Aging / Alzheimer's Disease

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    Behavioral profiling of aged glutathione-deficient mice exposed to an oxidative stressor
    (2019-03-05) Sumien, Nathalie PhD; Davis, Delaney
    Purpose Aging is associated with a decrease in brain function and vitality, along with an increased risk to stressors. Oxidative stress is a mechanism associated with aging, in which antioxidant defenses are overcome by the production of reactive oxygen species, leading to molecular damage and decreased cellular efficiency. Glutathione is a major antioxidant and indicator of cellular redox status, however its role in resilience remains unclear. To determine its involvement, we used the oxidative stressor paraquat (N,N′-dimethyl-4,4′-bipyridinium dichloride; PQ), a widely used herbicide that is highly toxic to animals and humans, in a mouse model of glutathione deficiency. The purpose of this study was to determine if paraquat-induced oxidative stress would exacerbate age-associated functional impairments in glutathione deficient mice. Methods Groups of old (18 months) male and female gclm+/+ and gclm-/- mice were assigned to a control group (saline) or a paraquat group (10 mg/kg; once via i.p.). One week following the injection, animals underwent behavioral testing of motor, affective and cognitive function (bridge walking, wire suspension, coordinated running, locomotor activity, elevated zero maze, fear conditioning, and active avoidance). Results Gclm-/- exhibited less anxious behavior than the gclm+/+, and PQ had no effect on that measure. Gclm-/- were more active than the gclm+/+, and PQ reduced that activity especially in females. PQ treatment seemed to improve cognitive flexibility, and improved associative learning in males only. PQ improved balance and strength of the gclm-/- in females, but worsened the strength in gclm+/+ males. Conclusion Overall, this study indicates that PQ did not exacerbate any phenotype associated with glutathione deficiency, and in some instances, it made the mice better. These outcomes do not support an involvement of glutathione in resiliency, however its life-long deficiency may have led to upregulation of other protective mechanisms making the mice stronger in adverse situations.
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    Genome-wide study highlights novel genes associated with Alzheimer’s-Hypertension comorbidity showing utility over CSF biomarkers
    (2019-03-05) Phillips, Nicole R.; Pathak, Gita A.
    Purpose: The aging population (65 and older) is heavily burdened with comorbidities. As the incidence of Alzheimer’s continues to rise in the aging demographic, understanding underlying causes of prevalent comorbid patterns in Alzheimer’s (AD) is crucial for early diagnosis and treatment. According to the 2011 Alzheimer’s association report, hypertension is the most prevalent comorbid condition affecting 60% of the Alzheimer’s population. However, there are no known biomarkers or risk scores associated with the AD-hypertension comorbidity; additionally, the genetic underpinnings of hypertension as a comorbidity to AD remains understudied. Hypothesis: We hypothesize that genetic variants underlie comorbidity patterns of Alzheimer’s disease and hypertension, which are distinct from genetic risk factors of Alzheimer’s disease alone. Methods: Leveraging the data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we conducted comorbidity analyses comparing healthy cohort (controls) vs Alz+/Hyp- vs Alz+/Hyp+. We compared CSF biomarkers – amyloid β, tau and p-tau in three cohorts using one-way ANOVA. We, then evaluated genome wide profiles in three groups using 535,762 SNP markers in 677 individuals (after QC). SNPs were clumped into genes based on position ± 50kb and p-value, followed by mining their role in gene-expression pathways. Results: The CSF biomarkers were not significantly different in the disease groups, indicating that these biomarkers are not able to discriminate between comorbid AD-hypertension pathology. When comparing the control with Alzheimer’s individuals, genome-wide study identifies known - TOMM40 and novel genes -PML and KMO which are known to have role in multiple CNS disorders. Interestingly, when comparing controls vs Alz+Hyp+, we observe several genes in the chromosome 16 region, including SLC9A3R2 - a known hypertension gene. This gene-cluster was also found to be co-expressed via other intermediate genes, underscoring their involvement in mitochondrial pathways. Conclusion: While the CSF biomarkers- amyloid β, tau and p-tau are known for their diagnostic contribution in vascular dementia, their profile is unaltered in Alzheimer’s-hypertension comorbidity, requiring investigation of other possible pathogenic causes. This study replicates genes known for Alzheimer’s, along with identifying possible risk loci to the developing Alzheimer’s and hypertension, thus showing potential utility over CSF profiles.
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    Analysis of 436,390 genetic variants in 9,765 elderly individuals implicates TOMM40, MARK4, CLPTM1 and VDAC1/FSTL4 in the inverse relationship between Alzheimer's and cancer
    (2019-03-05) Zhou, Zhengyang; Phillips, Nicole; Pathak, Gita A.
    Purpose A rapidly aging demographic, aged 65 and older, is expected to double by 2060 reaching 98 million and creating demands for better healthcare. While the number of co-occurring diseases increase in the aging population, Alzheimer’s and cancer have been reported to be inversely related – a lower than expected probability of the secondary disease after the primary disease diagnosis. This fueled our interest in exploring genetic variation that is responsible for the inverse relationship between AD and cancer. Rationale & Hypothesis Age is a risk factor for both AD and cancer, and our goal was to compare late-onset AD with two most prevalent age-related cancers – breast and prostate cancer. We hypothesize that harmonizing the age to study the cross-phenotypic effects of genetic variants between AD and cancer against a common control group will identify genetic variants that contribute to their inverse relationship. Methods Genomic SNP data from ADNI (Alzheimer’s Disease Neuroimaging Initiative), ADGC (Alzheimer’s Disease Genetics Consortium) and BPC3 (Breast and Prostate Cancer Care Consortium) which contained 757, 6065, and 11893 individuals respectively included genotypes for up to 700,000 SNP markers. Standard quality control measures were implemented. Individuals with age of disease onset between 60- 80 years were included, and Bayesian multinomial regression was used to compare cases (AD and cancer) against controls in a two-stage replication study. Results A total of 4 SNPs that replicated in the two study stages. In males, two risk loci were significant with opposite odds ratios – rs2075650 mapped to TOMM40 , and an intergenic SNP- rs4298154 on chr 4. Since TOMM40 is near APOE region, we conditioned on APOE SNPs – rs429358 and rs769449, to identify secondary hits. 8 SNPs in the MARK4 region were significant with the inverse hit. In females, rs2075650 was also significant, and conditional analysis resulted in variants in CLPTM1. A non-coding SNP in the VDAC1/ FSTL4 region was also replicated in females. Conclusion Our novel approach has identified four genic regions that have cross-phenotypic effects when comparing AD and cancer: TOMM40/APOE, MARK4, CLPTM1, and VDAC/FSTL4. These genes have been previously implicated independently in AD and cancer and are known to be involved in mitochondrial pathways; however, this is the first study to directly demonstrate that genetic variability in these genes underlies the inverse comorbidity of AD and cancer.
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    Analysis of mitochondrial protein sulfenation during aging in the rat brain
    (2019-03-05) Yan, Liang-Jun
    Purpose: The purpose of the present study was to identify mitochondrial proteins that undergo changes in cysteine sulfenation during aging. Methods: Studies were conducted in rats when they were 5 or 30 months of age. Following blocking of free protein thiols with N-ethylmaleimide, protein sulfenic acids were reduced by arsenite to free thiol groups that were subsequently labeled with biotin-maleimide. Samples were then comparatively analyzed by 2-dimensional Western blots, and proteins showing changes in sulfenation were selectively identified by mass spectrometry peptide sequencing. Result: Five proteins were identified. Proteins showing an age-related decrease in sulfenation include pyruvate carboxylase and pyruvate dehydrogenase; while those showing an age-related increase in sulfenation include aconitase, mitofilin, and tubulin (α-1). Conclusion: Results of the present study provide a general picture of mitochondrial protein sulfenation in brain oxidative stress and implicate the involvement of protein sulfenation in overall decline of mitochondrial function during brain aging.
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    Recruiting elders into research
    (2019-03-05) Wong, Lillian; Izurieta, Haydee; Large, Stephanie; Ruiz, Daisy; Hall, James PhD; O'Bryant, Sid PhD; Johnson, Leigh; Vintimilla, Raul
    Hypothesis/Objective Recruiting older adults into research is a complex task and utilizing ineffective recruitment methods is a waste of research grant money and researcher time. Research in aging and Alzheimer’s disease is particularly sensitive to low levels of enrollment and study completion, as it tends to have a higher participant burden (several study visits, time-consuming appointments and transportation issues). Enrolling sufficient participants is vital for the results of the study to be significant and representative of the population. The purpose of this study was to examine the most effective methods of recruitment in a cohort of adults 50 years or older. Methods The Health and Aging Brain Study among Latino Elders (HABLE) Study is a community based, epidemiological study of cognitive aging among Mexican American and non-Hispanic White elders. The study will recruit 1,000 Mexican Americans and 1,000 Non-Hispanic Whites. The HABLE study uses a combination of community based participatory research methods and targeted marketing for recruitment. On first contact, all participants are asked, “how did you hear about us?”; this information was compared with data from our outreach and advertising tracking system which includes information on the number and type of recruitment events (such as conferences, community talks, etc.), and marketing materials (such as postcards, paid advertisements, etc). Results The total number of new potential participant contacts was 2,136. Of that, 1038 (49%) were scheduled for a study visit; of those scheduled, 856 (82%) completed the study. The majority of participants reporting hearing about the study via: word of mouth (29%), print advertisement (19%) and community outreach at senior centers and churches (16%). Only a small fraction of participants heard about the research through free social media recruitment (1%) and health fair/conference/sponsorship (7%). Conclusions Out of all our recruitment strategies, word of mouth was the most effective. Additionally, print advertising (brochures, postcards and newspaper advertisements placed in various locations in the community) and community outreach in local senior centers or churches were highly successful. The data shows that a combination of mass advertising (print) and face-to-face recruitment (being present in community outreach events) is crucial in getting adults 50 years or older to enroll in aging research.
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    The Impact of High Intensity Aerobic Exercise on Cardiovascular Function in Older Adults
    (2019-03-05) Watson, Taylin; Salvatore, Michael; Bugnariu, Nicoleta; Wilson, Mary-Catherine
    1 Purpose Cardiovascular disease (CVD) is a leading cause of mortality in the United States, and age alone is a risk factor for developing CVD1. Regular aerobic exercise can help prevent arterial stiffening that occurs with age, thus decreasing the risk of CVD1,4. Regular exercise has also been found to reduce resting pulse rate, another risk factor for CVD and adverse outcomes5. This study investigated the impact of a 3-4 month high intensity aerobic exercise regimen upon baseline cardiovascular function in sedentary middle age adults. 2. Methods Subjects were randomly assigned to an exercise or non-exercise group. The exercise group completed 36, 1-hour exercise sessions, 3 times a week over 3-4 months. Exercise was standardized for each subject and consisted of a 10-minute warm-up (range of motion exercise, walking, stretching), followed by a fast pace walk/jog on a treadmill for 40 minutes, and concluded with a 10-minute cooldown. A high intensity exercise at minimum 80% max heart rate was aimed for as long as possible in each session. Exercise intensity was progressively increased over the weeks of training. Heart rate, blood pressure and oxygen levels were monitored throughout the exercise sessions. Data was analyzed and compared between pre- and post-intervention with T-tests. 3. Results Preliminary results from the exercise group show normalization of the cardiovascular function during exercise as measured by heart rate, blood pressure, and oxygen saturation. Compared to baseline values, after the exercise training, average resting heart rate measurement decreased significantly from 88 bpm to 75 bpm. The maximum blood pressure values at the highest exercise intensity also decreased significantly between the first and last session of exercise, from 248/180 to 189/145. The oxygen saturation at the highest exercise intensity increased from 91 in the first exercise session to 96 in the last exercise session. No changes in HR, BP or SpO2were observed in the non-exercise group 4. Conclusion A program of sustained, high intensity aerobic exercise, at the upper limits of currently prescribed maximum heart rate is feasible in middle age and older sedentary individuals without adverse effects. Total exercise time and maximum exercise intensity increased for all subjects in the experimental group.
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    Developing Interprofessional Collaboration to Advance Innovative Service Delivery in Geriatric Health Settings
    (2019-03-05) Severance, Jennifer; Saville, Neika; Hawley, Diane; Knebl, Janice; Johnston, Leah
    Purpose: Interprofessional collaboration is essential in geriatric healthcare settings due to the complex needs of older adults. The University of North Texas Health Science Center and Texas Christian University’s Harris College of Nursing partnered together to design the Geriatric Practice Leadership Institute (GPLI) ten-month training program with an aim of cultivating interprofessional team development and growth in order to enhance value-based patient-focused care to older adults in the developing primary healthcare systems. Methods: Leadership training and quality improvement strategies were integrated into curricula for health professionals (n=33) attending four one-day sessions held between September-December 2018. Content focused on 4 domains: 1) Leading Self and Interprofessional Teams to Drive Patient Outcomes; 2) Leading Organizational Change Toward Quality Outcomes; and 3) the Aging Network and Safe Healthcare Delivery for Older Adults. Teams developed a geriatrics-related quality improvement project in their area of practice with support from faculty and an assigned Coach. Evaluation surveys using Likert scale items were administered after each session. Open-ended responses were examined using qualitative thematic analysis. Results: Trainee feedback shows improved knowledge and skills in collaborating as a health care team to improve patient care and safety, and improved understanding of unique and shared roles and responsibilities and of ways to work collaboratively in patient care. Ninety-six percent better understand the need for a common language for team discussion and assessment, and 92% would recommend the training. Qualitative responses indicated the trainees intended to modify their professional practice as a leader and team member; and in the development, implementation, or evaluation of their project. Perceived challenges to meeting team goals include time restraints, coordinating schedules for group meetings, and stakeholder engagement within their organizations. Conclusion: Focusing on the development of interprofessional team collaboration and communication can foster development of interventions that improve geriatrics care in health systems. Interprofessional teamwork in conjunction with leadership training can produce rapid change in health practices. Projects developed within the GPLI are sustainable, providing continuous data collection for future use.
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    Intermittent hypoxia training: novel intervention for treating mild cognitive impairment
    (2019-03-05) Wang, Hong; Schenck, Hannah; Hall, James; Ross, Sarah; Kline, Geoffrey; Chen, Shande; Mallet, Robert T.; Shi, Xiangrong
    Purpose: Although intermittent hypoxic training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This study was to test if IHT was safe as a novel intervention for treating patients with MCI. Methods: MCI patients (age 69±3) alternately breathed 10% O2 and room-air (each 5 min) for 8 cycles/session, 3 sessions/week for 8 weeks. Before and after IHT, mean arterial pressure (MAP), arterial-O2 saturation (SaO2), cerebral tissue oxygenation (ScO2) and middle cerebral artery flow velocity (VMCA) were assessed, and cognitive performance was tested by mini-mental status exam (MMSE), California verbal learning test-II (CVLT-II), digit span, trail making test-B (TMT-B), and controlled oral word association test (COWAT). Results: Resting MAP fell from 101±3 to 95±3 mmHg (P2increased from 67.9±1.2 to 70.7±1.6% (PMCA(pre vs post: 46.8±3.0 vs 44.2±1.9 cm/s, P=0.21). During the 5th min of hypoxic challenge, SaO2 similarly fell to 70.3±2.9 and 73.8±1.4% pre- and post-IHT, respectively. The hypoxia-induced VMCA increase doubled from 4.5±2.2 before to 9.2±1.8 cm/s after IHT (P2 during 5-min hypoxia remained greater post- vspre-IHT (P Conclusions: IHT can be safely applied to enhance ScO2 and cerebral vasodilation during hypoxia, and potentially to improve short-term memory and concentration ability in MCI patients.
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    Mechanisms Underlying Membrane Androgen Receptor-Induced Neurodegeneration
    (2019-03-05) Duong, Phong; Wilson, Elizabeth; Cunningham, Rebecca; Tenkorang, Mavis
    Purpose: A common characteristic of several neurodegenerative disorders is oxidative stress (OS). Many neurodegenerative disorders are more prevalent in men and postmenopausal women. Our lab has shown testosterone via a non-genomic mechanism exacerbates OS damage in neurons. Indeed, our lab was the first to discover the presence of the androgen receptor (AR) splice variant, AR45, in the brain. We found testosterone can initiate signaling cascades via this membrane associated AR (mAR), leading to increased OS. However, the mechanism for OS generation is unknown. NADPH Oxidase 1 and 2 (NOX 1/2) are major OS generators, and potential targets for androgen-induced OS and cell death. Based on our studies showing protein-protein interactions between NOX1/2, AR45 and Gαq, we hypothesize testosterone increases OS by activating mAR complexed with NOX 1/2, initiating IP3 signaling. Method: Using an immortalized neuronal cell line (N27 cells), we exposed cells to hydrogen peroxide (H2O2) prior to testosterone (100 nM) or DHT-BSA (500nM). Inhibitors were used to examine AR, IP3 and NOX1/2 signaling. Cell viability and OS were quantified. In addition to in vitro experiments, we examined the effects of NOX 1/2 on DHT exacerbation of chronic intermittent hypoxia, CIH (AHI=10) induced OS by treating adult male Long Evans rats with the NOX1/2 inhibitor, apocynin (4mg/kg). Results: Classical AR antagonists did not block testosterone’s negative effects, indicating classical AR does not mediate these effects. Since AR antagonists do not block mAR, we used an AR protein degrader, ASC-J9 (5uM). ASC-J9 blocked testosterone’s negative effects. Next, we examined signaling cascades associated with proteins complexed with mAR-AR45. To block NOX actions, we used apocynin (10 uM). Apocynin did not alter H2O2-induced cell loss, indicating H2O2 increases OS via a non-NOX mechanism. However, apocynin completely blocked testosterone induced cell loss and OS, suggesting the involvement of NOX1/2. Consistent with our in vitro data, apocynin also decreased OS generation in DHT-treated rats exposed to CIH, during sleep phase for 7 days. Inhibition of IP3 receptor blocked testosterone’s negative effects, indicating that testosterone may activate IP3 signaling via the mAR-NOX complex. Conclusion: NOX and IP3 play a crucial role in mAR-induced neurodegeneration. Future studies will examine the mAR-NOX complex as a therapeutic target for neurodegenerative diseases.
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    Scripted Improvisation and Effects on Emotional Resiliency, Stress, and Positive Aspects of Caregiving
    (2019-03-05) Reuter, Kristen; Hammack, Lilly; Quiceno, Mary
    Background: As the United States population continues to age, more people will be diagnosed with Alzheimer’s Disease (AD) and dementia. Along with this increase in diagnosis comes an increase in the need for people to serve as caregivers for these individuals. Caregivers play a crucial role in the health and wellbeing of the people they care for, and there is incomplete research on techniques that can help caregivers handle challenges, avoid burnout, and come up with novel ways to approach problems they may face. Improvisation techniques are one avenue that may provide caregivers with solutions to these issues. Purpose: the purpose of this research is to study the effects of scripted improvisation on caregivers of people who have AD and/or dementia, and to see if improvisation increases emotional resiliency, reduces stress, and increases positive attitudes toward caregiving. Methods: 6 participants, aged 18 and older, who are caregivers for people with AD and/or dementia participated in a one-hour scripted improvisation workshop. Questionnaires (the Short Form Zarit Burden Interview (ZBI-12), The Resilience Scale™ (RS™), My Stress Thermometer, and Positive Aspects of Caregiving assessments) were completed beforehand to obtain baseline data regarding stress, depression, and positive affect towards caregiving. Techniques include paired improvisation and group techniques, with discussion afterward about how to apply techniques to their interactions with people who have AD and/or dementia. Two weeks later, these same questionnaires were completed by the participants and the data was analyzed to determine any effects from the improvisation workshop. Results: The improvisation session was completed on February 13, 2019. We anticipate analyses of the data to show an increased score on the positive aspects of caregiving after the scripted improvisation session, and decreased self-reported levels of stress and depression from the caregivers. Results are still pending acquisition of follow-up data from the participants. Conclusions: Scripted improvisation is an avenue that can be used to increase caregiver fulfillment and decrease stress caused by caregiving for a person with AD or dementia. Further research is needed to explain the impact of this techniques, as well as apply the techniques to caregivers for people with other chronic conditions.
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    Rapamycin decreases presenilin-1 in SK-N-SH cells
    (2019-03-05) Hontiveros, Silahis; Das, Hriday
    Purpose: Presenilin-1 (PS1) protein is the catalytic subunit of the γ-secretase complex, and participates in the processing of β-amyloid precursor protein (APP) to produce Aβ peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. NICD subsequently migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that exist as two complexes known as mTORC1 and mTORC2. mTORC1 controls cellular homeostasis, and its activity is inhibited by a FDA approved drug rapamycin. mTOR activity has been directly linked to learning and memory. It has been reported that the buildup of Aβ increases the mTOR signaling, whereas decreasing mTOR signaling reduces Aβ levels suggesting an interrelationship between mTOR signaling and Aβ. Administration of rapamycin in 3XTg-AD mouse model of Alzheimer's disease (AD) rescues cognitive deficits and ameliorates Aβ and Tau pathology. But the precise molecular mechanisms by which rapamycin reduces Aβ in AD is not well characterized. The purpose of this research to dissect the mechanisms by which rapamycin inhibits PS1 expression and PS1/γ-secretase activity in human neuroblastoma SK-N-SH cells. Methods: SK-N-SH cell line was maintained in Dulbecco’s modified Eagle medium containing 10% fetal bovine serum, 1% penicillin/streptomycin. Cells were treated with DMSO or different concentrations of rapamycin for 24 h. Total RNA and protein were prepared from treated cells. Amount of mRNA and protein expression were determined by real time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and western blot analysis respectively. Expression of proteins were confirmed by immunofluorescence staining (IFS) of DMSO and rapamycin treated cells. All data was analyzed using prism software and presented as means ± SEM. Comparison was made between groups by one-way ANOVA and Student–Newman–Keuls (SNK) test. A probability was considered to be significant with less than 0.05. Results: Rapamycin decreases the expression of p-mTOR, PS1, NICD, and Hes 1 proteins as well as PS1-mRNA in SK-N-SH cells. Conclusions: Rapamycin decreases PS1 protein levels and PS1/γ-secretase-mediated Notch 1 processing by inhibiting PS1 transcription. Hence we conclude that rapamycin may potentially reduce Aβ in AD by decreasing the transcription of the PS1 gene.