderly. In t elderly, falls are the leading cause of injury death, nonfatal injuries, and hospital admissions for trauma. Determining reasons why some individuals are at higher risk for falling will lead to better understanding of this phenomenon and a reduction of these outcomes. ARS- funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts, along with researchers at Brigham and Women�s Hospital, a Boston Medical Center evaluated whether individuals who are assessed to at higher risk for falling have a specific pattern of brain pathology evident during brain imaging. They found that people who are clinically assessed to be at risk for falls had abnormalities in the underlying pathways that connect areas of the brain and that facilitate integrated functioning. These abnormalities were also associated with greater impairment in cognitive function. This information helps us to understan why certain individuals are at higher risk of falling and will aid in assessing this risk and making recommendations for physical activity. 05 Cardiovascular disease is associated with cognitive dysfunction in dialysis patients. Cognitive impairment is common in dialysis patients, but it is unclear what factors put individuals at higher risk. ARS-funde researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts i collaboration with researchers at Tufts Medical Center evaluated whether the presence of cardiovascular disease is a risk factor for cognitive dysfunction. They found that those dialysis patients who also had cardiovascular disease performed worse on cognitive tests than did those dialysis patients without cardiovascular disease. With the increasing prevalence of obesity, diabetes, and hypertension in the U.S. population recognizing potential consequences of cardiovascular disease is importan Identifying those dialysis patients who are at high risk for developing cognitive impairment will aid in planning patient care and the need for support systems. 06 Short-term folate deficiency increases brain homocysteine. Short-term dietary vitamin B-induced deficiency results in hyperhomocysteinemia and dysregulation of choline metabolism particularly in the adult group of animals. ARS-funded researchers at JMUSDA-HNRCA at Tufts University in Boston, Massachusetts evaluated the impact of B-vitamin deficiency on behavior, cholinergic gene expression, and choline-containing lipid metabolism in the brain for two age groups of rats. It was found that short-term vitamin B deficiency resulted in hyperhomocysteinemia and diminished levels of brain choline-containing lipids but did not significantly affect brain vitamin B levels and cholinergic genes expression regardless of age. Study results also showed that short-term vitamin B deficiency did not affect performance on a test of memory in either age group. These findings are important because they reveal that although behavior is not altered following short-term vitamin B deficien there are changes in brain chemistry. These results highlight age-relat differential sensitivity to vitamin B deficiency and the need to evaluat the longer-term effects of vitamin B deficiency on neurocognition.
Impacts
(N/A)
Publications
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Progress 10/01/10 to 09/30/11
Outputs
Progress Report Objectives (from AD-416) LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using other animal models of human cognitive decline. Approach (from AD-416) LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. The progress and the period covered is divided in the 2 major spheres of activity: human studies including observational and nutritional intervention studies, and laboratory based studies with animal models of age-related cognitive decline. It corresponds with problem statements 2A, �Identify roles of food, nutrients, food components and physical activity in promoting health and preventing disease� and 4A, �Understanding mechanisms by which nutrition promotes healthy development and function from conception to old age.� Having completed the collection of all data in the NAME study (Nutrition, Aging, and Memory in Elders), ARS-funded researchers from Tufts University proceeded with the analysis of this rich set of data from over 1200 elders receiving homecare in the Boston area. The main objective of the NAME study was to examine the associations of nutritional factors, especially B vitamins and homocysteine, and cognitive function in the elderly. Brain pathology, as measured by magnetic resonance imaging (MRI), was assessed in a subset 360 NAME participants. The researchers observed that nutritional factors, especially blood homocysteine, which is dependent on B vitamins in the diet and in supplements, could be used to predict the likelihood of cerebrovascular disease and cognitive decline. Researchers completed all of the data collection for a large multi-center trial studying the effect of B vitamin supplementation and blood homocysteine lowering on cardiovascular complications and cognitive decline in middle-aged participants who had undergone kidney transplant. Cognitive function was measured yearly in over 1300 subjects in this randomized control trial of high and low B vitamin treatment. Preliminary analyses have demonstrated that the B vitamin treatment did result in some protection against decline in short-term memory without evidence that other forms of cognitive function, including executive function and decision making were affected. There are scientific articles and papers deriving from this study including the baseline, that blood homocysteine levels had only a minor effect in predicting cognitive function in renal transplant patients. Animal models were used to study the effect of vitamin B deficiency induced high homocysteine levels on animal behavior and cognition including estimation of biochemical changes which might underlie the vitamin deficiency effect and explain behavioral and cognitive abnormalities. The prominent finding was the relationship between changes in the small blood vessels in the brain of mice when they became B vitamin deficient and the relationship between these blood vessel changes and behavioral or cognitive performance on the water maze which tests learning and cognitive function in these animals. Future experiments will examine further the relationships and the biochemical basis for abnormal vascular and nervous tissue function and brain in the presence of vitamin deficiency. Accomplishments 01 The Relationship between Homocysteine and Neurodegenerative Disorders Established. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, conducted a study to examine the potentially causal relationship of nutritional factors and cognitive impairment in elders. subset of 323 participants from the cross-sectional Nutrition, Aging and Memory (NAME) study underwent magnetic resonance imaging (MRI) and cognitive testing. Total homocysteine plasma concentrations were also ascertained. Brain MRIs were assessed for the presence of small and larg blood vessel infarcts, and qualitative grading of white matter hyperintensity and hippocampal and total brain atrophy was performed. T researchers found that elevated plasma homocysteine was associated with neuroimaging markers of cerebrovascular disease, independent of other cerebrovascular risk factors. They did not find an association between homocysteine and hippocampal atrophy, and there was only an association with total brain atrophy in those participants with evidence of cerebrovascular disease. In analyses of measures of cognitive function, homocysteine level was inversely related to executive function in those with cerebrovascular disease, but not to memory or attention. These findings support the hypothesis that homocysteine is an independent risk factor for cerebrovascular disease, with smaller direct effects on neuronal function. The association of homocysteine with executive dysfunction, but not memory impairment, also supports this interpretatio This study is important because it details the relationship between homocysteine and neurodegenerative disorders. 02 B Vitamin Supplementation Improves Cognitive Function in Renal Transplan Recipients. Blood homocysteine is a marker for increased risk of cerebrovascular disease, stroke, and cognitive decline. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, looked at t relationship between high homocysteine levels and renal transplant patients. The researchers assessed the effect of homocysteine lowering with B vitamin supplementation on cognitive decline in renal transplant recipients. In a double-blinded trial of high- versus low-dose B vitami supplementation, 1350 participants underwent annual cognitive testing fo up to 7 years. The researchers found that short-term memory of newly learned information was better for the high-dose than the low-dose treatment group. They also found that there were no differences between the two groups for initial learning of information or for tests of executive and visuospatial functions. This is important because renal transplant patients have persistently high homocysteine levels which remain in the range associated with increased risk of cerebrovascular disease and cognitive decline in the general population. It was found th hyperhomocysteinemia and B-vitamin deficiency may be treatable risk factors for cognitive decline. 03 Short-term Folate Deficiency and Homocysteine Findings. To study how die induced folate deficiency affects choline and acetylcholine concentratio in the brain and peripheral tissues, ARS-funded researchers at JMUSDA- HNRCA at Tufts University, Boston, MA, fed both young and adult male Sprague Dawley rats either control or folate deficient diets for 10 week It was found that adult rats have less efficient adaptation to folate deficiency than young rats as reflected through changes in choline and acetylcholine metabolism in the brain and peripheral tissues. The researchers also found that in adult rats, the adaptation of brain choli and acetylcholine metabolism to folate deficiency was associated with th dysregulation of their metabolism in the peripheral tissues. This accomplishment is significant because it highlights the different effect of folate deficiency amongst age-groups. 04 Development of Non-Invasive Near-Infrared Spectroscopy Measurement Syste ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have developed a new non-invasive near-infrared spectroscopy (NIRS) measurement system which allows them to measure blood flow and the amoun of oxygen it carries to the brain. This development can assist research the areas of Alzheimer�s disease and other dementias where there is ofte considerable damage to the brain�s small blood vessels. Using this new method, researchers were able to find that folate deficient rats had significantly lower brain blood flow and less oxygen delivery than contr rats. This animal model is important because compromised brain circulati may be related to cognitive decline. The new non-invasive NIRS method i helpful in detecting these measurements in rats and in humans.
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Progress 10/01/09 to 09/30/10
Outputs
Progress Report Objectives (from AD-416) LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using transgenic and other animal models of human cognitive decline. Approach (from AD-416) LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. In the past year we have continued our progress in studies of nutritional effects on brain aging, both human and animal. In human studies we have completed the analysis of genetic factors associated with cognitive decline and dementia-related changes in brain on magnetic resonance imaging in 1,000 Boston elderly residents in-home care, with special attention to B vitamin related pathways of metabolism. In laboratory studies we have further documented the relationship between vitamin folic acid deficiency and choline containing membrane substances in brain, which affect behavior and cognition. We have now established the benefits of using a new form of spectroscopy to measure blood flow in the brain of living animals in a way which predicts and explains some of the functional deficits associated with B vitamins and folic acid deficiency. Application of this technique can now progress in human studies, which will measure oxygen delivery to brain. We have closed enrollment and completed cognitive data collection in ancillary study of cognitive outcomes in multicenter randomized double- blinded placebo-controlled trial of the effect of B-vitamins on homocysteine-lowering and cardiovascular risk reduction in kidney transplant recipients. The parent trial has been completed and with it our collection of cognitive data. Un-blinding is expected later in 2010 and laboratory measures of blood vitamin and homocysteine status is due to be completed by the end of 2011, followed by a final analysis of effect of B-vitamin treatment on cognitive function. We have completed the determination of genetic variability in several genes that are involved in folate and homocysteine metabolism, and which are suspected to influence the increased risk of age-associated cognitive changes, brain disease. A first publication reports on findings that plasma vitamin B-6 and folate appears to modify the risk of hypertension and stroke in individuals with a particular genetic variant. This work will contribute to our understanding of general and personalized nutritional requirements for the promotion of healthy brain aging. We have developed a novel, non-invasive near infrared spectroscopy instrument to evaluate brain circulation in rat models of cognitive impairment to measure diet-induced changes in brain circulation and oxygen delivery. In rat, folate deficiency significantly reduces brain oxygen delivery, tissue hemoglobin concentration and oxygenation and vascular reactivity despite normal arterial oxygen saturation. In contrast, vitamin B12 deficiency in rat does not induce neurodegeneration, impair cognition or alter brain oxygen delivery. Our current instrument and methods are ready to study brain vascular health in rat models of other conditions, and to test the efficacy of nutritional or pharmacological interventions for preserving brain circulation. This work will pave the way for the long-term application of these methods to studying the effect of nutrition and nutritional interventions on brain circulation and cognition in humans. For publications related to this project, see parent project 1950-51000- 070-00D. Accomplishments 01 Demonstration of the relationship between brain blood vessel pathology a nutritional folate deficiency. ARS-funded researchers from Tufts University in Boston, MA have shown a diminishing effect of short term nutritional folate (B vitamin) deficiency on cognitive function in anima These declining cognitive functions in folate-deficient animals were demonstrated to be accompanied by a decrease in the capillary blood supp to the brain by tissue examination. This same deficiency model of cognitive decline allows examination of other factors in Alzheimer�s disease including fat and other B vitamins. 02 Folate and choline are two metabolically related essential nutrients whi play an important role in cognitive functions in humans and animals. ARS funded researchers from Tufts University in Boston, MA have shown folic acid (B vitamin) deficiency leads to dysregualtion of the brain choline metabolism and this is demonstrated by altered levels of choline containing substances in brain cell membranes. There is a higher ability to compensate nutritional folate deficiency in young than in adult age, implicating the adult group as a target for study of folate-choline interactions and their role in brain plasticity and cognitive functions. 03 Vitamin K is present in high concentrations in the brain and has been implicated in the regulation of fat metabolism. ARS-funded researchers from Tufts University in Boston, MA have developed an animal model that exploits the difference in the brain�s ability to metabolize two dietary forms of vitamin K. This animal model allowed us to investigate the effe of vitamin K on brain myelin, a well-known contributor to age-related cognitive decline. Our findings of a positive relationship between myeli fat and concentration of vitamin K in blood suggest that this animal mod may be useful for investigation of the effect of the dietary vitamin K o fat metabolism and behavior functions in humans.
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Publications
- Bhadelia, R.A., Price, L., Tedesco, K.L., Scott, T., Qiu, W., Patz, S., Folstein, M., Rosenberg, I.H., Caplan, L., Bergethon, P. 2009. Diffusion Tensor Imaging White Matter Lesions the Corpus Callosum and Gait in the Elderly. Stroke. 40:3816-3820.
- Allen, L.H., Rosenberg, I.H., Oakley, G.P., Omenn, G.S. 2010. Considering the case for vitamin B12 fortification of flour. Food and Nutrition Bulletin. 31(1):S36-46.
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