Systolic Blood Pressure Is Associated with Increased Brain Amyloid Load in Mild Cognitively Impaired Participants: Alzheimer's Disease Neuroimaging Initiatives Study.

BACKGROUND: Cardiovascular disease (CVD), including elevated blood pressure (BP), is known to promote Alzheimer's disease (AD) risk. Although brain amyloid load is a recognized hallmark of pre-symptomatic AD, its relationship to increased BP is less known. The objective of this study was to examine the relationship of BP to brain estimates of amyloid-ß (Aß) and standard uptake ratio (SUVr). We hypothesized that increased BP is associated with increased SUVr. METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we stratified BP according to the Seventh Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Classification (JNC VII). Florbetapir (AV-45) SUVr was derived from the averaged frontal, anterior cingulate, precuneus, and parietal cortex relative to the cerebellum. A linear mixed-effects model enabled the elucidation of amyloid SUVr relationships to BP. The model discounted the effects of demographics, biologics, and diagnosis at baseline within APOE genotype groups. The least squares means procedure was used to estimate the fixed-effect means. All analyses were performed using the Statistical Analysis System (SAS). RESULTS: In non-ɛ4 carrier MCI subjects, escalating JNC categories of BP was associated with increasing mean SUVr using JNC-4 as a reference point (low-normal (JNC1) p = 0.018; normal (JNC-1) p = 0.039; JNC-2 p = 0.018 and JNC-3 p = 0.04). A significantly higher brain SUVr was associated with increasing BP despite adjustment for demographics and biological variables in non-ɛ4 carriers but not in ɛ4-carriers. This observation supports the view that CVD risk may promote increased brain amyloid load, and potentially, amyloid-mediated cognitive decline. CONCLUSION: Increasing levels of JNC classification of BP is dynamically associated with significant changes in brain amyloid burden in non-ɛ4 carriers but not in ɛ4-carrier MCI subjects. Though not statistically significant, amyloid burden tended to decrease with increasing BP in ɛ4 homozygote, perhaps motivated by increased vascular resistance and the need for higher brain perfusion pressure.

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.

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.

Exercise modulates APOE expression in brain cortex of female APOE3 and APOE4 targeted replacement mice.

Apolipoprotein E (ApoE) is the main cholesterol carrier of the brain and the ε4 gene variant (APOE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold. Several studies indicate that APOE4 modulates critical factors for neuronal function, including brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Both proteins show exercise-induced upregulation, which is presumed to mediate many of the beneficial effects of physical activity including improved cognition; however, there is variability in results between individuals potentially in-part due to genetic variations including APOE isoform. This study aimed to determine if the two most prevalent human APOE isoforms influence adaptive responses to exercise-training. Targeted replacement mice, homozygous for either APOE3 or APOE4 were randomized into exercised and sedentary groups. Baseline locomotor function and voluntary wheel-running behavior was reduced in APOE4 mice. Exercised groups were subjected to daily treadmill running for 8 weeks. ApoE protein in brain cortex was significantly increased by exercise in both genotypes. PGC-1α mRNA levels in brain cortex were significantly lower in APOE4 mice, and only tended to increase with exercise in both genotypes. Hippocampal BDNF protein were similar between genotypes and was not significantly modulated by treadmill running. Behavioral and biochemical variations between APOE3 and APOE4 mice likely contribute to the differential risk for neurological and vascular diseases and the exercise-induced increase in ApoE levels suggests an added feature of the potential efficacy of physical activity as a preventative and therapeutic strategy for neurogenerative processes in both genotypes.

The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning.

Accumulating evidence suggests that α-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether α-synuclein level in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also explored whether this relationship was mediated by proinflammatory cytokines TNF-α and IL-6, along with sIL-6R and vascular endothelial growth factor (VEGF). Using a cross-sectional Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 148) sample, we examined the relationship between α-synuclein and participants' performance on Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 13) at baseline. Mediation analyses were utilized, adjusting for age, education, APOEe4, and Geriatric Depression Scale scores. All biological markers were measured in CSF. Participants in the current sample were 58.3% males, 41.7% females, and Caucasian (95.5%); their average education and age were 15.5 (standard deviation [SD] = 2.97) and 74.4 (SD = 7.51) years, respectively. Higher accumulation of α-synuclein was associated with poorer MMSE scores (ß = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (ß = 0.27, SE = 2.15, p = .025) and IL-6r (ß = 0.22, SE = 1.66, p < .026). In addition, α-synuclein was associated with poorer performance on the ADAS-Cog 13 (ß = 0.34, p = .005) and mediated by VEGF (ß = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. α-Synuclein may serve as an additional biomarker for determining poor cognitive functioning. VEGF and IL-6 soluble receptors were significant mediators of the relationship between α-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.

The Role of Transportation in the Enrollment of Elderly African Americans into Exercise and Memory Study: GEMS Study.

BACKGROUND: Understanding the factors driving recruitment and enrollment of African Americans (AA)s in clinical translational research will assure that underrepresented populations benefit from scientific progress and new developments in the diagnosis and treatment of Alzheimer's disease and related disorders. While transportation is pivotal to volunteers' ability to participate in research, its contribution to enrollment in exercise studies on AD is yet to be elucidated. Thus, this research focuses on identifying factors that influence the recruitment and enrollment of African Americans in biomedical studies and determining whether the availability of transportation motivates participation in time-demanding exercise studies on AD. METHODS: We analyzed recruitment data collected from 567 volunteers ages 55 and older screened through various recruitment sources and considered for enrollment in our exercise and memory study. To determine whether transportation influenced the enrollment of African Americans (AA)s in biomedical studies, multiple logistic regression analysis was performed to identify significant factors that drive enrollment. Furthermore, the association of race and demographic factors on the availability of transportation was assessed. RESULTS: Demographic factors, age at screening, education, gender, and cognitive scores were not significantly different among those enrolled compared to control (not-enrolled). In the relationship of enrollment to transportation, enrolled participants were more likely to have access to transportation (79.12%) than not-enrolled participants who had less access to transportation (71.6%); however, the association was not statistically significant. However, race differentially influenced the likelihood of enrollment, with elderly AAs being significantly less likely to have transportation (p = 0.020) than the Whites but more likely than "others" to have transportation. CONCLUSION: Our findings suggest that access to transportation may be a key factor motivating enrollment in an exercise and memory study in a predominantly AA sample. Notably, AAs in our sample were less likely to have transportation than Whites. Other demographic factors and cognitive scores did not significantly influence enrollment in our sample. A larger sample and more detailed assessment of transportation are needed to further discern the role of transportation in clinical trials.

Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study.

The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aß in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer's disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.

Aerobic Exercise Training-Induced Changes on DNA Methylation in Mild Cognitively Impaired Elderly African Americans: Gene, Exercise, and Memory Study - GEMS-I.

BACKGROUND: DNA methylation at CpG sites is a vital epigenetic modification of the human genome affecting gene expression, and potentially, health outcomes. However, evidence is just budding on the effects of aerobic exercise-induced adaptation on DNA methylation in older mild cognitively impaired (MCI) elderly African American (AAs). Therefore, we examined the effects of a 6-month aerobic exercise-intervention on genome-wide DNA methylation in elderly AA MCI volunteers. DESIGN: Elderly AA volunteers confirmed MCI assigned into a 6-month program of aerobic exercise (eleven participants) underwent a 40-min supervised-training 3-times/week and controls (eight participants) performed stretch training. Participants had maximal oxygen consumption (VO2max) test and Genome-wide methylation levels at CpG sites using the Infinium HumanMethylation450 BeadChip assay at baseline and after a 6-month exercise program. We computed false discovery rates (FDR) using Sidak to account for multiplicity of tests and performed quantitative real-time polymerase chain-reaction (qRT-PCR) to confirm the effects of DNA methylations on expression levels of the top 5 genes among the aerobic participants. CpG sites identified from aerobic-exercise participants were similarly analyzed by the stretch group to quantify the effects of exercise-induced methylation changes among the group of stretch participants. RESULTS: Eleven MCI participants (aerobic: 73% females; mean age 72.3 ± 6.6 years) and eight MCI participants (stretch: 75% female; mean age 70.6 ± 6.7 years) completed the training. Aerobic exercise-training was associated with increases in VO2max and with global hypo- and hypermethylation changes. The most notable finding was CpG hypomethylation within the body of the VPS52 gene (P = 5.4 × 10-26), a Golgi-associated protein, involved in intracellular protein trafficking including amyloid precursor protein. qRT-PCR confirmed a nearly twofold increased expression of VPS52. Other top findings with FDR q-value < 10-5, include hypomethylations of SCARB1 (8.8 × 10-25), ARTN (6.1 × 10-25), NR1H2 (2.1 × 10-18) and PPP2R5D (9.8 × 10-18). CONCLUSION: We conclude that genome-wide DNA methylation patterns is associated with exercise training-induced methylation changes. Identification of methylation changes around genes previously shown to interact with amyloid biology, intracellular protein trafficking, and lipoprotein regulations provide further support to the likely protective effect of exercise in MCI. Future studies in larger samples are needed to confirm our findings.

Exercise Training Induced Changes In Nuclear Magnetic Resonance-Measured Lipid Particles In Mild Cognitively Impaired Elderly African American Volunteers: A Pilot Study.

PURPOSE: Poor cardiorespiratory fitness (CRF) is linked to cognitive deterioration, but its effects on lipid heterogeneity and functional properties in older African American (AA) subjects with mild cognitive impairment (MCI) need elucidation. This study determined whether exercise training-induced changes in blood lipid particle sizes (LPS) were associated with CRF determined by VO2Max in elderly AAs with MCI. Given the pivotal role of brain-derived neurotrophic factor (BDNF) on glucose metabolism, and therefore, "diabetic dyslipidemia", we also determined whether changes in LPS were associated with the levels of serum BDNF. METHODS: This analysis included 17 of the 29 randomized elderly AAs with MCI who had NMR data at baseline and after a 6-month training. We used Generalized Linear Regression (GLM) models to examine cardiorespiratory fitness (VO2Max) effects on training-induced change in LPS in the stretch and aerobic groups. Additionally, we determined whether the level of BDNF influenced change in LPS. RESULTS: Collectively, mean VO2Max (23.81±6.17) did not differ significantly between aerobic and stretch groups (difference=3.17±3.56, P=0.495). Training-related changes in very low-density lipoprotein, chylomicrons, and total low-density lipoprotein (LDL) particle sizes correlated significantly with VO2Max, but not after adjustment for age and gender. However, increased VO2Max significantly associated with reduced total LDL particle size after similar adjustments (P = 0.046). While stretch exercise associated with increased protective large high-density lipoprotein particle size, the overall effect was not sustained following adjustments for gender and age. However, changes in serum BDNF were associated with changes in triglyceride and cholesterol transport particle sizes (P < 0.051). CONCLUSION: Promotion of stretch and aerobic exercise to increase CRF in elderly AA volunteers with MCI may also promote beneficial changes in lipoprotein particle profile. Because high BDNF concentration may reduce CVD risk, training-related improvements in BDNF levels are likely advantageous. Large randomized studies are needed to confirm our observations and to further elucidate the role for exercise therapy in reducing CVD risk in elderly AAs with MCI.

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.

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.

Possession of the Apolipoprotein E (APOE) gene ε4 allele is the most prevalent genetic risk factor for late onset Alzheimer's 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 APOEε4 (ε4) carrier status on changes in BDNF expression after a standardized exercise program. African Americans, age 55years 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 ε4 carriers and non-ε4 carriers. A significant association between ε4 status and serum BDNF levels was detected. Non-ε4 carriers showed a significant increase in BDNF levels at the 6month time point while ε4 carriers did not. We believe we have identified a relationship between the ε4 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.

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.