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 transgenic and 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
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.
1. Demonstration of the relationship between brain blood vessel pathology and 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 animals. These declining cognitive functions in folate-deficient animals were demonstrated to be accompanied by a decrease in the capillary blood supply 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.
2. Folate and choline are two metabolically related essential nutrients which 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.
3. 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 effect of vitamin K on brain myelin, a well-known contributor to age-related cognitive decline. Our findings of a positive relationship between myelin fat and concentration of vitamin K in blood suggest that this animal model may be useful for investigation of the effect of the dietary vitamin K on fat metabolism and behavior functions in humans.
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.