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 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.
1. Near Infrared Spectroscopy approach for assessing cerebral vascular health. 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 cells. 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 resulting 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 health together with the ability to detect the first signs of dysfunction.
2. The methylenetetrahydrofolate reductase gene C677T polymorphism is not associated with cognitive dysfunction and depression in folate-sufficient 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 evaluated 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.
3. Higher intakes of added sugars and sugar-sweetened beverages is associated 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 Tufts 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 greater intakes of total sugars, added sugars, and sugar-sweetened beverages, but 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.
4. Brain imaging patterns can predict risk of falling in the elderly. In the 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, and Boston Medical Center evaluated whether individuals who are assessed to be 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 understand why certain individuals are at higher risk of falling and will aid in assessing this risk and making recommendations for physical activity.
5. 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-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts in 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 important. 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.
6. 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 deficiency, there are changes in brain chemistry. These results highlight age-related differential sensitivity to vitamin B deficiency and the need to evaluate the longer-term effects of vitamin B deficiency on neurocognition.