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United States Department of Agriculture

Agricultural Research Service

Research Project: NEUROCOGNITION/NEUROSCIENCE
2011 Annual Report


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.

LAB: Neuroscience 1. Use cell models to develop mechanistic interpretations of the positive benefits of berry polyphenols and fatty acids by examining their direct effects on deficits in stress and protective signaling.

2. Establish the effects of dietary berry fruit extracts and/or fatty acids on behavioral and neuronal deficits in aging to assess the mechanisms involved and the most effective polyphenols/fatty acids in animal and human models.


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.

LAB: Neuroscience The focus of the current project is to elucidate the mechanisms involved in the beneficial effects of berry fruit and polyunsaturated fatty acids (PUFAs) from fish or nut oils on reducing neurodegeneration mediated by oxidative stress (OS) and inflammation (INF). Mixed neuron/ glial cultures obtained from rats of different ages will be employed to delineate the neuroprotective effects of berry fruit or PUFA against OS/INF and subsequent stress mediated by glial cells. Additionally, muscarinic receptor-transfected COS-7 cells will be used to assess OS/INF localization and the effects of membrane lipids on the cellular responses to OS/INF. Extensive motor and cognitive assessments will also be made of senescent animals fed diets containing berry fruit or PUFAs. Finally, we will translate the behavioral findings obtained in our animal studies to the human condition by examining the effects of berry fruit or walnut supplementation on human gait and motor ability. This project will contribute to fundamental new knowledge of the putative role of berry fruit and PUFAs on reducing OS/INF and behavioral deficits in aging. These studies will span basic cellular signaling, animal behavior and cognition, and human motor abilities, allowing for a comprehensive examination of the beneficial effects of berry fruit and nutritional PUFAs on the aging brain.


3.Progress Report
We have shown that supplementation with fruits, vegetables, and nuts can forestall and reverse the deleterious effects of aging on neuronal (brain cell) functioning and behavior. While polyphenolic compounds found in these foods may have direct effects on oxidative stress (OS) and inflammation in aging, they also may enhance protective cellular communication (signaling) neuronal housekeeping (autophagy), and neuronal growth. Discovery of these additional mechanisms might lead to important dietary information for an aging population. Additionally, determining which components might be responsible for the beneficial effects is also important, although it might be that the combination of polyphenols or fatty acids present in berries or nuts may have synergistic effects which provide increased protection from age-related declines relative to individual constituent compounds. This year we continued to study the mechanisms responsible for the beneficial effects of berry fruit and fatty acids and whether or not whole foods were better than individual components, using brain cells (in vitro) and animal models. We showed that both acai fruit (and its individual components) and walnuts were able to rescue neurons through induction of autophagy, a process by which toxic debris is recycled and cleared in neurons. We continued studies showing that berry fruit, particularly acai, reduced oxidative stress and inflammation caused by chemicals, in different types of brain cells such as microglia, astrocytes, and neurons. The berries were able to protect neurons through auxiliary effects on astrocytes when they were co-cultured with the neurons, as they are in the brain. Additionally, we began to examine individual components from berry fruit and fatty acids from walnuts to determine which might be responsible for their beneficial effects. We showed that different components of the berries and walnuts were effective against inflammatory and oxidative stress in brain cells, although the whole fruit or nut was also effective, and not toxic like the individual components. Another study indicated that different components of blueberries (i.e., stilbenes and anthocyanins) were effective in preventing stress-induced calcium imbalance and inflammation, but the stilbenes were more effective than the anthocyanins. We continued to examine whether the specific polyphenolic components in the different berries work differentially to produce their beneficial effects. Using brain cells we carried out experiments to examine various treatment durations and doses for the blueberries (BBs) and strawberries (SBs), individually and in combination, on inflammatory markers to elucidate individual vs. synergistic effects. We found that in general, BB was more effective than SB and that combinations were not more effective than BB alone. In an animal study, we examined the effects of BB and SB or their combination on cognition and decreases in inflammation; this work is still ongoing. Therefore, it may be that the individual polyphenols in the different berries might exert their effects through different and/or independent mechanisms.


4.Accomplishments
1. Lab: Nutrition & Neurocognition. 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. Lab: Nutrition & Neurocognition. 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. Lab: Nutrition & Neurocognition. 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. Lab: Nutrition & Neurocognition. 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.

5. LAB: Nutrition and Neuroscience. Walnuts and their fatty acids protect brain cells. Walnuts, which are rich in polyunsaturated fatty acids (PUFAs) and other phytonutrients, have been demonstrated to improve memory and cognition in aging. Part of the loss in cognitive function in aging may be due to oxidative and inflammatory stress-induced loss of cellular calcium buffering ability. Therefore, ARS researchers at JMUSDA-HNRCA at Tufts University in Boston, MA, carried out experiments in neurons (brain cells) to examine if pretreatment with walnut extract or the PUFAs in walnuts would protect against cell death and calcium dysregulation due to oxidative stress and inflammation. The data indicate that the whole walnut and omega-3 fatty acids, but not omega-6 fatty acids, protect against age-related cellular dysfunction via antioxidant and anti-inflammatory mechanisms and demonstrate that not all PUFAs are equivalent in their beneficial effects. We submitted a manuscript detailing these results this year.

6. LAB: Nutrition and Neuroscience. Acai fruit extracts protect brain cells following stress. Acai fruit is a popular Amazonian fruit and emerging evidence suggests that it may have health-promoting antioxidant and anti-inflammatory properties. ARS researchers at JMUSDA-HNRCA at Tufts University researchers in Boston, MA, found that microglial cells (a type of brain glial cell) pretreated with acai fruit extracts were better able to recover from an induced inflammation than were untreated cells. This protection of microglial cells by acai pulp extracts was also accompanied by concentration-dependent reductions in inflammatory mediators. These results indicate that acai fruit can reduce stress-mediated signaling, which is one mechanism to combat some of the inflammatory and oxidative mediators of aging at the cellular level. Additionally, acai fruit seems to have benefits on neuroprotection beyond the traditionally known antioxidant effects and the protective effects of acai fruit on brain cells could have implications for improved cognitive functions. We submitted a manuscript detailing these results this year.

7. LAB: Nutrition and Neuroscience. Completion of all follow up of cognitive status for the FACT study (FAVORIT [Folic Acid for Vascular Outcome Reduction in Transplantation] Ancillary Cognitive Trial). Blood homocysteine is a marker for increased risk of cerebrovascular disease, stroke, and cognitive decline. ARS researchers at JMUSDA-HNRCA at Tufts University in 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. ARS funded researchers from Tufts University in Boston, MA were also able to find that hyperhomocysteinemia and B-vitamin deficiency may be treatable risk factors for cognitive decline.


Review Publications
Malin, D.H., Lee, D.R., Goyarzu, P., Chang, Y., Ennis, L.J., Beckett, E., Shukitt Hale, B., Joseph, J.A. 2011. Short-term blueberry-enriched antioxidant diet prevents and reverses object recognition memory loss in aged rats. Nutrition. 27:338-342.

Rabin, B.M., Joseph, J.A., Shukitt Hale, B., Carrihill-Knoll, K. 2012. Interaction between age of irradiation and age of testing in the disruption of operant performance using a ground-based model for exposure to cosmic rays. American Aging Association. 34:121-131.

Rabin, B.M., Carrihill-Knoll, K., Shukitt Hale, B. 2011. Operant responding following exposure to HZE particles and its relationship to particle energy and LET. Advances in Space Research. 48:370-377.

Popkin, B.M., D'Anci, K.E., Rosenberg, I.H. 2010. Water, hydration, and health. Nutrition Reviews. 68(8):439-458.

Crivello, N., Blusztajn, J., Joseph, J.A., Shukitt Hale, B., Smith, D. 2010. Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age. Nutrition Research. 30(10):722-730.

Elks, C.M., Mariappan, N., Shukitt Hale, B., Joseph, J.A., Ingram, D.K., Francis, J. 2011. A blueberry enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress. PLoS One. 6(9)e24028.

Last Modified: 11/25/2014
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