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issn:1028-415
1.  Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: A preliminary 1H MRS study 
Nutritional neuroscience  2016;19(4):145-155.
Objective
To use proton magnetic resonance spectroscopy (1H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD).
Methods
Metabolite concentrations were determined by 1H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined.
Results
Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (−40%, P < 0.0001) and there was a trend in the low-dose group (−20%, P = 0.06). There were no significant baseline–endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (−12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2).
Discussion
These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.
doi:10.1179/1476830514Y.0000000135
PMCID: PMC5206765  PMID: 24915543
Docosahexaenoic acid; Adolescent; Dorsolateral prefrontal cortex; Anterior cingulated cortex; Proton magnetic resonance spectroscopy; Major depressive disorder
2.  Fetal and neonatal iron deficiency but not copper deficiency increases vascular complexity in the developing rat brain 
Nutritional neuroscience  2015;18(8):365-375.
Objectives
Anemia caused by nutritional deficiencies, such as iron and copper deficiencies, is a global health problem. Iron and copper deficiencies have their most profound effect on the developing fetus/infant, leading to brain development deficits and poor cognitive outcomes. Tissue iron depletion or chronic anemia can induce cellular hypoxic signaling. In mice, chronic hypoxia induces a compensatory increase in brain blood vessel outgrowth. We hypothesized that developmental anemia, due to iron or copper deficiencies, induces angiogenesis/vasculogenesis in the neonatal brain.
Methods
To test our hypothesis, three independent experiments were performed where pregnant rats were fed iron- or copper-deficient diets from gestational day 2 through mid-lactation. Effects on the neonatal brain vasculature were determined using qPCR to assess mRNA levels of angiogenesis/vasculogenesis-associated genes and GLUT1 immunohistochemistry (IHC) to assess brain blood vessel density and complexity.
Results
Iron deficiency, but not copper deficiency, increased mRNA expression of brain endothelial cell- and angiogenesis/vasculogenesis-associated genes (i.e. Glut1, Vwf, Vegfa, Ang2, Cxcl12, and Flk1) in the neonatal brain, suggesting increased cerebrovascular density. Iron deficiency also increased hippocampal and cerebral cortical blood vessel branching by 62% and 78%, respectively.
Discussion
This study demonstrates increased blood vessel complexity in the neonatal iron-deficient brain, which is likely due to elevated angiogenic/vasculogenic signaling. At least initially, this is probably an adaptive response to maintain metabolic substrate homeostasis in the developing iron-deficient brain. However, this may also contribute to long-term neurodevelopmental deficits.
doi:10.1179/1476830515Y.0000000037
PMCID: PMC4681608  PMID: 26177275
Iron deficiency; Copper deficiency; Anemia; Brain; Development; Neovasculogenesis; Angiogenesis; Blood-brain-barrier
3.  Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus 
Nutritional neuroscience  2008;11(4):172-182.
Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study, we investigated whether polyphenols in blueberries can reduce the deleterious effects of inflammation induced by central administration of kainic acid by altering the expression of genes associated with inflammation. To this end, 4-month-old male Fischer-344 (F344) rats were fed a control, 0.015% piroxicam (an NSAID) or 2% blueberry diet for 8 weeks before either Ringer's buffer or kainic acid was bilaterally micro-infused into the hippocampus. Two weeks later, following behavioral evaluation, the rats were killed and total RNA from the hippocampus was extracted and used in real-time quantitative RT-PCR (qRT-PCR) to analyze the expression of inflammation-related genes. Kainic acid had deleterious effects on cognitive behavior as kainic acid-injected rats on the control diet exhibited increased latencies to find a hidden platform in the Morris water maze compared to Ringer's buffer-injected rats and utilized non-spatial strategies during probe trials. The blueberry diet, and to a lesser degree the piroxicam diet, was able to improve cognitive performance. Immunohistochemical analyses of OX-6 expression revealed that kainic acid produced an inflammatory response by increasing the OX-6 positive areas in the hippocampus of kainic acid-injected rats. Kainic acid up-regulated the expression of the inflammatory cytokines IL-1β and TNF-α, the neurotrophic factor IGF-1, and the transcription factor NF-κB. Blueberry and piroxicam supplementations were found to attenuate the kainic acid-induced increase in the expression of IL-1β, TNF-α, and NF-κB, while only blueberry was able to augment the increased IGF-1 expression. These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.
doi:10.1179/147683008X301487
PMCID: PMC5015125  PMID: 18681986
Morris water maze; memory; inflammation; aging; oxidative stress; antioxidants; anti-inflammatories; dietary supplementation; blueberries; piroxicam; OX-6; cytokines; flavonoids
4.  The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis 
Nutritional Neuroscience  2015;18(3):125-136.
Objectives
To explore the association between dietary factors including fat, fruit and vegetable intake, dairy and meat consumption, and health-related quality of life (HRQOL), disability and relapse rate in a large international sample of people with multiple sclerosis (MS).
Methods
Participants with MS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic and clinical characteristics, HRQOL, disability, relapse rate, and the Diet Habits Questionnaire (DHQ).
Results
Of 2469 participants with confirmed MS, 2087 (84.5%) provided complete data on their dietary habits (DHQ total score). Multivariate regression models demonstrated that every 10-point increase on the DHQ total score was associated with nearly a six-point and five-point increase in physical and mental HRQOL, respectively, and 30.0% reduced likelihood of a higher level of disability. After controlling for age and gender, and the other dietary covariates, ‘healthy’ consumption of fruit and vegetables and dietary fat predicted better quality of life and less likelihood of higher disability when compared to respondents with a ‘poor’ diet. For those with relapsing–remitting MS, the DHQ total significantly predicted a lower relapse rate and reduced odds of increasing disease activity, but the model fit was poor and the predicted change only marginal.
Discussion
This study supports significant associations of healthy dietary habits with better physical and mental HRQOL and a lower level of disability. Further research is urgently required to explore these associations including randomized controlled trials of dietary modification for people with MS.
doi:10.1179/1476830514Y.0000000117
PMCID: PMC4485697  PMID: 24628020
Diet; Disability; Multiple sclerosis; Quality of life; Relapse
5.  Environment, dysbiosis, immunity and sex-specific susceptibility: A translational hypothesis for regressive autism pathogenesis 
Nutritional Neuroscience  2015;18(4):145-161.
Background
Autism is an increasing neurodevelopmental disease that appears by 3 years of age, has genetic and/or environmental etiology, and often shows comorbid situations, such as gastrointestinal (GI) disorders. Autism has also a striking sex-bias, not fully genetically explainable.
Objective
Our goal was to explain how and in which predisposing conditions some compounds can impair neurodevelopment, why this occurs in the first years of age, and, primarily, why more in males than females.
Methods
We reviewed articles regarding the genetic and environmental etiology of autism and toxins effects on animal models selected from PubMed and databases about autism and toxicology.
Discussion
Our hypothesis proposes that in the first year of life, the decreasing of maternal immune protection and child immune-system immaturity create an immune vulnerability to infection diseases that, especially if treated with antibiotics, could facilitate dysbiosis and GI disorders. This condition triggers a vicious circle between immune system impairment and increasing dysbiosis that leads to leaky gut and neurochemical compounds and/or neurotoxic xenobiotics production and absorption. This alteration affects the ‘gut-brain axis’ communication that connects gut with central nervous system via immune system. Thus, metabolic pathways impaired in autistic children can be affected by genetic alterations or by environment–xenobiotics interference. In addition, in animal models many xenobiotics exert their neurotoxicity in a sex-dependent manner.
Conclusions
We integrate fragmented and multi-disciplinary information in a unique hypothesis and first disclose a possible environmental origin for the imbalance of male:female distribution of autism, reinforcing the idea that exogenous factors are related to the recent rise of this disease.
doi:10.1179/1476830513Y.0000000108
PMCID: PMC4485698  PMID: 24621061
Environmental autism; Gut dysbiosis; Immune system; Sex bias; Xenobiotics
6.  Differential sensitivity of Pak5, Pak6, and Pak5/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight 
Nutritional neuroscience  2013;17(3):109-115.
Objectives
PAK5 and PAK6 are protein kinases highly expressed in the brain. Previously, we observed that Pak6 knockout mice gained significantly more weight during development than Pak5 knockout mice as well as wild-type controls and double-knockout mice lacking both Pak5 and Pak6. In this study, we assessed the effects of exercise on food intake and weight gain of these mice as well as their sensitivity to the stimulant effects of amphetamine.
Methods
Mice of each genotype were placed in cages with free access to run wheel exercise or in cages without run wheels for a total of 74 days. Food and fluid intake as well as body weight of each mouse were measured on a weekly basis. Finally, mice were given a high dose of amphetamine and activity levels were observed immediately thereafter for 90 minutes. Brains and testes of mice were assayed for protein levels of the estrogen alpha and progesterone receptors.
Results
While run wheel mice consumed significantly more food, they weighed less than non-run wheel mice. In addition, although Pak6 knockout mice consumed the same amount of food as wild-type mice, they were significantly heavier regardless of run wheel condition. Pak5 knockout mice were found to be more active than other genotypes after amphetamine treatment. Finally, protein levels of the progesterone and estrogen alpha receptors were altered in brain and testes of the Pak6 knockout mice.
Discussion
Collectively, these data suggest that PAK6 play a role in weight gain unrelated to exercise and caloric intake and that Pak5 knockout mice are more sensitive to the stimulant effects of amphetamine.
doi:10.1179/1476830513Y.0000000072
PMCID: PMC4365912  PMID: 23710594
PAK; Run wheel; Exercise; Body Weight; Amphetamine
7.  [No title available] 
PMCID: PMC3796166  PMID: 23484464
8.  Damaging effects of a high-fat diet to the brain and cognition: A review of proposed mechanisms 
Nutritional neuroscience  2013;17(6):241-251.
The prevalence of obesity is growing and now includes at least one-third of the adult population in the United States. As obesity and dementia rates reach epidemic proportions, an even greater interest in the effects of nutrition on the brain have become evident. This review discusses various mechanisms by which a high fat diet and/or obesity can alter the brain and cognition. It is well known that a poor diet and obesity can lead to certain disorders such as type II diabetes, metabolic syndrome, and heart disease. However, long-term effects of obesity on the brain need to be further examined. The contribution of insulin resistance and oxidative stress is briefly reviewed from studies in the current literature. The role of inflammation and vascular alterations are described in more detail due to our laboratory’s experience in evaluating these specific factors. It is very likely that each of these factors plays a role in diet-induced and/or obesity-induced cognitive decline.
doi:10.1179/1476830513Y.0000000092
PMCID: PMC4074256  PMID: 24192577
Cognition; Brain Health; Obesity; Inflammation; Cerebrovascularization
9.  Early malnutrition predicts parent reports of externalizing behaviors at ages 9–17 
Nutritional neuroscience  2011;14(4):138-144.
Objective
To determine whether externalizing behaviors are more prevalent in youth who have experienced an episode of malnutrition in the first year of life than in healthy comparison youth.
Method
Parents of previously malnourished youth and a matched healthy comparison group completed a behavior rating scale when the youth were 9–15 years of age and again, 2 years later, when they were 11–17 years of age. Longitudinal multiple regression analysis was applied to evaluate group differences adjusted for baseline age, sex, household standard of living, and maternal depressive symptoms.
Results
Early childhood malnutrition was associated with problems in executive functioning at both occasions. Malnutrition also predicted discernibly higher parent-reported levels of aggression toward peers at 9–15 years than at 11–17 years. These findings were independent of baseline age, sex, household standard of living, and maternal depressive symptoms. Problem behaviors in general decreased during follow-up.
Conclusion
Parents report persisting problems with executive functioning through adolescence in youth who suffered an episode of moderate-to-severe protein-energy malnutrition in the first year of life, while reports of aggression, although more common when this cohort were younger, did not persist at follow-up.
doi:10.1179/147683011X13009738172521
PMCID: PMC4193901  PMID: 21902884
Executive function; Aggression; Malnutrition; Youth; Cross-cultural; Longitudinal study
10.  Prenatal protein malnutrition alters the proportion but not numbers of parvalbumin-immunoreactive interneurons in the hippocampus of the adult Sprague-Dawley rat 
Nutritional neuroscience  2011;14(4):165-178.
Prenatal protein malnutrition alters the structure and function of the adult rat hippocampal formation. The current study examines the effect of prenatal protein malnutrition on numbers of parvalbumin-immunoreactive (PV-IR) GABAergic interneurons, which are important for perisomatic inhibition of hippocampal pyramidal neurons. Brain sections from prenatally protein malnourished and normally nourished rats were stained for parvalbumin and PV-IR neurons were quantified using stereology in the dentate gyrus, CA3/2 and CA1 subfields, and the subiculum for both cerebral hemispheres. Results demonstrated that prenatal malnutrition did not affect the number of PV-IR interneurons in the hippocampus. Since prenatal protein malnutrition reduces total neuron numbers in the CA1 subfield (1), this results in an altered ratio of PV-IR interneurons to total neuronal numbers (from 1:22.9 in controls to 1:20.5 in malnourished rats). Additionally, there was no hemispheric asymmetry of either PV-IR neuron numbers or ratio of PV-IR:total neuron numbers.
doi:10.1179/147683011X13009738172396
PMCID: PMC4139119  PMID: 21902887
Undernutrition; Hemispheric asymmetry; Inhibition; CA1 subfield; CA3 subfield; Stereology
11.  Low docosahexaenoic acid status is associated with reduced indices in cortical integrity in the anterior cingulate of healthy male children: A 1H MRS Study 
Nutritional neuroscience  2013;16(4):183-190.
Docosahexaenoic acid (DHA, 22:6n-3) is the principal omega-3 fatty acid in mammalian brain gray matter, and emerging preclinical evidence suggests that DHA has neurotrophic and neuroprotective properties. This study investigated relationships among DHA status, neurocognitive performance, and cortical metabolism measured with proton magnetic resonance spectroscopy (1H MRS) in healthy developing male children (aged 8–10 years, n = 38). Subjects were segregated into low-DHA (n = 19) and high-DHA (n = 19) status groups by a median split of erythrocyte DHA levels. Group differences in 1H MRS indices of cortical metabolism, including choline (Cho), creatine (Cr), glutamine + glutamate + γ-aminobutyric acid (Glx), myo-inositol (mI), and N-acetyl aspartate (NAA), were determined in the right and left dorsolateral prefrontal cortex (R/L-DLPFC, BA9) and bilateral anterior cingulate cortex (ACC, BA32/33). Group differences in neurocognitive performance were evaluated with the Kaufman Brief Intelligence Test and identical-pairs version of the continuous performance task (CPT-IP). Subjects in the low-DHA group consumed fish less frequently (P = 0.02), had slower reaction times on the CPT-IP (P = 0.007), and exhibited lower mI (P = 0.007), NAA (P = 0.007), Cho (P = 0.009), and Cr (P = 0.01) concentrations in the ACC compared with the high-DHA group. There were no group differences in ACC Glx or any metabolite in the L-DLPFC and R-DLPFC. These data indicate that low-DHA status is associated with reduced indices of metabolic function in the ACC and slower reaction time during sustained attention in developing male children.
doi:10.1179/1476830512Y.0000000045
PMCID: PMC4101902  PMID: 23582513
Docosahexaenoic acid; myo-inositol; dorsolateral prefrontal cortex; Anterior cingulate cortex; Proton magnetic resonance spectroscopy; omega-3 fatty acid; omega-6 fatty acid
12.  Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation 
Nutritional neuroscience  2013;16(4):174-182.
Objectives
Proliferating adult stem cells in the subgranular zone of the dentate gyrus have the capacity not only to divide, but also to differentiate into neurons and integrate into the hippocampal circuitry. The present study identifies several hippocampal genes putatively regulated by zinc and tests the hypothesis that zinc deficiency impairs neuronal stem cell differentiation.
Methods
Genes that regulate neurogenic processes were identified using microarray analysis of hippocampal mRNA isolated from adult rats fed zinc-adequate or zinc-deficient (ZD) diets. We directly tested our hypothesis with cultured human neuronal precursor cells (NT2), stimulated to differentiate into post-mitotic neurons by retinoic acid (RA), along with immunocytochemistry and western analysis.
Results
Microarray analysis revealed the regulation of genes involved in cellular proliferation. This analysis also identified a number of genes known to be involved in neuronal differentiation, including the nuclear RA receptor, retinoid X receptor (RXR), doublecortin, and a transforming growth factor-beta (TGF-β) binding protein (P < 0.05). Zinc deficiency significantly reduced RA-induced expression of the neuronal marker proteins doublecortin and β-tubulin type III (TuJ1) to 40% of control levels (P < 0.01). This impairment of differentiation may be partially mediated by alterations in TGF-β signaling. The TGF-β type II receptor, responsible for binding TGF-β during neuronal differentiation, was increased 14-fold in NT2 cells treated with RA (P < 0.001). However, this increase was decreased by 60% in ZD RA-treated cells (P < 0.001).
Discussion
This research identifies target genes that are involved in governing neurogenesis under ZD conditions and suggests an important role for TGF-β and the trace metal zinc in regulating neuronal differentiation.
doi:10.1179/1476830512Y.0000000043
PMCID: PMC3757569  PMID: 23582512
Hippocampus; Neurogenesis; NT2; RXR; TGF-β
13.  Combined Vitamin C & E deficiency induces motor defects in gulo−/−/SVCT2+/− mice 
Nutritional neuroscience  2012;16(4):10.1179/1476830512Y.0000000042.
Objectives
Key antioxidants, vitamins C and E, are necessary for normal brain development and neuronal function. In this study, we depleted both of these vitamins in two mouse models to determine if oxidative stress due to combined vitamin C and E dietary deficiency altered their neurological phenotype. The first model lacked both alleles for the Gulonolactone oxidase gene (Gulo−/−) and therefore was unable synthesize vitamin C. To obtain an additional cellular deficiency of vitamin C, the second model also lacked one allele for the cellular vitamin C transporter gene (Gulo−/−/SVCT2+/−).
Methods
The experimental treatment was 16 weeks of vitamin E deprivation followed by 3 weeks of vitamin C deprivation. Mice were assessed for motor coordination deficits, vitamin levels, and oxidative stress biomarkers.
Results
In the first model, defects in motor performance were more apparent in both vitamin C-deficient groups (VE+VC−, VE−VC−) compared to vitamin C-supplemented groups (VE+VC+, VE−VC+) regardless of vitamin E level. Analysis of brain cortex and liver confirmed decreases of at least 80% for each vitamin in mice on deficient diets. Vitamin E deficiency doubled oxidative stress biomarkers (F2-isoprostanes and malondialdehyde). In the second model, Gulo−/−/SVCT2+/− mice on the doubly deficient diets showed deficits in locomotor activity, Rota-rod performance, and other motor tasks, with no concomitant change in anxiety or spatial memory.
Discussion
Vitamin E deficiency alone caused a modest oxidative stress in brain that did not affect motor performance. Adding a cellular deficit in vitamin C to dietary deprivation of both vitamins significantly impaired motor performance.
doi:10.1179/1476830512Y.0000000042
PMCID: PMC3869026  PMID: 23321552
Ascorbic acid; Brain; Mouse behavior; Oxidative stress; SVCT2; Vitamin C deficiency; Vitamin E deficiency
14.  Diet-induced effects on neuronal and glial elements in the middle-aged rat hippocampus 
Nutritional neuroscience  2011;14(1):32-44.
Consumption of a high-fat and/or high-cholesterol diet can have detrimental effects on the brain. In the present study, dietary treatment with saturated fats, trans fats, or cholesterol to middle-aged Fischer 344 rats resulted in alterations to serum triglyceride and cholesterol levels, organ weights, and hippocampal morphology. Previously, we demonstrated that a 10% hydrogenated coconut oil and 2% cholesterol diet resulted in worse performance on the 12-day water radial arm maze, increased cholesterol and triglyceride levels, and decreased dendritic microtubule associated protein 2 (MAP2) staining in the hippocampus. The diets administered herein were used to examine components from the previous diet and further examine their effects on hippocampal morphology. Specifically, neuronal morphology, dendritic integrity, fatty acid metabolism, microgliosis, and blood vessel structure in the hippocampus and/or adjacent structures were explored. Our results indicate alterations to peripheral and neural systems following each of the diets.
doi:10.1179/174313211X12966635733358
PMCID: PMC4073499  PMID: 21535919
Saturated fat; Trans fat; Morphology; Aging; Dietary effects
15.  Can a reward-based behavioural test be used to investigate the effect of protein–energy malnutrition on hippocampal function? 
Nutritional neuroscience  2007;10(0):145-150.
Our laboratory is investigating the effects of protein–energy malnutrition (PEM) on cognitive outcome following global ischemia. Here, we investigated whether PEM independently impairs working memory in the T-maze and if the associated food reward reverses PEM. Gerbils were fed 12.5% (control diet) or 2% protein. A loss of body weight (20.1%) in the 2% protein group and decreased food intake and serum albumin concentration compared to controls (17.5% and 18.2%, respectively) indicated that PEM was achieved. Based on T-maze criterion frequently used in ischemia studies, no difference was observed in the mean (±SEM) number of trials required (control 5.2 ± 0.7; PEM 4.9 ± 0.4; p = 0.758) or the number of animals reaching criterion (control 10/12; PEM 12/12; p = 0.140). Using more stringent criterion, PEM animals required fewer trials (control 7.3 ± 0.7; PEM 5.4 ± 0.4; p = 0.035), and more reached criterion (control 8/12; PEM 12/12; p = 0.028). PEM may increase motivation to obtain a food reward.
PMCID: PMC3859586  PMID: 18019396 CAMSID: cams3783
Protein–energy malnutrition; gerbil; T-maze; reward; nutrition; global ischemia
16.  Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates 
Nutritional neuroscience  2012;16(1):10.1179/1476830512Y.0000000024.
Objectives
Xanthophyll pigments lutein and zeaxanthin cross the blood-retina barrier to preferentially accumulate in the macular region of the neural retina. There they form macular pigment, protecting the retina from blue light damage and oxidative stress. Lutein and zeaxanthin also accumulate in brain tissue. The objective of the study was to evaluate the relationship between retinal and brain levels of these xanthophylls in non-human primates.
Methods
Study animals included rhesus monkeys reared on diets devoid of xanthophylls that were subsequently fed pure lutein or pure zeaxanthin (both at 3.9 μmol/kg*d, n=6/group) and normal rhesus monkeys fed a stock diet (0.26 μmol/kg*d lutein and 0.24 μmol/kg*d zeaxanthin, n=5). Retina (4 mm macular punch, 4-8 mm annulus and periphery) and brain tissue (cerebellum, frontal cortex, occipital cortex and pons) from the same animals were analyzed by reverse phase HPLC.
Results
Lutein in the macula and annulus were significantly related to lutein levels in the cerebellum, occipital cortex and pons, both in bivariate analysis and after adjusting for age, sex and n–3 fatty acid status. In the frontal cortex the relationship was marginally significant. Macular zeaxanthin was significantly related to zeaxanthin in the cerebellum and frontal cortex, while the relationship was marginally significant in the occipital cortex and pons in a bivariate model.
Discussion
An integrated measure of total macular pigment optical density, which can be measured noninvasively, has the potential to be used as a biomarker to assess brain lutein and zeaxanthin status.
doi:10.1179/1476830512Y.0000000024
PMCID: PMC3824968  PMID: 22780947
brain; cognition; lutein; macula; zeaxanthin
17.  Infant malnutrition predicts conduct problems in adolescents 
Nutritional neuroscience  2012;15(4):186-192.
Objectives
The purpose of this study was to compare the prevalence of conduct problems in a well-documented sample of Barbadian adolescents malnourished as infants and a demographic comparison group and to determine the extent to which cognitive impairment and environmental factors account for this association.
Methods
Behavioral symptoms were assessed using a 76-item self-report scale in 56 Barbadian youth (11–17 years of age) with histories of protein–energy malnutrition (PEM) limited to the first year of life and 60 healthy classmates. Group comparisons were carried out by longitudinal and cross-sectional multiple regression analyses at 3 time points in childhood and adolescence.
Results
Self-reported conduct problems were more prevalent among previously malnourished youth (P < 0.01). Childhood IQ and home environmental circumstances partially mediated the association with malnutrition. Teacher-reported classroom behaviors at earlier ages were significantly correlated with youth conduct problems, confirming the continuity of conduct problems through childhood and adolescence.
Discussion
Self-reported conduct problems are elevated in children and adolescents with histories of early childhood malnutrition. Later vulnerability to increased conduct problems appears to be mediated by the more proximal neurobehavioral effects of the malnutrition on cognitive function and by adverse conditions in the early home environment.
doi:10.1179/1476830512Y.0000000012
PMCID: PMC3782078  PMID: 22584048
Conduct problem; Malnutrition; Adolescence; Cross-cultural; Longitudinal study
18.  Oil palm phenolics confer neuroprotective effects involving cognitive and motor functions in mice 
Nutritional Neuroscience  2013;16(5):207-217.
Objectives
Phenolics are important phytochemicals which have positive effects on chronic diseases, including neurodegenerative ailments. The oil palm (Elaeis guineensis) is a rich source of water-soluble phenolics. This study was carried out to discover the effects of administering oil palm phenolics (OPP) to mice, with the aim of identifying whether these compounds possess significant neuroprotective properties.
Methods
OPP was given to BALB/c mice on a normal diet as fluids for 6 weeks while the controls were given distilled water. These animals were tested in a water maze and on a rotarod weekly to assess the effects of OPP on cognitive and motor functions, respectively. Using Illumina microarrays, we further explored the brain gene expression changes caused by OPP in order to determine the molecular mechanisms involved. Real-time quantitative reverse transcription-polymerase chain reaction experiments were then carried out to validate the microarray data.
Results
We found that mice given OPP showed better cognitive function and spatial learning when tested in a water maze, and their performance also improved when tested on a rotarod, possibly due to better motor function and balance. Microarray gene expression analysis showed that these compounds up-regulated genes involved in brain development and activity, such as those under the regulation of the brain-derived neurotrophic factor. OPP also down-regulated genes involved in inflammation.
Discussion
These results suggest that the improvement of mouse cognitive and motor functions by OPP is caused by the neuroprotective and anti-inflammatory effects of the extract.
doi:10.1179/1476830512Y.0000000047
PMCID: PMC3736891  PMID: 23433062
Antioxidants; Gene expression; Microarray; Neurodegeneration; Oil palm phenolics
19.  Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice 
Nutritional neuroscience  2009;12(5):203-218.
The present study investigated the relationships among oxidative stress, β-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer’s disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1g/kg diet, Expt. 1) or in combination with a high (750 IU/kg diet, Expts. 1 and 2) or lower (400 IU/kg diet, Expt. 2) dose of vitamin E. Oxidative stress, measured by F4-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low EC diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2 the lower vitamin EC treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.
doi:10.1179/147683009X423364
PMCID: PMC3730134  PMID: 19761651
Vitamin C; Vitamin E; oxidative stress; Alzheimer’s disease; cognition
20.  Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins 
Nutritional neuroscience  2011;14(5):226-236.
Epidemiological studies have demonstrated that the consumption of fruits and vegetables is associated with reduced risk for cardiovascular disease and stroke. Detailed investigations into the specific dietary components of these foods have revealed that many polyphenolic constituents exert anti-oxidant effects on key substrates involved in the pathogenesis and progression of ischemic injury. These data have perpetuated the belief that the protective effects of flavonoids result from direct anti-oxidant actions at the levels of the cerebral vasculature and brain parenchyma. While many in vitro studies using purified extracts support this contention, first-pass metabolism alters the bioavailability of flavonoids such that the achievable concentrations after oral consumption are not consistent with this mechanism. Importantly, oral consumption of flavonoids may promote neural protection by facilitating the expression of gene products responsible for detoxifying the ischemic microenvironment through both anti-oxidative and anti-inflammatory actions. In particular, the transcriptional factor nuclear factor erythroid 2-related factor 2 has emerged as a critical regulator of flavonoid-mediated protection through the induction of various cytoprotective genes. The pleiotropic effects associated with potent transcriptional regulation likely represent the primary mechanisms of neural protection, as the flavonoid concentrations reaching ischemic tissues in vivo are sufficient to alter intracellular signal transduction but likely preclude the one-to-one stoichiometry necessary to confer protection by direct anti-oxidation. These data reflect an exciting new direction in the study of complementary and alternative medicine that may lead to the development of novel therapies for ischemic/hemorrhagic stroke, traumatic brain injury, and other neurological disorders.
doi:10.1179/1476830511Y.0000000013
PMCID: PMC3443635  PMID: 22005287
Ischemia; Nuclear factor (erythroid-derived 2)-like 2; Polyphenol; Stroke; Therapy; Complementary and alternative medicine
21.  Natural mood foods: The actions of polyphenols against psychiatric and cognitive disorders 
Nutritional Neuroscience  2012;15(3):127-133.
Objectives
Polyphenols, natural compounds found in plant-based foods, possess special properties that can battle oxidative stress and stimulate the activation of molecules that aid in synaptic plasticity, a process that underlies cognitive function. Unlike many traditional treatments, polyphenols affect a broad range of mechanisms in the brain that can assist in the maintenance of cognitive and mental health, as well as the recovery from neurodegenerative diseases. Examining the molecular basis underlying the link between food intake and brain function has presented the exciting possibility of using diet as a viable method to battle cognitive and psychiatric disorders.
Methods
We will discuss the molecular systems that link polyphenols, the gut, and the brain, as well as introduce published human and animal studies demonstrating the effects of polyphenol consumption on brain plasticity and cognition.
Results
By influencing cellular energy metabolism and modulating the signaling pathways of molecules involved with brain plasticity, dietary factors – formerly recognized for just their effects on bodily systems – have emerged as affecters of the brain.
Conclusion
Thus, the consumption of diets enriched with polyphenols may present the potential of dietary manipulation as a non-invasive, natural, and inexpensive therapeutic means to support a healthy brain.
doi:10.1179/1476830511Y.0000000035
PMCID: PMC3355196  PMID: 22334236
BDNF; Cognition; Metabolism; Polyphenol; Psychiatric disorder; Synaptic plasticity
22.  Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus 
Nutritional neuroscience  2011;14(2):59-65.
Objective
Perinatal iron deficiency results in persistent hippocampus-based cognitive deficits in adulthood despite iron supplementation. The objective of the present study was to determine the long-term effects of perinatal iron deficiency and its treatment on hippocampal anatomy and neurochemistry in formerly iron-deficient young adult rats.
Methods
Perinatal iron deficiency was induced using a low-iron diet during gestation and the first postnatal week in male rats. Hippocampal size was determined using volumetric magnetic resonance imaging at 8 weeks of age. Hippocampal neurochemical profile, consisting of 17 metabolites indexing neuronal and glial integrity, energy reserves, amino acids, and myelination, was quantified using high-field in vivo 1H NMR spectroscopy at 9.4 T (N = 11) and compared with iron-sufficient control group (N = 10).
Results
The brain iron concentration was 56% lower than the control group at 7 days of age in the iron-deficient group, but had recovered completely at 8 weeks. The cross-sectional area of the hippocampus was decreased by 12% in the formerly iron-deficient group (P = 0.0002). The hippocampal neurochemical profile was altered: relative to the control group, creatine, lactate, N-acetylaspartylglutamate, and taurine concentrations were 6–29% lower, and glutamine concentration 18% higher in the formerly iron-deficient hippocampus (P < 0.05).
Discussion
Perinatal iron deficiency was associated with reduced hippocampal size and altered neurochemistry in adulthood, despite correction of brain iron deficiency. The neurochemical changes suggest suppressed energy metabolism, neuronal activity, and plasticity in the formerly iron-deficient hippocampus. These anatomic and neurochemical changes are consistent with previous structural and behavioral studies demonstrating long-term hippocampal dysfunction following perinatal iron deficiency.
doi:10.1179/1476830511Y.0000000001
PMCID: PMC3170050  PMID: 21605501
Hippocampus; 1H NMR spectroscopy; Iron; Newborn; Perinatal iron deficiency
23.  Iron Deficiency in Infancy and Neurocognitive Functioning at 19 Years: Evidence of Long-Term Deficits in Executive Function and Recognition Memory 
Nutritional neuroscience  2010;13(2):54-70.
Iron deficiency in infancy negatively impacts a variety of neurodevelopmental processes at the time of nutrient insufficiency, with persistent central nervous system alterations and deficits in behavioral functioning, despite iron therapy. In rodent models, early iron deficiency impairs the hippocampus and the dopamine system. We examined the possibility that young adults who had experienced chronic, severe iron deficiency as infants would exhibit deficits on neurocognitive tests with documented frontostriatal (Trail Making Test, Intra-/Extra-dimensional Shift, Stockings of Cambridge, Spatial Working Memory, Rapid Visual Information Processing) and hippocampal specificity (Pattern Recognition Memory, Spatial Recognition Memory). Participants with chronic, severe iron deficiency in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning. There was also evidence of impairment on a hippocampus-based recognition memory task. We suggest that these deficits may result from the long-term effects of early iron deficiency on the dopamine system, the hippocampus, and their interaction.
doi:10.1179/147683010X12611460763689
PMCID: PMC3151652  PMID: 20406573
Iron deficiency; development; memory; executive functioning
24.  High dietary cholesterol facilitates classical conditioning of the rabbit’s nictitating membrane response 
Nutritional neuroscience  2007;10(1-2):31-43.
Studies have shown that modifying dietary cholesterol may improve learning and that serum cholesterol levels can be positively correlated with cognitive performance. Rabbits fed a 0, 0.5, 1 or 2% cholesterol diet for eight weeks and 0.12ppm copper added to their drinking water received trace and then delay classical conditioning pairing tone with corneal air puff during which movement of the nictitating membrane (NM) across the eye was monitored. We found that the level of classical conditioning and conditioning-specific reflex modification (CRM) as well as the number of beta amyloid-labeled neurons in the cortex and hippocampus were a function of the concentration of cholesterol in the diet. The data provide support for the idea that dietary cholesterol may facilitate learning and memory.
PMCID: PMC3115564  PMID: 17539481
Beta amyloid; cholesterol; classical conditioning; nictitating membrane response; learning; rabbit
25.  Classical conditioning of the rabbit’s nictitating membrane response is a function of the duration of dietary cholesterol 
Nutritional neuroscience  2007;10(3-4):159-168.
Modifying dietary cholesterol may improve learning and memory but very high cholesterol can cause pathophysiology and death. Rabbits fed 2% cholesterol for 8, 10 or 12 weeks with 0.12 ppm copper added to distilled water and rabbits fed a normal diet without copper added to distilled water (0 weeks) were given a difficult trace classical conditioning task and an easy delay conditioning task pairing tone with corneal air puff. The majority of cholesterol-fed rabbits survived the deleterious effects of the diet but survival was an inverse function of the diet duration. Compared to controls, the level of classical conditioning and conditioning-specific reflex modification were an inverted “U”-shaped function of diet duration. Highest levels of responding occurred in rabbits on cholesterol for 10 weeks and trace conditioning was negatively correlated with the number of hippocampal β-amyloid-positive neurons. Rabbits on the diet for 12 weeks responded at levels comparable to controls. The data provide support for the idea that dietary cholesterol may facilitate learning and memory but there is an eventual trade off with pathophysiological consequences of the diet.
PMCID: PMC3115567  PMID: 18019398
β-Amyloid; cholesterol; classical conditioning; nictitating membrane response; learning; rabbit

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