Medicine and Health Sciences Commons^™

Meditation On The Soles Of The Feet Practice Provides Some Control Of Aggression For Individuals With Alzheimer’S Disease, Nirbhay N. Singh, Giulio E. Lancioni, Oleg N. Medvedev, Rachel E. Myers

Faculty and Research Publications

Alzheimer’s disease is a progressive neurodegenerative condition that affects cognition, mental and physical health, and functionality of older people. As the disease progresses from the mild to moderate stage, there is a concomitant increase in several behavioral variables, chiefly agitation, anger, and aggression. Currently, there are no evidence-based treatments for these behaviors in this population. Three individuals with moderate Alzheimer’s disease were taught an informal mindfulness practice, meditation on the Soles of the Feet (SoF), as a self-management strategy within a multiple-baseline design across participants. All three were able to learn and use the SoF practice to manage their verbal …

The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi

Arts & Sciences Electronic Theses and Dissertations

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …

Multifunctional Donepezil Analogues As Cholinesterase And Bace1 Inhibitors, Keith D. Green, Marina Y. Fosso, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC₅₀ = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC₅₀ = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was …

Mitochondrial Metabolism In Major Neurological Diseases, Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson, Ramon Sun

Molecular and Cellular Biochemistry Faculty Publications

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly …

Cyclophilin 40 As A Novel Disaggregase, Jeremy Dustin Baker

USF Tampa Graduate Theses and Dissertations

The negative health and economic impacts of neurodegenerative diseases on Americans is astounding and accelerating with an aging population. The Alzheimer’s Association reports that 5.7 million Americans suffer from Alzheimer’s disease (AD), a number which is expected to increase to 14 million by 2050. In economic terms, AD and other neurodegenerative disorders will cost the US over $275 billion in 2018, rising to over $1 trillion annually by 2050. AD causes gross brain atrophy and is most damaging throughout the cortex and the hippocampus, regions required for higher cognitive function and memory. AD presents as tangles within neurons composed of …

Proteolysis Of Cx3cl1 Impacts Cx3cr1 Signaling And Therapeutic Benefits In A Tauopathy Model, Dylan John Finneran

USF Tampa Graduate Theses and Dissertations

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and the most common form of dementia. The hallmark pathologies of AD are extracellular aggregates of amyloid-beta, intracellular aggregates of microtubule associated protein tau and increased neuroinflammation. Current therapeutics offer only symptomatic relief and clinical trials investigating therapeutic benefits of non-steroidal anti-inflammatory drugs have yielded no positive results. Therefore, recent work has focused on immunomodulators, such as CD200 and fractalkine, as potential therapeutic targets for AD.

Fractalkine (CX3CL1; FKN) is expressed as a transmembrane protein with an N-terminal chemokine domain followed by a long, mucin-like stalk. FKN can signal as a membrane-bound …

Therapeutic Effect Of Rho Kinase Inhibitor Fsd-C10 In A Mouse Model Of Alzheimer's Disease., Qing-Fang Gu, Jie-Zhong Yu, Hao Wu, Yan-Hua Li, Chun-Yun Liu, Ling Feng, Guang-Xian Zhang, Bao-Guo Xiao, Cun-Gen Ma

Department of Neurology Faculty Papers

Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of …

Rna Binding Proteins Co-Localize With Small Tau Inclusions In Tauopathy, Brandon F. Maziuk, Daniel J. Apicco, Anna Lourdes Cruz, Lulu Jiang, Peter E. A. Ash, Edroaldo Lummertz De Rocha, Cheng Zhang, Wai Haung Yu, John Leszyk, Jose F. Abisambra, Hu Li, Benjamin Wolozin

Sanders-Brown Center on Aging Faculty Publications

The development of insoluble, intracellular neurofibrillary tangles composed of the microtubule-associated protein tau is a defining feature of tauopathies, including Alzheimer’s disease (AD). Accumulating evidence suggests that tau pathology co-localizes with RNA binding proteins (RBPs) that are known markers for stress granules (SGs). Here we used proteomics to determine how the network of tau binding proteins changes with disease in the rTg4510 mouse, and then followed up with immunohistochemistry to identify RNA binding proteins that co-localize with tau pathology. The tau interactome networks revealed striking disease-related changes in interactions between tau and a multiple RBPs, and biochemical fractionation studies demonstrated …

Longitudinal Alzheimer's Degeneration Reflects The Spatial Topography Of Cholinergic Basal Forebrain Projections, Taylor W. Schmitz, Marieke Mur, Meghmik Aghourian, Marc Andre Bedard, R. Nathan Spreng

Brain and Mind Institute Researchers' Publications

© 2018 The Author(s) The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain's cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer's disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To …

Treatment Of Mci And Alzheimer's Disease, Mark A. Lovell, Bert C. Lynn

Chemistry Faculty Patents

The present invention provides, among other things, therapeutic compositions and methods that can effectively treat, slow or prevent a neurological disease (e.g., a neurodegenerative disease, e.g., mild cognitive impairment (MCI) or Alzheimer's disease (AD)), in particular, based on therapeutically effective amount of nifedipine, oxidized or nitroso nifedipine derivatives, lactam (e.g., a compound of formula (Ic) or (Ic-i), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof.

The Comparison Of Effective Education Methods To Increase Knowledge About Alzheimer's Disease., Lillian M. Kopsolias

College of Arts & Sciences Senior Honors Theses

Alzheimer’s disease (AD) is a disease most people recognize, but have many misconceptions about. One way to decrease the amount of misconceptions about AD is to educate the general public on the disease. Many educational methods, such as person-centered care education, have been researched, but none have focused on the general public. Therefore, the purpose of this study is to compare two educational methods used today, reading a passage from a reliable online source (traditional educational method) and watching documentaries (person-centered care educational method), to find if a specific way of presenting them will prove efficient for Alzheimer’s education. The …

The Effects Of Occupation-Based Activities On Problem Behaviors And Quality Of Life Of People With Dementia, Kelly Souza, Nicole Utt

School of Occupational Therapy Master's Capstone Projects (2016-2021)

Cathryn Schaffer and Sonia Nurkse, occupational therapists in an inpatient rehabilitation unit at Good Samaritan of Multicare in Puyallup, WA, proposed a research question: Can occupation-based activities be used to improve quality of life and/or reduce problem behaviors in adults with dementia-related cognitive impairment? Five databases were searched for articles published from 2007 to 2017, resulting in 23 articles that met search criteria. Interventions that did not take extensive time, training, or resources were included with the intention that they would be easily incorporated into a caregiver or health professional’s routine. Multiple interventions were found that address problem behaviors and/or …

Targeting The Hsp90/Aha1 Complex For The Treatment Of Tauopathies, Lindsey Brooke Shelton

USF Tampa Graduate Theses and Dissertations

The microtubule associated protein, tau, is involved in regulating microtubule stability and axonal transport. When tau becomes hyperphosphorylated it can disassociate from the microtubules and start to aggregate. These tau aggregates are the hallmarks of many diseases known as tauopathies. The heat shock protein 90 kDa (Hsp90) chaperone network is highly involved in modulating client proteins, including tau. However, during aging and disease the Hsp90 chaperone network becomes highly imbalanced with some Hsp90/co-chaperone complexes increasing, while others are repressed. This imbalance in Hsp90/co-chaperone complexes could result in a worsening of tau pathology in Alzheimer’s disease.

Hsp90 inhibition has been of …

Association Between Alzheimer's Disease And Rural Northeast Tennessee Region Between 2013 And 2015, Sylvester Olubolu Orimaye, Jodi Southerland

Appalachian Student Research Forum

Background: Alzheimer’s disease (AD) is a type of Dementia and a neurodegenerative disease that is characterized by the gradual degrading of both memory and cognitive functions. According to the World Health Organization (WHO), the prevalence of AD is increasing globally. Currently, AD is the sixth leading cause of mortality in the United States. As the ageing population increases in the United States, it is possible that AD will move up the ladder in the top cause of mortality. Although the prevalence of AD in most urban parts of developed nations such as the United States is widely known, little is …

Representing Diversity In The Dish: Using Patient-Derived In Vitro Models To Recreate The Heterogeneity Of Neurological Disease, Layla T. Ghaffari, Alexander Starr, Andrew T. Nelson, Rita Sattler

Department of Neuroscience Faculty Papers

Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic …

Insulin-Degrading Enzyme Is Not Secreted From Cultured Cells, Eun Suk Song, David W. Rodgers, Louis Hersh

Molecular and Cellular Biochemistry Faculty Publications

Insulin-degrading enzyme (IDE) functions in the catabolism of bioactive peptides. Established roles include degrading insulin and the amyloid beta peptide (Aβ), linking it to diabetes and Alzheimer’s disease. IDE is primarily located in the cytosol, and a longstanding question is how it gains access to its peptide substrates. Reports suggest that IDE secreted by an unconventional pathway participates in extracellular hydrolysis of insulin and Aβ. We find that IDE release from cultured HEK-293 or BV-2 cells represents only ~1% of total cellular IDE, far less than has been reported previously. Importantly, lactate dehydrogenase (LDH) and other cytosolic enzymes are released …

Amyloid-Beta Solubility In The Treatment Of Alzheimer's Disease, Michael Paul Murphy

Molecular and Cellular Biochemistry Faculty Publications

No abstract provided.

Neurodegenerative Disease Biomarkers Aβ1–40, Aβ1–42, Tau, And P-Tau181 In The Vervet Monkey Cerebrospinal Fluid: Relation To Normal Aging, Genetic Influences, And Cerebral Amyloid Angiopathy, Jason A. Chen, Scott C. Fears, Anna J. Jasinska, Alden Huang, Noor B. Al-Sharif, Kevin E. Scheibel, Thomas D. Dyer, Anne M. Fagan, John Blangero, M. J. Jorgensen, J. R. Kaplan, N. B. Freimer, Giovanni Coppol

School of Medicine Publications and Presentations

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood.

Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits.

Results: Aβ1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume …

Genetic Manipulation Of Lactate Metabolism To Regulate Memory And Alzheimer's Disease Pathogenesis, Brainscan , Western University, Robert Cumming, Robert Bartha, Tim Scholl

Project Summaries

Our project will attempt to determine the relative importance of astrocyte or neuronal directed lactate generation on memory by modifying mouse models to either suppress or overexpress the lactate producing enzyme in either cell type. Using these newly created transgenic mouse models, we aim to understand the processes of production and utilization of lactate and its effect on memory and cognition in health and in AD across the lifespan. The outcome of our study may lead to entirely new clinical approaches to treating cognitive and neurodegenerative disorders via drugs which alter lactate metabolism.

Pet And Mri Measurements Of Neuroinflammation And Brain Plasticity After A Stroke, Brainscan , Western University, Jonathan Thiessen, Shawn Whitehead, Justin Hicks, Matthew Fox

Project Summaries

We are going to assess brain structure and function using magnetic resonance imaging (MRI) and positron emission tomography (PET) to study white matter inflammation and the density of synapses over time, alongside a behavioural assessment of motor and executive function. This kind of comprehensive assessment, especially using PET to measure synaptic density, has not been done before.

Integrating Behavioural, Imaging And Transcriptional Profiling To Discover The Impact Of Midlife Stress In Alzheimer's Disease, Brainscan , Western University, Tim Bussey, Flavio Beraldo, Chakravarty Maller, Rosemary Bagot, Sylvain Williams, Claudia Kleinman

Project Summaries

We will be integrating this cognitive assessment with imaging of brain structure and function to understand the mechanisms by which a risk factor, in this case modifiable life stress, influences Alzheimer's disease-related decline. The resultant data will be integrated and disseminated using a new open-access neuroinformatics platform developed at Western (MouseBytes.ca), which will become a unique resource for open science investigations and set the standard for sharing of behavioural data across the world.

The Price Of Progress: Funding And Financing Alzheimer's Disease Drug Development, Jeffrey Cummings, Carl Reiber, Parvesh Kumar

School of Medicine Faculty Publications

Introduction Advancing research and treatment for Alzheimer's disease (AD) and the search for effective treatments depend on a complex financial ecosystem involving federal, state, industry, advocacy, venture capital, and philanthropy funding approaches. Methods We conducted an expert review of the literature pertaining to funding and financing of translational research and drug development for AD. Results The federal government is the largest public funder of research in AD. The National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, and National Center for Advancing Translational Science all fund aspects of research in AD drug development. Non-National …

White Matter Hyperintensities And The Mediating Role Of Cerebral Amyloid Angiopathy In Dominantly-Inherited Alzheimer’S Disease, Seonjoo Lee, Molly E. Zimmerman, Atul Narkhede, Sara E. Nasrabady, Giuseppe Tosto, Irene B. Meier, Tammie L.S. Benzinger, Daniel S. Marcus, Anne M. Fagan, Nick C. Fox, Nigel J. Cairns, David M. Holtzman, Virginia Buckles, Bernardino Ghetti, Eric Mcdade, Ralph Martins, Andrew J. Saykin, Colin L. Masters, John M. Ringman, Stefan Fӧrster, Peter R. Schofield, Reisa A. Sperling, Keith A. Johnson, Jasmeer P. Chhatwal, Stephen Salloway, Stephen Correia, Clifford R. Jack, Jr, Michael Weiner, Randall J. Bateman, John C. Morris, Richard Mayeux, Adam M. Brickman

Research outputs 2014 to 2021

Introduction: White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD.

Participants and methods: Participants (n = 175, …

Inflammation As A Central Mechanism In Alzheimer's Disease, Jefferson W. Kinney, Shane M. Bemiller, Andrew S. Murtishaw, Amanda M. Leisgang, Arnold M. Salazar, Bruce T. Lamb

Psychology Faculty Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed …

Efficient Production Of A Mature And Functional Gamma Secretase Protease, Imran Khan, Sudarsan Krishnaswamy, Miheer Sabale, David M. Groth, Linda Wijaya, Michael Morici, Imre Berger, Christiane Schaffitzel, Paul E. Fraser, Ralph N. Martins, Giuseppe Verdile

Research outputs 2014 to 2021

Baculoviral protein expression in insect cells has been previously used to generate large quantities of a protein of interest for subsequent use in biochemical and structural analyses. The MultiBac baculovirus protein expression system has enabled, the use of a single baculovirus to reconstitute a protein complex of interest, resulting in a larger protein yield. Using this system, we aimed to reconstruct the gamma (γ)-secretase complex, a multiprotein enzyme complex essential for the production of amyloid-β (Aβ) protein. A MultiBac vector containing all components of the γ-secretase complex was generated and expression was observed for all components. The complex was active …

Therapeutic Cocktail Approach For Treatment Of Hyperhomocysteinemia In Alzheimer’S Disease, Michael Leon, Darrell Sawmiller, R. Douglas Shytle, Jun Tan

Neurosurgery and Brain Repair Faculty Publications

In the United States, Alzheimer's disease (AD) is the most common cause of dementia, accompanied by substantial economic and emotional costs. During 2015, more than 15 million family members who provided care to AD patients had an estimated total cost of 221 billion dollars. Recent studies have shown that elevated total plasma levels of homocysteine (tHcy), a condition known as hyperhomocysteinemia (HHcy), is a risk factor for AD. HHcy is associated with cognitive decline, brain atrophy, and dementia; enhances the vulnerability of neurons to oxidative injury; and damages the blood–brain barrier. Many therapeutic supplements containing vitamin B12 and folate have …

Factors Influencing Alzheimer's Disease Healthcare Utilization Patterns In Puerto Rico, Carlamarie Noboa

Walden Dissertations and Doctoral Studies

Alzheimer's disease (AD) is associated with substantial healthcare utilization costs, resulting in a public health priority. In this study, the relationship between the demographic characteristics of age, gender, and type of health insurance; the presence of comorbidities of older Puerto Rican residents diagnosed with AD; and their healthcare utilization patterns (i.e., medical office and emergency room visits and hospital admissions) was examined using Andersen's behavioral model. Data from the 2013 Puerto Rico Health Study was used in this retrospective cohort design study. All AD cases aged -?¥ 60 years were extracted using systematic random sampling. One-way ANOVA-WELCH, Mann-Whitney U test, …

Biomedical Informatics Applications For Precision Management Of Neurodegenerative Diseases, Justin B. Miller, Guogen Shan, Joseph Lombardo, Gustavo Jimenez-Maggoria

Public Health Faculty Publications

Modern medicine is in the midst of a revolution driven by “big data,” rapidly advancing computing power, and broader integration of technology into healthcare. Highly detailed and individualized profiles of both health and disease states are now possible, including biomarkers, genomic profiles, cognitive and behavioral phenotypes, high-frequency assessments, and medical imaging. Although these data are incredibly complex, they can potentially be used to understand multi-determinant causal relationships, elucidate modifiable factors, and ultimately customize treatments based on individual parameters. Especially for neurodegenerative diseases, where an effective therapeutic agent has yet to be discovered, there remains a critical need for an interdisciplinary …

Left Lateralized Cerebral Glucose Metabolism Declines In Amyloid-Β Positive Persons With Mild Cognitive Impairment, Christopher M. Weise, Kewei Chen, Yinghua Chen, Xiaoying Kuang, Cary R. Savage, Eric M. Reiman

Center for Brain, Biology and Behavior: Papers & Publications

Background: Previous publications indicate that Alzheimer's Disease (AD) related cortical atrophy may develop in asymmetric patterns, with accentuation of the left hemisphere. Since fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide a sensitive and specific marker of neurodegenerative disease progression, we sought to investigate the longitudinal pattern of rCMRgl in amyloid-positive persons with mild cognitive impairment (MCI) and dementia, hypothesizing asymmetric declines of cerebral glucose metabolism. Methods: Using florbetapir PET and cerebrospinal fluid (CSF) measures to define amyloid-β (Aβ) positivity, 40 Aβ negative (Aβ-) cognitively unimpaired controls (CU; 76 ± 5y), …

A Story To Tell Among Minority Alzheimer's Patient Caregivers: A Phenomenological Study, Albertina Lashonda Walker

Walden Dissertations and Doctoral Studies

The level of burden experienced by caregivers of patients diagnosed with Alzheimer's disease is high. Studies that examine this burden by taking into account cultural and spiritual differences are limited, particularly with regard to minority populations. The purpose of this study was to investigate the burden and challenges faced by minority caregivers providing in-home care to Alzheimer's patients. Guided by social support theory, a phenomenological study design was used with semi-structured interviews of 12 caregivers to examine their perspectives on the burden and challenges they face, including their lived experiences, cultural and spiritual values, and interaction with health professionals. Thematic …