Aging / Alzheimer's Disease

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    Potential Mechanisms by which Chronic Benzodiazepine Promotes Motoric Aging in Mice
    (2018-03-14) Jung, Marianna; Metzger, Daniel; Tan, Sabrina
    PURPOSE Benzodiazepines (BZDs) are among the most commonly prescribed medications in elderly to treat hyperexcitatory disorders such as anxiety and insomnia. However, its high or a repeated dose is frequently administered to patients, which often provokes side effects including motoric impairment. Here, we investigated whether chronic BZD (lorazepam) age-dependently deteriorates motoric functions in mice. METHODS To decipher underlying mechanisms, we measured mitochondrial BZD-receptor (mBZD-R) and amyloid-β (Aβ) of which excess amount is associated with mitochondrial deficit and neurodegeneration. We also measured reactive oxygen species (ROS) and cell survival in HT22 cells, the cell line that has been used to determine oxidative mechanisms. Young (3 months old) and old (15 months old) mice received BZD (lorazepam, 1 mg/kg) with or without mBZD-R inhibitor (PK11195) for 4 weeks. Motoric function was tested using Rotarod; a quicker fall from rotating rod indicates a poorer motoric function. Upon humane sacrifice, cerebellum was collected to measure mBZD-R using immunoblot and amyloid-β using sandwich ELISA. Separately, HT22 cells were treated with lorazepam (0-25 µM) for 3 days. The cells were then tested for mitochondrial ROS, whole cell ROS, and cell viability using MitoSox, DCFDA, and Calcein assays, respectively. RESULTS BZD-received old mice showed poorer motoric function, increased mBZD-R, and Aβ accumulation in cerebellum more severely than old control or young-BZD mice. PK11195 injection tended to improve the motoric function of BZD mice. Chronic BZD treatment to HT22 cells showed an increase in mitochondrial ROS in a manner attenuated by PK11195 treatment and accompanied by reduced cell survival. CONCLUSIONS These data suggest that chronic BZD exacerbates the motoric deterioration in aged mice. These data also raise a possibility that a deleterious interaction between mBZD-R and mitochondrial ROS is a part of the underlying mechanistic network responsible for the motoric aging.
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    Alzheimer's and Automation: A Match Made in Research?
    (2018-03-14) Pierce, Melissa; Hall, James MD; O'Bryant, Sid Ph.D; Conger, Tori
    Alzheimer’s and Automation: A Match Made in Research? Presenter: Tori Conger and Melissa Pierce Classification: Staff Authors: Tori Conger,, UNT Health Science Center, Melissa Pierce,, UNT Health Science Center, Dr. James Hall MD,, UNT Health Science Center, Dr. Sid O’Bryant Ph.D, , UNT Health Science Center Objective: Alzheimer’s is a disease that destroys memory, alters mental function, disrupts the autonomic nervous system and is detected only after an individual has had the disease for several years. Our research is dedicated to early detection of Alzheimer’s through blood-based biomarkers, clinical testing and MRIs. We are projected to see upwards of 3,000 people over a 5-year period. With one lab, four staff, and minimal sample process time, our research was in need of a system that could increase productivity, reduce human error and allow our samples to be fully processed from blood draw to freezer in under two hours. Our solution: the Hamilton Robotics Easyblood robot combined with a customized LIMS system. Methods: The lab was in need of a system to fully capture the blood collection process. To capture this information, a LIMS system was developed to document each milestone the sample reached such as time of blood draw, time into centrifuge, etc. The Easyblood robot was programmed to aliquot blood fractions (GLP-1 plasma, plasma, buffy coat and serum) to fit our needs based on each project’s protocol. For the LIMS system and Easyblood robot to communicate with each other, an SQL server database was utilized to link the LIMS system to Easyblood through a developed common bond: barcoded collection kits. Each collection kit (EDTA, SST, and p800 tube) has a project barcode and each tube in the collection kit has its own barcode, denoted by sample type. Results: With the implementation of the Easyblood robot and the LIMS system, the lab is able to track the blood collection process from beginning to end. This information enables lab personnel to process multiple samples at one time, easily identify the samples, reduce the amount of time between collection and storage and minimize human error. Conclusion: The two systems working in conjunction with each other allows for increased consistency, simplicity, and reliability in processing blood-based samples. IRB # 2015-171 IBC # 2017-0056
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    Tissue-specific effects of Exercise and Antioxidant Intake on Protein Damage in Young and Old Mice
    (2018-03-14) Scott, Amanda; Mock, J.; Wong, Jessica; Vann, Philip; Davis, Delaney; Sumien, Nathalie; Jafri, Saad
    1. Purpose: While oxidative stress is not the only factor involved in the aging process, it has been demonstrated that manipulating oxidative stress can affect function and delay age-related declines. Interventions such as moderate exercise and antioxidant supplementation have been shown to affect oxidative stress and improve function. With many individuals combining interventions, it is imperative to determine how they might interact. We hypothesized that exercise or antioxidants alone would decrease oxidative damage, and combining them would further decrease oxidative damage. 2. Methods: Cardiac and skeletal muscle tissues were homogenized and used to determine the levels of protein damage assessed by measuring carbonyl concentrations. The samples were collected from a prior study during which 4 and 20 month old C57BL/6 male mice were placed into one of four treatment groups: sedentary/ control diet, sedentary/ antioxidant diet, exercise/ control diet, and exercise/ antioxidant diet. The exercise consisted of a moderate aerobic treadmill forced exercise, and the antioxidant diet contained α-tocopherol (0.825mg/g diet) and ascorbate (1.65mg/g diet). The effects of age and treatment were analyzed by two-way ANOVAs, followed by pairwise comparisons. 3. Results: There was no main effect of age on protein oxidation in homogenates from cardiac or skeletal muscles. There was no effect of exercise, antioxidant or the combination on carbonyls in the skeletal muscles. However, in the cardiac muscles, all the treatments decreased protein oxidation especially in the old mice (only significantly in the old exercise group). There was no noticeable interaction between antioxidant and exercise treatments. 4. Conclusion: Overall, the effects of treatment were only observed in the cardiac muscle signifying a potential tissue-dependent response to exercise and antioxidants. Interestingly, there was no beneficial or antagonistic interaction between the two interventions. Other tissues will also be studied to strengthen this argument.
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    Predictors of estrogen's neuroprotective efficacy
    (2018-03-14) Brock, Courtney; Rybalchenko, Nataliya; Sumien, Nathalie; Singh, Meharvan; Toofan, Jessica
    Purpose: The precipitous decline in ovarian hormones after the menopause may put women at greater risk for age-associated cognitive decline and serves as the basis for considering hormone therapy to support brain health, despite equivocal results in clinical trials studies to-date. Data from our lab show that estrogen replacement (after ovariectomy) in young animals increases brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. However, in middle-aged animals, the effect of 17b-estradiol (E2) is diminished, supporting the existence of a window of opportunity for these hormones, and thus, reason to explore the underlying molecular mechanisms. In this study, we evaluated the expression of BDNF, estrogen receptors (ERs), and other relevant molecules of cognition (TrkB, p75, and RbAp48) in young and middle-aged animals to determine if changes in their expression was correlated with the effect of estrogen. To better establish any causal relationship to our findings, we also conducted studies in vitro to determine which ERs are critical to mediating the effects of E2 on BDNF. Methods: In-Vivo: Real time rtPCR was used to evaluate the expression of BDNF, TrkB, p75, RbAp48, and ERa mRNA in the hippocampus of female ovariectomized (OVX) Sprague Dawley rats that were 4 months (young) and 10 months (middle-aged) of age. In-Vitro: The effect of E2 (10nM, 24 hours) on BDNF mRNA expression was evaluated in ERa transfected, differentiated SH-SY5Y cells (as a model of ER negative neurons). In parallel, we also evaluated the effect of E2 on cell viability (using the MTT assay). Results: Our in vivo data show that ERa, BDNF, TrkB, RbAp48 in hippocampal mRNA are significantly decreased in middle-aged OVX rats as compared to young OVX. There was also a significant increase in the pro-cell death p75 receptor in middle-aged rats. In vitro data revealed a significant increase in ERa mRNA expression post-transfection, with an approximate 30% transfection efficiency. Treatment of ERa-transfected SH-SY5Y cells with E2 did not induce a significant increase in BDNF, nor did it protect the cells from amyloid-beta-induced cytotoxicity. Conclusion: The hippocampal mRNA expression analyses we performed in vivo suggest that indeed, there are changes in relevant molecules of cognitive function with age, that in turn, could diminish the protective effects of E2. Further, ERa expression was not sufficient to mediate the effect of E2 on BDNF expression or cell viability.
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    The Effect of Hearing Aids on Balance
    (2018-03-14) Patterson, Rita; Bugnariu, Nicoleta; Kowalewski, Victoria DPT
    Purpose: Older adults with hearing loss fall more often compared to older adults with normal hearing. Although some clinical balance outcome measures have been identified as potential assessment tools for older adults with hearing loss who are risk for falling, no study has assessed reactive balance outcome measures for older adults with hearing loss to determine fall risk. This study assessed whether number of steps during loss of balance, while simultaneously listening and responding to a standardized audiology test, could be a feasible reactive balance outcome measure to use to identify older adults with hearing loss who have balance deficits. Methods: 20 young adults, 20 older adults with normal hearing, and 20 older adults with hearing loss performed an auditory-balance dual-task of listening to a standardized audiology test, the BKB-SIN, while simultaneously responding to forward loss of balance requiring participants to take a step. Backward surface translations were provided on a treadmill at a slow and fast speed and randomized with the auditory sentences. Results: Results showed no significant difference between young adults, older adults with normal hearing, and older adults with hearing loss on balance or auditory scores. Conclusions: Further research needs to be performed to identify proper assessments and treatment interventions for older adults with hearing loss who have balance deficits.
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    Testosterone in the bedroom - not always good
    (2018-03-14) Duong, Phong; Cunningham, Rebecca L.; Snyder, Brina D.
    Purpose: There are no effective therapeutics to prevent the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). This deficit highlights the need to identify early contributors to neurodegenerative pathophysiology, such as examining common comorbidities. One such comorbidity is sleep apnea. To examine the relationship between sleep apnea and neurodegeneration, we used a rodent model of chronic intermittent hypoxia (CIH) to simulate the hypoxic events experienced by patients with sleep apnea. Interestingly, in male rats CIH causes an increase in oxidative stress (OS) and inflammation, along with a decrease in circulating testosterone (T). Currently, studies have been equivocal about the role of the major male sex hormone, T, in neuroprotection and neurodegeneration. It has been proposed that an OS environment may predispose T to be neurotoxic via androgen receptor activation. Methods: To address if OS is the switch for testosterone’s neuroprotective or neurotoxic actions, male Long-Evans rats were assigned to different hormone groups: gonadally intact, gonadectomized (GDX), GDX + T (TRT) or GDX + dihydotestosterone (DHT). DHT is an androgen receptor agonist metabolized from T. Two weeks after hormone replacement, rats were exposed to CIH or room air (AHI = 8) for 12 days. During the last 5 days of CIH, cognitive and motor behavioral tests were conducted. Results: As expected, elevated OS as well as spatial memory and fine motor impairments were observed in response to CIH in gonadally intact rats. This suggests CIH-induced OS results in behavioral deficits associated with early-stages of neurodegenerative diseases. GDX rats exhibited only cognitive impairments, regardless of CIH exposure, indicating sex hormones play a role in memory. Irrespective of CIH exposure, TRT prevented OS generation as well as motor and cognitive impairments. Interestingly, CIH induced OS and cognitive impairments were exacerbated in DHT male rats, compared to gonadally intact rats. Conclusions: These results indicate that the androgen receptor is involved in T’s negative effects in an OS environment. Since sleep apnea is a common comorbidity of neurodegeneration, the observed sex differences may be due to a negative interaction between OS and androgen receptor activation. Therefore, men with sleep apnea who have elevated OS may be susceptible to neurodegenerative pathophysiology.
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    Incorporating health literacy principles into student’s curriculum will improve confidence and overall ability to effectively communicate with older adults
    (2018-03-14) Nowamooz, Neika; Knebl, Janice; Yeager, Ericka
    Purpose: Adults over age 65 are at a higher risk for low health literacy. According to a survey from the National Assessment of Adult Literacy (NAAL), more than half of seniors (59%) have below basic literacy levels. In order to combat this issue, educating health professional students on health literacy strategies can increase the understanding of such disparities, and enhance communication capabilities with seniors. Methods: Students encompassing seven health professions between two universities (n=620) were assembled into interprofessional teams and assigned a senior mentor (n=171). The teams were asked to develop a presentation covering a designated health topic of their mentor’s choice using health literacy principles. Following the presentation, a sampling of the senior mentors (n=75) and all of the students involved were surveyed and results were evaluated for effectiveness. Among the older adults and students, the response rate was 91% and 75% respectively. Results: According to students surveyed, 70% agreed that as a result of this visit, they now understand how to effectively communicate with older adults using health literacy strategies. Seventy-four percent of students also felt more confident about their knowledge of health care needs for older adults.. When reviewing senior mentor responses, 98% said after the presentation, they feel better informed on the given subject. Additionally, 85% were able to recall two pieces of information learned, and 98% feel they will be able to apply what they learned from the presentation to their health. When estimating if any change had occurred because of the presentation, 98% of seniors said they experienced some amount of positive change. Conclusions: Application of health literacy strategies within interprofessional healthcare teams can have a positive effect on future communication and confidence when discussing health matters with older adults.
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    The relationship of Hypertension and related Cardiovascular Risk factors to Executive Functioning in Mexican-Americans
    (2018-03-14) Hall, James; Johnson, Leigh; O'Bryant, Sid; Vintimilla, Raul
    Background: The effect of high blood pressure on cognitive domains is unclear but the literature suggests that the primary impact is on cognitive impairment in executive functions and slowing of mental processing speed. These cognitive functions are especially vulnerable to vascular change. Hispanics are at increased risk for cardiovascular disease, cognitive decline and dementias, and there is no sufficient literature about this relationship in this growing segment of the population. The purpose of this study was to examine the link between blood pressure and executive functioning in Mexican-Americans. Methods: Data were analyzed in 426 participants from the Health and Aging Brain Among Latino Elders study (HABLE). Cardiovascular disease (CVD) risks include hypertension, dyslipidemia, diabetes mellitus, and abdominal circumference over 40 inches. The presence of these risks was determined from self-report, use of medication, and lab results. Trails B was used as an index of executive function and entered as the dependent variable in the models. A one-way ANOVA was conducted to assess the effect of CVD risk factors on executive function. Linear regressions were utilized to examine the relationship between hypertension and other CVD risk factors with executive function. Age was entered as a covariate in the model. Results: Within the total sample, ANOVA revealed a statically significance difference between groups (F (4,495) = 3.15, p = .01). The post hoc tests showed that the individuals with two (M = 7.7, SD = 3.7), three (M = 7.4, SD = 3.9) or four (M = 6.9, SD = 3.6) risk factors differ significantly at p B = -1.6, 95% CI [-2.36, -.80], p = .00). Hypertension explained a 4% of variance in Trails B scores, (R2 = .04, F (1,398) = 15.78, p = .00). None of the other CVD risk were significant. Conclusion: Our findings suggested a relationship between diagnosis of hypertension and executive function in Mexican-Americans. No other CVD risk factors independently had a significant link with executive function. Having more than one CVD risks regardless of its nature was related to lower executive functioning. The results of this study support literature that suggested that the effects of high blood pressure on cognitive domains primarily involve executive functioning.
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    Epigenetic Risk Factors for Mild Cognitive Impairment, Alzheimer’s Disease and Metabolic Dysfunction in Mexican Americans
    (2018-03-14) Silzer, Talisa; Sun, Jie; Phillips, Nicole; Johnson, Leigh; O'Bryant, Sid; Barber, Robert C.; Abraham Daniel, Ann
    Purpose: Alzheimer’s is the most common form of dementia and the 5th leading cause of death for those over 651. The population of Mexican American elders will grow seven-fold by 20502 with rates of mild cognitive decline (MCI) and Alzheimer’s disease (AD) increasing exponentially1. Mexican Americans are diagnosed with MCI and AD at younger ages than non-Hispanic whites3; 4. In addition, Mexican Americans who are diagnosed with AD are 1) less likely to carry the ApoEε4 genotype3-5., 2) suffer a greater burden of type 2 diabetes3; 6, 3) experience greater metabolic-related cognitive decline7; 8 and 4) display a proteomic signature of AD that is heavily metabolic in nature4; 9, compared to non-Hispanic whites, whose proteomic signature for AD is dominated by inflammatory proteins. We hypothesized that differentially methylated regions of DNA (DMRs) are associated with age at onset of cognitive decline (MCI/AD) and metabolic dysfunction (metabolic syndrome/type 2 diabetes) in Mexican Americans. Methods: To test this hypothesis, we assayed genomic DNA methylation in samples from 14 female Mexican American participants enrolled in the Health and Aging Brain study in Latino Elders (HABLE). Participants were diagnosed with cognitive decline (n=4), metabolic dysfunction (n=3), both (n=4), or as a control (n=3). We isolated DNA from leukocytes and bisulfite treated the samples before running them on an Illumina MethylationEPIC chip in accordance with manufacturer’s recommendations to assay genomic DNA methylation. Results: Several interesting biological pathways showed significantly different methylation status between groups. When the participants were split on cognitive decline, DNA in the amyloid secretase, EGF receptor signaling, PDGF signaling, gonadotropin-releasing hormone receptor and Wnt signaling pathways were significantly hypermethylated in cases. In comparison, analyses based on metabolic dysfunction showed significant DNA hypomethylation in the beta1 and beta2 adrenergic receptor signaling pathways and hypomethylation of the gonadotropin releasing hormone receptor pathway in cases. Conclusions: The etiology of cognitive decline appears to differ between Mexican Americans and non-Hispanic whites. Future work will resolve how dementia risk differs between these and other ethnic groups. The knowledge gained from these studies will be critical to a better understanding of AD pathophysiology and the development of ethnicity-focused AD treatment options. Acknowledgements: Research reported here was supported by the National Institute On Aging of the National Institutes of Health under Award Number R01AG054073. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research team also thanks the local Fort Worth community and participants of the Health & Aging Brain Study.