1a. 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.
1b. 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.
3. Progress Report
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.
1. 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. A 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 large blood vessel infarcts, and qualitative grading of white matter hyperintensity and hippocampal and total brain atrophy was performed. The 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 interpretation. This study is important because it details the relationship between homocysteine and neurodegenerative disorders.
2. B Vitamin Supplementation Improves Cognitive Function in Renal Transplant 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 the 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 vitamin supplementation, 1350 participants underwent annual cognitive testing for 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 that hyperhomocysteinemia and B-vitamin deficiency may be treatable risk factors for cognitive decline.
3. Short-term Folate Deficiency and Homocysteine Findings. To study how diet induced folate deficiency affects choline and acetylcholine concentrations 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 weeks. 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 choline and acetylcholine metabolism to folate deficiency was associated with the dysregulation of their metabolism in the peripheral tissues. This accomplishment is significant because it highlights the different effects of folate deficiency amongst age-groups.
4. Development of Non-Invasive Near-Infrared Spectroscopy Measurement System. 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 amount of oxygen it carries to the brain. This development can assist research in the areas of Alzheimer’s disease and other dementias where there is often 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 control rats. This animal model is important because compromised brain circulation may be related to cognitive decline. The new non-invasive NIRS method is helpful in detecting these measurements in rats and in humans.