Oyonumo Ntekim

A standardized randomized 6-month aerobic exercise-training down-regulated pro-inflammatory genes, but up-regulated anti-inflammatory, neuron survival and axon growth-related genes.

There is considerable support for the view that aerobic exercise may confer cognitive benefits to mild cognitively impaired elderly persons. However, the biological mechanisms mediating these effects are not entirely clear. As a preliminary step towards informing this gap in knowledge, we enrolled older adults confirmed to have mild cognitive impairment (MCI) in a 6-month exercise program. Male and female subjects were randomized into a 6-month program of either aerobic or stretch (control) exercise. Data collected from the first 10 completers, aerobic exercise (n=5) or stretch (control) exercise (n=5), were used to determine intervention-induced changes in the global gene expression profiles of the aerobic and stretch groups. Using microarray, we identified genes with altered expression (relative to baseline values) in response to the 6-month exercise intervention. Genes whose expression were altered by at least two-fold, and met the p-value cutoff of 0.01 were inputted into the Ingenuity Pathway Knowledge Base Library to generate gene-interaction networks. After a 6-month aerobic exercise-training, genes promoting inflammation became down-regulated, whereas genes having anti-inflammatory properties and those modulating immune function or promoting neuron survival and axon growth, became up-regulated (all fold change≥±2.0, p<0.01). These changes were not observed in the stretch group. Importantly, the differences in the expression profiles correlated with significant improvement in maximal oxygen uptake (VO2max) in the aerobic program as opposed to the stretch group. We conclude that three distinct cellular pathways may collectively influence the training effects of aerobic exercise in MCI subjects. We plan to confirm these effects using rt-PCR and correlate such changes with the cognitive phenotype.

APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: A pilot study

Abstract Possession of the Apolipoprotein E (APOE) gene &egr;4 allele is the most prevalent genetic risk factor for late onset Alzheimers disease (AD). Recent evidence suggests that APOE genotype differentially affects the expression of brain‐derived neurotrophic factor (BDNF). Notably, aerobic exercise‐induced upregulation of BDNF is well documented; and exercise has been shown to improve cognitive function. As BDNF is known for its role in neuroplasticity and survival, its upregulation is a proposed mechanism for the neuroprotective effects of physical exercise. In this pilot study designed to analyze exercise‐induced BDNF upregulation in an understudied population, we examined the effects of APOE&egr;4 (&egr;4) carrier status on changes in BDNF expression after a standardized exercise program. African Americans, age 55 years and older, diagnosed with mild cognitive impairment participated in a six‐month, supervised program of either stretch (control treatment) or aerobic (experimental treatment) exercise. An exercise‐induced increase in VO2Max was detected only in male participants. BDNF levels in serum were measured using ELISA. Age, screening MMSE scores and baseline measures of BMI, VO2Max, and BDNF did not differ between &egr;4 carriers and non‐&egr;4 carriers. A significant association between &egr;4 status and serum BDNF levels was detected. Non‐&egr;4 carriers showed a significant increase in BDNF levels at the 6 month time point while &egr;4 carriers did not. We believe we have identified a relationship between the &egr;4 allele and BDNF response to physiologic adaptation which likely impacts the extent of neuroprotective benefit gained from engagement in physical exercise. Replication of our results with inclusion of diverse racial cohorts, and a no‐exercise control group will be necessary to determine the scope of this association in the general population. HighlightsOlder adult men but not women demonstrate exercise‐induced increases in VO2Max.Exercise‐induced up‐regulation of BDNF varies by APOE genotype.Muted BDNF response to physiological adaptations may explain &egr;4‐related AD risk.

Best strategies to recruit and enroll elderly Blacks into clinical and biomedical research

Background Historically, Blacks have been disproportionately underrepresented in clinical trials. Outcomes associated with low Blacks’ participation in research include poor understanding of the predictors and treatment of the disease, increasing health disparities, poor health equity, and suboptimal wellness of the nation as a whole. To address this gap in research participation, we analyzed our recruitment data to identify the most effective strategies for enrolling older Blacks in clinical trials. Methods Data used in these analyses were obtained from 3,266 potential volunteers, ages 50 or older, who completed a Mini-Mental State Exam as part of recruitment and screening for various clinical studies on Alzheimer’s disease. In order to determine the most effective strategies for engaging Blacks in clinical research, we used tests of proportion to assess significant differences in recruitment sources, counts, and percentages for optimal recruitment strategies by gender. Finally, we employed regression analyses to confirm our findings. Results Of the total 3,266 screened, 2,830 Black volunteers were identified for further analysis. Overall, more women than men (73.8% vs 26.2%) participated in our recruitment activities. However, a significantly higher proportion of men than women were engaged through family (3.86% vs 1.30%, p=0.0004) and referral sources (5.89% vs 2.59%, p=0.0005). Compared to other sources for recruitment, we encountered a higher proportion of volunteers at health fairs (42.95%), and through advertisements (14.97%). In our sample, years of education and age did not appear to influence the likelihood of an encounter, screening, and potential participation. Conclusion Our findings indicate Black men and women in our sample were predominantly recruited from health fairs and through advertisements tailored to their health needs and interests. Conversely, we mostly engaged Black men through family referrals and persons known to them, indicating a need for trust in their decision to engage study personnel and/or participate in clinical trials.

The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Neuroinflammation and reactive oxygen species are thought to mediate the pathogenesis of Alzheimer’s disease (AD), suggesting that mild cognitive impairment (MCI), a prodromal stage of AD, may be driven by similar insults. Several studies document that hypoxia-inducible factor 1 (HIF-1) is neuroprotective in the setting of neuronal insults, since this transcription factor drives the expression of critical genes that diminish neuronal cell death. HIF-1 facilitates glycolysis and glucose metabolism, thus helping to generate reductive equivalents of NADH/NADPH that counter oxidative stress. HIF-1 also improves cerebral blood flow which opposes the toxicity of hypoxia. Increased HIF-1 activity and/or expression of HIF-1 target genes, such as those involved in glycolysis or vascular flow, may be an early adaptation to the oxidative stressors that characterize MCI pathology. The molecular events that constitute this early adaptation are likely neuroprotective, and might mitigate cognitive decline or the onset of full-blown AD. On the other hand, prolonged or overwhelming stressors can convert HIF-1 into an activator of cell death through agents such as Bnip3, an event that is more likely to occur in late MCI or advanced Alzheimer’s dementia.

Associations of Pulse and Blood Pressure with Hippocampal Volume by APOE and Cognitive Phenotype: The Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Background: It is increasingly evident that high blood pressure can promote reduction in global and regional brain volumes. While these effects may preferentially affect the hippocampus, reports are inconsistent. Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined the relationships of hippocampal volume to pulse pressure (PPR) and systolic (SBP) and diastolic (DBP) blood pressure according to apolipoprotein (APOE) ɛ4 positivity and cognitive status. The ADNI data included 1,308 participants: Alzheimer disease (AD = 237), late mild cognitive impairment (LMCI = 454), early mild cognitive impairment (EMCI = 254), and cognitively normal (CN = 365), with up to 24 months of follow-up. Results: Higher quartiles of PPR were significantly associated with lower hippocampal volumes (Q1 vs. Q4, p = 0.034) in the CN and AD groups, but with increasing hippocampal volume (Q1, p = 0.008; Q2, p = 0.020; Q3, p = 0.017; Q4 = reference) in the MCI groups. In adjusted stratified analyses among non-APOE ɛ4 carriers, the effects in the CN (Q1 vs. Q4, p = 0.006) and EMCI groups (Q1, p = 0.002; Q2, p = 0.013; Q3, p = 0.002; Q4 = reference) remained statistically significant. Also, higher DBP was significantly associated with higher hippocampal volume (p = 0.002) while higher SBP was significantly associated with decreasing hippocampal volume in the EMCI group (p = 0.015). Conclusion: Changes in PPR, SBP, and DBP differentially influenced hippocampal volumes depending on the cognitive and APOE genotypic categories.

EFFECTS OF EXERCISE ON PLASMA NITRITE/NITRATE LEVELS, AND NITRIC OXIDE SYNTHASE ACTIVITY IN ELDERLY AFRICAN AMERICANS WITH MILD COGNITIVE IMPAIRMENT

P3-187 EFFECTS OF EXERCISE ON PLASMA NITRITE/NITRATE LEVELS, AND NITRIC OXIDE SYNTHASE ACTIVITY IN ELDERLY AFRICAN AMERICANS WITH MILD COGNITIVE IMPAIRMENT Oyonumo Ntekim, Julius S. Ngwa, Joanne S. Allard, Thomas V. Fungwe, Graham A. Lennox, Richard F. Gillum, Chimene Castor, Thomas O. Obisesan, Howard University, Washington, DC, USA; Howard University College of Medicine, Washington, DC, USA; Howard University, Washington, DC, USA; College of Nursing and Allied Health Sciences, Washington, DC, USA; Howard University College of Medicine, Washington DC, USA. Contact e-mail: oyonumo.ntekim@ howard.edu

Plasma Lipid Profiles of Transgenic mice expressing the Human ApoB100XCETP are altered differentially by Diets enriched with defined Fatty Acids

Dietary fat is known to modulate plasma lipid profiles. Synthesis of high density lipoproteins (HDL), which has protective effects on vascular disease is also influenced by dietary fats, but the mechanisms are unclear. The hapoB100XCETP transgenic mouse was used to investigate the effects of fatty acids on the metabolism of plasma lipoproteins, including the pathway leading to synthesis HDL. Male transgenic mice were fed with diets formulated to provide TG (33% energy) as tripalmitin (TP), triolein (TO), tristearin (TS) or equicaloric substitution of fat with carbohydrate (sucrose) for 4 weeks. Analysis of plasma profile showed that HDL-cholesterol were 53.7+14; 64.6+8.6; 50.2+3.3; 47.0+9.2 and 45.2+4.9 mg/dL for control, oleate, palmitate, stearate and sucrose based diets, respectively. LDL-cholesterol levels were 51.7+7.0; 23.1+7.0; 38.9+2.2; 75.1+1.8 and 46.8.1.0 mg/dl, for control, TO, TP, TS and sucrose, respectively. Hepatic Lecithin-cholesterol acyltransferase (LCAT) protein levels increased by 2-fold in mice fed TS or TO diets, compared to TP, while sucrose had no effect. The scavenger receptor class B type I (SR-B1) which plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues increased in livers of animals fed TP and TO, while TS and sucrose did not have a similar effects. These results suggests that fatty acids can uniquely impact HDL, in addition, the ApoB100XCETP mouse is a useful model for the evaluation of how dietary components affect the risk of developing atherosclerosis and heart disease. key words: ApoB100, CETP, TC, HDL-C, LDL-C & TG, Transgenic.

Pulse pressure and systolic blood pressure associated with hippocampal volume by apolipoprotein (APO) carriers and Alzheimer disease status: Alzheimer’s disease neuroimaging initiative (ADNI) study

Values are m CN: Control G PRESSURE ASSOCIATEDWITH HIPPOCAMPAL VOLUME BYAPOLIPOPROTEIN (APO) CARRIERS AND ALZHEIMER DISEASE STATUS: ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) STUDY Julius S. Ngwa, Oyonumo Ntekim, Thomas V. Fungwe, Sheree M. Johnson, Joanne S. Allard, Chimene Castor, Richard F. Gillum, Thomas O. Obisesan, Howard University College of Medicine, Washington, DC, USA; Howard University, Washington, DC,