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- Creators: Department of Psychology
- Creators: Harrington Bioengineering Program
- Resource Type: Text
- Status: Published
Description
Alzheimer’s Disease (AD) affects over 5 million individuals in the U.S. and has a direct cost estimated in excess of $200 billion per year. Broadly speaking, there are two forms of AD—early-onset, familial AD (FAD) and late-onset-sporadic AD (SAD). Animal models of AD, which rely on the overexpression of FAD-related mutations, have provided important insights into the disease. However, these models do not display important disease-related pathologies and have been limited in their ability to model the complex genetics associated with SAD.
Advances in cellular reprogramming, have enabled the generation of in vitro disease models that can be used to dissect disease mechanisms and evaluate potential therapeutics. To that end, efforts by many groups, including the Brafman laboratory, to generated patient-specific hiPSCs have demonstrated the promise of studying AD in a simplified and accessible system. However, neurons generated from these hiPSCs have shown some, but not all, of the early molecular and cellular hallmarks associated with the disease. Additionally, phenotypes and pathological hallmarks associated with later stages of the human disease have not been observed with current hiPSC-based systems. Further, disease relevant phenotypes in neurons generated from SAD hiPSCs have been highly variable or largely absent. Finally, the reprogramming process erases phenotypes associated with cellular aging and, as a result, iPSC-derived neurons more closely resemble fetal brain rather than adult brain.
It is well-established that in vivo cells reside within a complex 3-D microenvironment that plays a significant role in regulating cell behavior. Signaling and other cellular functions, such as gene expression and differentiation potential, differ in 3-D cultures compared with 2-D substrates. Nonetheless, previous studies using AD hiPSCs have relied on 2-D neuronal culture models that do not reflect the 3-D complexity of native brain tissue, and therefore, are unable to replicate all aspects of AD pathogenesis. Further, the reprogramming process erases cellular aging phenotypes. To address these limitations, this project aimed to develop bioengineering methods for the generation of 3-D organoid-based cultures that mimic in vivo cortical tissue, and to generate an inducible gene repression system to recapitulate cellular aging hallmarks.
Advances in cellular reprogramming, have enabled the generation of in vitro disease models that can be used to dissect disease mechanisms and evaluate potential therapeutics. To that end, efforts by many groups, including the Brafman laboratory, to generated patient-specific hiPSCs have demonstrated the promise of studying AD in a simplified and accessible system. However, neurons generated from these hiPSCs have shown some, but not all, of the early molecular and cellular hallmarks associated with the disease. Additionally, phenotypes and pathological hallmarks associated with later stages of the human disease have not been observed with current hiPSC-based systems. Further, disease relevant phenotypes in neurons generated from SAD hiPSCs have been highly variable or largely absent. Finally, the reprogramming process erases phenotypes associated with cellular aging and, as a result, iPSC-derived neurons more closely resemble fetal brain rather than adult brain.
It is well-established that in vivo cells reside within a complex 3-D microenvironment that plays a significant role in regulating cell behavior. Signaling and other cellular functions, such as gene expression and differentiation potential, differ in 3-D cultures compared with 2-D substrates. Nonetheless, previous studies using AD hiPSCs have relied on 2-D neuronal culture models that do not reflect the 3-D complexity of native brain tissue, and therefore, are unable to replicate all aspects of AD pathogenesis. Further, the reprogramming process erases cellular aging phenotypes. To address these limitations, this project aimed to develop bioengineering methods for the generation of 3-D organoid-based cultures that mimic in vivo cortical tissue, and to generate an inducible gene repression system to recapitulate cellular aging hallmarks.
ContributorsBounds, Lexi Rose (Author) / Brafman, David (Thesis director) / Wang, Xiao (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Background: Noninvasive MRI methods that can accurately detect subtle brain changes are highly desirable when studying disease-modifying interventions. Texture analysis is a novel imaging technique which utilizes the extraction of a large number of image features with high specificity and predictive power. In this investigation, we use texture analysis to assess and classify age-related changes in the right and left hippocampal regions, the areas known to show some of the earliest change in Alzheimer's disease (AD). Apolipoprotein E (APOE)'s e4 allele confers an increased risk for AD, so studying differences in APOE e4 carriers may help to ascertain subtle brain changes before there has been an obvious change in behavior. We examined texture analysis measures that predict age-related changes, which reflect atrophy in a group of cognitively normal individuals. We hypothesized that the APOE e4 carriers would exhibit significant age-related differences in texture features compared to non-carriers, so that the predictive texture features hold promise for early assessment of AD. Methods: 120 normal adults between the ages of 32 and 90 were recruited for this neuroimaging study from a larger parent study at Mayo Clinic Arizona studying longitudinal cognitive functioning (Caselli et al., 2009). As part of the parent study, the participants were genotyped for APOE genetic polymorphisms and received comprehensive cognitive testing every two years, on average. Neuroimaging was done at Barrow Neurological Institute and a 3D T1-weighted magnetic resonance image was obtained during scanning that allowed for subsequent texture analysis processing. Voxel-based features of the appearance, structure, and arrangement of these regions of interest were extracted utilizing the Mayo Clinic Python Texture Analysis Pipeline (pyTAP). Algorithms applied in feature extraction included Grey-Level Co-Occurrence Matrix (GLCM), Gabor Filter Banks (GFB), Local Binary Patterns (LBP), Discrete Orthogonal Stockwell Transform (DOST), and Laplacian-of-Gaussian Histograms (LoGH). Principal component (PC) analysis was used to reduce the dimensionality of the algorithmically selected features to 13 PCs. A stepwise forward regression model was used to determine the effect of APOE status (APOE e4 carriers vs. noncarriers), and the texture feature principal components on age (as a continuous variable). After identification of 5 significant predictors of age in the model, the individual feature coefficients of those principal components were examined to determine which features contributed most significantly to the prediction of an aging brain. Results: 70 texture features were extracted for the two regions of interest in each participant's scan. The texture features were coded as 70 initial components andwere rotated to generate 13 principal components (PC) that contributed 75% of the variance in the dataset by scree plot analysis. The forward stepwise regression model used in this exploratory study significantly predicted age, accounting for approximately 40% of the variance in the data. The regression model revealed 5 significant regressors (2 right PC's, APOE status, and 2 left PC by APOE interactions). Finally, the specific texture features that contributed to each significant PCs were identified. Conclusion: Analysis of image texture features resulted in a statistical model that was able to detect subtle changes in brain integrity associated with age in a group of participants who are cognitively normal, but have an increased risk of developing AD based on the presence of the APOE e4 phenotype. This is an important finding, given that detecting subtle changes in regions vulnerable to the effects of AD in patients could allow certain texture features to serve as noninvasive, sensitive biomarkers predictive of AD. Even with only a small number of patients, the ability for us to determine sensitive imaging biomarkers could facilitate great improvement in speed of detection and effectiveness of AD interventions..
ContributorsSilva, Annelise Michelle (Author) / Baxter, Leslie (Thesis director) / McBeath, Michael (Committee member) / Presson, Clark (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Does assisted cycle therapy influence activities of daily living in older adults with Down syndrome?
Description
The aim of this study is to examine the relationship between Assisted Cycle Therapy, leisure time activity levels, fine motor control, and grip force in older adults with Down syndrome (DS), all of which affect activities of daily living (ADL) and therefore quality of life. This is relevant because this particular group is at risk for developing early onset Alzheimer's disease (AD), which presents itself uniquely in this population. The parent or guardian of six participants with DS completed Godin's Leisure Time Exercise Questionnaire and the participants themselves completed Purdue Pegboard and grip force assessments before and after an 8-week exercise intervention. The results were inconsistent with past research, with no change being seen in fine motor control or grip force and a decrease being seen in leisure activity. These findings are indicative of the importance of the effect of fatigue on leisure activity as well as maintaining elevated heart rate throughout exercise interventions.
ContributorsGomez, Elizabeth Danielle (Author) / Ringenbach, Shannon (Thesis director) / Coon, David (Committee member) / Barrett, The Honors College (Contributor) / T. Denny Sanford School of Social and Family Dynamics (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
This case study analyzed the internal controls of a real estate company using the widely accepted COSO framework. Testing of the internal environment and controls was completed using the COSO framework. The major internal control problem identified in the study was a lack of ethical standards in the control environment. In addition to this main problem, inadequate documentation, no separation of duties, and unqualified employees were also identified as violations of effective internal controls. The department of real estate ordered a "cease and desist" on August 8, 2013 due to illegal company activities. The company participated in illegal actions regarding: the trust account and company documentation and procedures. Material weaknesses were found in the company's internal controls; therefore the result of this study was an adverse opinion on internal controls.
ContributorsFrederick, Nicole Lorraine (Author) / Munshi, Perseus (Thesis director) / Benali, Kayla (Committee member) / Barrett, The Honors College (Contributor) / School of Accountancy (Contributor) / Department of Psychology (Contributor)
Created2013-12
Description
Cognitive technology has been at the forefront of the minds of many technology, government, and business leaders, because of its potential to completely revolutionize their fields. Furthermore, individuals in financial statement auditor roles are especially focused on the impact of cognitive technology because of its potential to eliminate many of the tedious, repetitive tasks involved in their profession. Adopting new technologies that can autonomously collect more data from a broader range of sources, turn the data into business intelligence, and even make decisions based on that data begs the question of whether human roles in accounting will be completely replaced. A partial answer: If the ramifications of past technological advances are any indicator, cognitive technology will replace some human audit operations and grow some new and higher order roles for humans. It will shift the focus of accounting professionals to more complex judgment and analysis.
The next question: What do these changes in the roles and responsibilities look like for the auditors of the future? Cognitive technology will assuredly present new issues for which humans will have to find solutions.
• How will humans be able to test the accuracy and completeness of the decisions derived by cognitive systems?
• If cognitive computing systems rely on supervised learning, what is the most effective way to train systems?
• How will cognitive computing fair in an industry that experiences ever-changing industry regulations?
• Will cognitive technology enhance the quality of audits?
In order to answer these questions and many more, I plan on examining how cognitive technologies evolved into their use today. Based on this historic trajectory, stakeholder interviews, and industry research, I will forecast what auditing jobs may look like in the near future taking into account rapid advances in cognitive computing.
The conclusions forecast a future in auditing that is much more accurate, timely, and pleasant. Cognitive technologies allow auditors to test entire populations of transactions, to tackle audit issues on a more continuous basis, to alleviate the overload of work that occurs after fiscal year-end, and to focus on client interaction.
The next question: What do these changes in the roles and responsibilities look like for the auditors of the future? Cognitive technology will assuredly present new issues for which humans will have to find solutions.
• How will humans be able to test the accuracy and completeness of the decisions derived by cognitive systems?
• If cognitive computing systems rely on supervised learning, what is the most effective way to train systems?
• How will cognitive computing fair in an industry that experiences ever-changing industry regulations?
• Will cognitive technology enhance the quality of audits?
In order to answer these questions and many more, I plan on examining how cognitive technologies evolved into their use today. Based on this historic trajectory, stakeholder interviews, and industry research, I will forecast what auditing jobs may look like in the near future taking into account rapid advances in cognitive computing.
The conclusions forecast a future in auditing that is much more accurate, timely, and pleasant. Cognitive technologies allow auditors to test entire populations of transactions, to tackle audit issues on a more continuous basis, to alleviate the overload of work that occurs after fiscal year-end, and to focus on client interaction.
ContributorsWitkop, David (Author) / Dawson, Gregory (Thesis director) / Munshi, Perseus (Committee member) / School of Accountancy (Contributor) / Department of Information Systems (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The nuclear pore complex is a structure that is found in the nuclear envelope. The nuclear pore complex is made of proteins known as nucleoporins, or Nups. There are many classes of Nups, one of which is Nups with phenylalanine-guanine repeats (FG-Nups). The FG-Nups help control the transport of material through the nuclear pore complex. One type of FG-Nup is NupL2. Previous mRNA data have shown that there is lower expression of NupL2 in Alzheimer's Disease brains than there is in control brains. However, these data are specific to mRNA expression, and do not necessarily extend to NupL2 protein levels. This study focuses on NupL2 levels in non-diseased samples and Alzheimer's Disease samples. Immunohistochemistry (IHC) with 3,3'-diaminobenzidine was performed on temporal neo-cortical brain tissue. Western blots were also performed to quantify the protein levels in non-diseased samples and Alzheimer's Disease samples, and were completed using middle temporal gyrus lysates. The IHC results show that there is more NupL2 protein expression in non-diseased samples than there is in Alzheimer's Disease samples. Likewise, the western blot data show higher NupL2 protein levels in non-diseased samples than in Alzheimer's Disease samples. Both the IHC data and the western blot data indicate that there are higher NupL2 expression levels in non-diseased samples than in Alzheimer's Disease samples. Decreased NupL2 expression in Alzheimer's Disease may indicate that it is not functioning properly. This could lead to the leaking of material between the nucleoplasm and the cytoplasm, which may in turn contribute to Alzheimer's Disease pathogenesis.
ContributorsKulkarni, Neha Uday (Author) / Coleman, Paul (Thesis director) / Mastroeni, Diego (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
With no known cure, Alzheimer's disease (AD) is the most common dementia, affecting more than 5.5 million Americans. Research has shown that women who undergo surgical menopause (i.e. removal of the ovaries) before the onset of natural menopause are at a greater risk for AD. It is hypothesized that this greater relative risk of developing AD is linked to ovarian hormone deprivation associated with surgical menopause. The purpose of these studies was to evaluate the behavioral changes that occur after a short-term (ST) and a long-term (LT) ovarian hormone deprivation in a mouse model of AD. Wildtype (Wt) or APP/PS1 (Tg) mutation mice underwent either a sham surgery or an ovariectomy (Ovx) surgery at three months of age. Study 1 consisted of a short-term cohort that was behaviorally tested one month following surgery on a battery of spatial memory tasks including, the Morris water maze, delayed matched-to-sample water maze, and visible platform task. Study 2 consisted of a long-term cohort that was behaviorally tested on the same cognitive battery three months following surgery. Results of Study 1 revealed that genotype interacted with surgical menopause status, such that after a short-term ovarian hormone deprivation, Ovx induced a genotype effect while Sham surgery did not. Results of Study 2 showed a similar pattern of effects, with a comparable interaction between genotypes and surgical menopause status. These findings indicate that the cognitive impact of ovarian hormone deprivation depends on AD-related genotype. Neuropathology evaluations in these mice will be done in the near future and will allow us to test relations between surgical menopause status, cognition, and AD-like neuropathology.
ContributorsPalmer, Justin M. (Author) / Bimonte-Nelson, Heather (Thesis director) / Oddo, Salvatore (Committee member) / Davis, Mary (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Alzheimer’s disease (AD) is a progressive cognitive and behavior disorder that is characterized by the deposition of extracellular Aβ plaques, intracellular neurofibrillary tangles, and neuroinflammation. Aβ is generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and, subsequently, y- secretase. In recent years, there has been an increasing interest in studying and understanding inflammation as a therapeutic target for AD. Inflammation manifests in the brain in the form of activated microglia and astrocytes. These cells are able to release high levels of inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α). TNF-α is a major cytokine, which is involved in early inflammatory events and plays a role in the progression of AD pathology. There are currently no treatments that target chronic neuroinflammation. However, previous work in our laboratory with transgenic mice modeling AD suggested that the anti-cancer drug lenalidomide could lower neuroinflammation and slow AD progression, though the cellular and molecular mechanisms are yet to be elucidated. Here we hypothesized that lenalidomide can modulate TNF-α production in microglia and decrease amyloidogenesis. Using immortal cell lines mimicking several brain cell types, we discovered that lenalidomide is likely to decrease inflammation by modulating microglia cells rather than neurons or astrocytes. In addition, the drug may prevent the overexpression of BACE1 upon inflammation, thus blocking the overproduction of Aβ. If confirmed, these results could lead to a better understanding of how inflammation regulates Aβ synthesis and provide novel cellular and molecular therapeutic targets to control the progression AD.
ContributorsGujju, Manasa (Author) / DeCourt, Boris (Thesis director) / Olive, M. Foster (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
As life expectancy increases worldwide, age related diseases are becoming greater health concerns. One of the most prevalent age-related diseases in the United States is dementia, with Alzheimer’s disease (AD) being the most common form, accounting for 60-80% of cases. Genetics plays a large role in a person’s risk of developing AD. Familial AD, which makes up less than 1% of all AD cases, is caused by autosomal dominant gene mutations and has almost 100% penetrance. Genetic risk factors are believed to make up about 49%-79% of the risk in sporadic cases. Many different genetic risk factors for both familial and sporadic AD have been identified, but there is still much work to be done in the field of AD, especially in non-Caucasian populations. This review summarizes the three major genes responsible for familial AD, namely APP, PSEN1 and PSEN2. Also discussed are seven identified genetic risk factors for sporadic AD, single nucleotide polymorphisms in the APOE, ABCA7, NEDD9, CASS4, PTK2B, CLU, and PICALM genes. An overview of the main function of the proteins associated with the genes is given, along with the supposed connection to AD pathology.
ContributorsRichey, Alexandra Emmeline (Author) / Brafman, David (Thesis director) / Raman, Sreedevi (Committee member) / School of International Letters and Cultures (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Alzheimer’s disease is a disease that can affect cognition, perception and behavior and is currently untreatable. It was discovered in the early 20th century and while significant scientific advancements have occurred, there is ambiguity that remains to be researched and understood. Latinos are the largest ethnic minority in the United States and while data still needs to be uncovered, possible risk factors for developing Alzheimer’s include heart issues, poverty and obesity, age and education level, to name a few. Poverty is linked to obesity, diabetes and a low education level, which in turn have been found to have an impact on Alzheimer’s and all factors impact cardiovascular and vascular health. Due to the collectivistic culture that is deeply rooted in Latinos, there is a strong sense of family that is upheld when caring for relatives who are afflicted and may be hesitant to receive the care that is needed. Other barriers include financial stability, linguistic and cultural barriers, underutilizing resources and health literacy. There are still research gaps that are yet to be filled like brain health and longitudinal studies for Latinos, but current treatments like diet and culturally competent professionals can help with the prognosis. Alzheimer’s is a complex disease, but with the numerous efforts made thus far, such as creating the LatinosAgainstAlzheimer’s Network, it will soon be able to be understood and hopefully eradicated.
ContributorsJimenez, Brittney (Author) / Wilson, Melissa (Thesis director) / Susan, Holechek (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05