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United States Department of Agriculture

Agricultural Research Service

Research Project: NEUROCOGNITION/NEUROSCIENCE
2012 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 walnuts and acai fruit pulp protect brain cells against stresses by attenuating oxidative stress and inflammation and by activating autophagy, a process by which toxic debris is recycled and cleared in neurons. These effects are seen in areas of the brain critical for motor function, learning and memory. We continued studies using exposure to cosmic rays as a model of accelerated aging. This exposure caused an increase in the number of highly toxic insoluble tau inclusions in neurons; these accumulations were prevented by pre-feeding the animals with blueberry or strawberry diets. Damaged tau proteins have been implicated in dementias such as Alzheimer’s Disease. We began testing several fruits/vegetables for their beneficial effects in reversing age-related deficits in behavioral and brain function when fed to old rats. We fed aged animals different species of acai fruit, tart cherries, or mushrooms at various doses and tested the rats on a battery of motor and cognitive tests. These foods were able to protect against age-induced deficits in behavior and we plan to further analyze this data and correlate the results with brain antioxidant and/or anti-inflammatory levels, as well as measures of signaling and autophagy, to understand the mechanisms of action through which the polyphenols in these foods could be producing their effects. Additionally, using consumption of a high fat diet as a model for increased brain inflammation and behavioral deficits, we showed that feeding mice a blueberry diet, along with a high fat diet, mitigated some of the adverse effects of the high fat diet on recognition memory. Therefore, perhaps small changes to a poor diet, such as incorporating more nutrient-dense foods, may allay or prevent the memory dysfunctions associated with consumption of a high fat diet. This report includes work of one HNRCA subordinate project funded via a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information, 1950-51000-070-12S(Nutritional determinants of brain aging and cognitive decline)


4.Accomplishments
1. Walnut-supplemented diet protects brain from age-associated toxic accumulation. Aging is a universal risk factor in many chronic diseases, biologically characterized by increases in oxidative and inflammatory stress, and accumulation of toxic debris in the brain. Walnuts, which are rich in polyunsaturated fatty acids (PUFAs) and other nutrients, have been demonstrated to improve learning and memory in aging. Therefore, ARS researchers at JMUSDA-HNRCA at Tufts University in Boston, MA found that feeding aged animals diets containing 6 or 9% walnuts, equivalent to 1-1.5oz/day for humans, protected brain cells by activating the brain’s natural housekeeping mechanisms. These results show the mechanisms of action of the walnut extend beyond the traditionally known antioxidant and anti-inflammatory benefits to neuronal housekeeping.

2. Exposure to cosmic rays causes accelerated aging. Exposure to high energy and charge radiation (cosmic rays) has been shown to cause memory, learning and behavioral deficits in young animals. ARS researchers at JMUSDA-HNRCA at Tufts University in Boston, MA, in collaboration with researchers at University of Maryland-Baltimore County, reported that cosmic rays cause biological damages to the brain cells of young animals similar to that seen in old animals – damages commonly known as “accelerated aging”. The radiation caused substantial accumulation of biological debris in the brain which is often toxic and a known cause of many diseases of the brain.

3. Stilbenes, found in blueberries, reduce inflammation in brain cells. It is not known whether the beneficial effects of blueberries on the aging brain are due to one specific component or a synergism of multiple components found in blueberries. Two stilbene compounds (pterostilbene and resveratrol) found in blueberries may contribute to these beneficial effects by decreasing both inflammatory and oxidative stress ARS researchers at JMUSDA-HNRCA at Tufts University in Boston, MA found that, in addition to whole blueberries, pterostilbene and resveratrol, as well as two anthocyanins found in blueberries, effectively curtailed the release of toxic substances from microglia (a type of brain immune cell). However, much higher concentrations of the individual components than that found in blueberries were needed to demonstrate this effect. These results suggest that the protective effects of blueberries on the brain may be due to a synergism of the activity of the compounds found in blueberries, and thus eating the whole fruit might be more beneficial than consuming any one component. These results lend further support that blueberries and their active components have the potential to contribute to “health span” in aging, as they are able to combat some of the inflammatory mediators of aging at the cellular level.

4. LAB: Neurocognition: 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, MA, 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.

5. 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, MA 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.

6. 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, MA 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.

7. 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, MA, 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.

8. 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, MA 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.

9. 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, MA 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 shortterm 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.


Review Publications
Poulose, S.M., Bielinski, D., Carrihill-Knoll, K., Rabin, B.M., Shukitt Hale, B. 2011. Exposure to O-16 particle irradiation causes age-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy.Radiation Research. 176:761-769.

Poulose, S.M., Fisher, D.R., Larson, J., Bielinski, D.F., Rimando, A.M., Carey, A.N., Schauss, A.G., Shukitt Hale, B. 2012. Anthocyanin-rich acai (Euterpe oleracea mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cells. Journal of Agricultural and Food Chemistry. 60:1084-1093.

Joseph, J.J., Shukitt Hale, B., Willis, L. 2010. Mitigation of oxidative stress and inflammatory signaling by fruit and walnut polyphenols: implications for cognitive aging. In: Santos-Buelga, C., Escribano-Bailon, M., Lattanzio V., editors. Recent Advances in Polyphenol Research. Volume 2. Oxford, England: Blackwell Publishing Ltd. 2:283-293.

Chang, J., Rimando, A.M., Pallas, M., Camins, A., Porquet, D., Reeves, J., Shukitt Hale, B., Smith, M.A., Joseph, J.A., Casadesus, G. 2011. Low-dose pterostilbene but not resveratrol is a potent neuromodulator in aging and Alzheimer’s Disease. Neurobiology of Aging. 33:2062-2071.

Miller, M.G., Shukitt Hale, B. 2012. Coffee and Alzheimer’s disease - animal & cellular evidences. In: Chu, YiFang, editor. Coffee: Emerging Health Effects and Disease Prevention. New York, NY: John Wiley. p. 77-96.

Poulose, S.M., Shukitt Hale, B. 2012. Effects of flavonoids on cognitive performance. In: Spencer, J., Crozier, A., editors. Flavonoids and Related Compounds: Bioavailability and Function. United Kingdom: Taylor and Francis Group LLC, CRC Press. p. 393-411.

Carey, A.N., Poulose, S.M., Shukitt Hale, B. 2012. The beneficial effects of tree nuts on the aging brain. Nutrition and Aging. 1:55-67.

Miller, M., Shukitt Hale, B. 2012. Berry fruit enhances beneficial signaling in brain. Journal of Agricultural and Food Chemistry. 60:5709-5715.

Poulose, S., Bielinski, D., Shukitt Hale, B. 2012. Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats. Journal of Nutritional Biochemistry. DOI: 10.1016/j.jnutbio.2012.06.09.

Troen, A., Scott, T., D'Anci, K., Moorthyk, D., Dobson, B., Rogers, G., Weiner, D., Levey, A., Dallal, G., Jacques, P., Selhub, J., Rosenberg, I. 2012. Cognitive dysfunction and depression in adult kidney transplant recipients: baseline findings from the FAVORIT Ancillary Cognitive Trial (FACT). Journal of Renal Nutrition. 22(2):268-276.e1-3.

Moorthy, D., Inga, P., Scott, T.M., Parnell, L.D., Lai, C., Crott, J.W., Ordovas, J.M., Selhub, J., Griffith, J., Rosenberg, I.H., Tucker, K.L., Troen, A.M. 2012. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. Journal of Nutrition. 142(8):1554-1560.

Sorensen, E., Sarnak, M., Tighiouart, H., Scott, T., Giang, L., Kirkpatrick, B., Lou, K., Weiner, D. 2012. The kidney disease quality of life cognitive function subscale and cognitive performance maintenance hemodialysis patients. American Journal of Kidney Diseases. DOI: 10.1053/j.ajkd.2011.12.029.

Koo, B., Bergethon, P., Qui, W., Scott, T., Hussain, M., Rosenberg, I., Caplan, L.R., Bhadelia, R.A. 2012. Clinical prediction of fall risk and white matter abnormalities: a diffusion tensor imaging study. Archives of Neurology. 69(9):733-738.

Shukitt Hale, B. 2012. Blueberries and neuronal aging. Gerontology Journal. 58:518-523.

Koo, B., Bergethon, P., Qui, W., Scott, T., Hussain, M., Rosenberg, I., Caplan, L., Bhadelia, R. 2012. Clinical prediction of fall risk and white matter abnormalities: a diffusion tensor imaging study. Archives of Neurology. 69(6):733-738.

Last Modified: 10/24/2014
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