Life Sciences Commons^™

High Volume Multiplex Staining Of Mouse Model In Alzheimer’S Associated Disease Pathology, Chloe Embry

Lewis Honors College Thesis Collection

Although neurodegenerative diseases are often clinically distinct, they typically share common pathological markers. One of the most common causes of clinical dementia is Alzheimer’s disease (AD). Pathologically, AD is defined by the presence of intercellular tangles composed of hyperphosphorylated tau proteins and extracellular plaques made of abnormally cleaved amyloid-beta proteins. However recent genome-wide association studies have also found that many of the predispositions for AD are located on or near genes highly expressed in microglia. In the healthy CNS, microglia act as the brain’s immune system and are chiefly involved in neuronal support and maintaining homeostasis throughout the CNS. Typically, …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …

Affective Computing For Late-Life Mood And Cognitive Disorders, Erin Smith, Eric A. Storch, Ipsit Vahia, Stephen T.C. Wong, Helen Lavretsky, Jeffrey L. Cummings, Harris A. Eyre

Brain Health Faculty Publications

Affective computing (also referred to as artificial emotion intelligence or emotion AI) is the study and development of systems and devices that can recognize, interpret, process, and simulate emotion or other affective phenomena. With the rapid growth in the aging population around the world, affective computing has immense potential to benefit the treatment and care of late-life mood and cognitive disorders. For late-life depression, affective computing ranging from vocal biomarkers to facial expressions to social media behavioral analysis can be used to address inadequacies of current screening and diagnostic approaches, mitigate loneliness and isolation, provide more personalized treatment approaches, and …

The Costs Of Developing Treatments For Alzheimer’S Disease: A Retrospective Exploration, Jeffrey L. Cummings, Dana P. Goldman, Nicholas R. Simmons-Stern, Eric Ponton

School of Medicine Faculty Publications

Introduction: With the exception of the recent accelerated approval of aducanumab, in over 26 years of research and development (R&D) investment in Alzheimer's disease (AD), only five novel drugs—all for symptomatic treatment only—have reached FDA approval. Here, we estimate the costs of AD drug development during this period in the private sector. Methods: To estimate private R&D funding, we collected information on AD clinical trials (n = 1099; phases 1–4) conducted between January 1, 1995 and June 21, 2021 from various databases. Costs were derived using previously published methodologies and adjusted for inflation. Results: Since 1995, cumulative private expenditures on …

Estimating Progression Rates Across The Spectrum Of Alzheimer’S Disease For Amyloid-Positive Individuals Using National Alzheimer’S Coordinating Center Data, Michele Potashman, Marric Buessing, Mihaela Levitchi Benea, Jeffrey Cummings, Soo Borson, Peter Pemberton-Ross, Andrew J. Epstein

School of Medicine Faculty Publications

Introduction: Published estimates of Alzheimer’s disease (AD) progression do not capture the full disease continuum. This study provides transition probabilities of individuals with amyloid-β (Aβ+) pathology across the disease continuum. Methods: Patient-level longitudinal data from the National Alzheimer’s Coordinating Center were used to estimate progression rates. Progression rates through five clinically defined AD stages—asymptomatic, mild cognitive impairment due to AD (MCI-AD), mild AD dementia, moderate AD dementia, severe AD dementia—and death were measured as transition probabilities. Rates were assessed in “incident” patients who recently entered the stage, controlling for covariates. Transition probabilities were generated from multinomial logit regression models that …

A Randomized, Double-Blind, Phase 2b Proof-Of-Concept Clinical Trial In Early Alzheimer’S Disease With Lecanemab, An Anti-Aβ Protofibril Antibody, Chad J. Swanson, Yong Zhang, Shobha Dhadda, Jinping Wang, June Kaplow, Robert Y.K. Lai, Lars Lannfelt, Heather Bradley, Martin Rabe, Akihiko Koyama, Larisa Reyderman, Donald A. Berry, Scott Berry, Robert Gordon, Lynn D. Kramer, Jeffrey L. Cummings

School of Medicine Faculty Publications

Background: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. Methods: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite …

Prediction Of Alzheimer’S Disease-Specific Phospholipase C Gamma-1 Snv By Deep Learning-Based Approach For High-Throughput Screening, Sung Hyun Kim, Sumin Yang, Key Hwan Lim, Euiseng Ko, Hyun Jun Jang, Mingon Kang, Pann Ghill Suh, Jae Yeol Joo

Computer Science Faculty Research

© 2021 National Academy of Sciences. All rights reserved. Exon splicing triggered by unpredicted genetic mutation can cause translational variations in neurodegenerative disorders. In this study, we discover Alzheimer’s disease (AD)-specific single-nucleotide variants (SNVs) and abnormal exon splicing of phospholipase c gamma-1 (PLCγ1) gene, using genome-wide association study (GWAS) and a deep learning-based exon splicing prediction tool. GWAS revealed that the identified single-nucleotide variations were mainly distributed in the H3K27ac-enriched region of PLCγ1 gene body during brain development in an AD mouse model. A deep learning analysis, trained with human genome sequences, predicted 14 splicing sites in human PLCγ1 gene, …

A Conformation Variant Of P53 Combined With Machine Learning Identifies Alzheimer Disease In Preclinical And Prodromal Stages, Giulia Abate, Marika Vezzoli, Letizia Polito, Antonio Guaita, Diego Albani, Moira Marizzoni, Emirena Garrafa, Alessandra Marengoni, Gianluigi Forloni, Giovanni B. Frisoni, Jeffrey L. Cummings, Maurizio Memo, Daniela Uberti

School of Medicine Faculty Publications

© 2020 by the authors. Li-censee MDPI, Basel, Switzerland. Early diagnosis of Alzheimer’s disease (AD) is a crucial starting point in disease man-agement. Blood-based biomarkers could represent a considerable advantage in providing AD-risk information in primary care settings. Here, we report new data for a relatively unknown blood-based biomarker that holds promise for AD diagnosis. We evaluate a p53-misfolding conformation rec-ognized by the antibody 2D3A8, also named Unfolded p53 (U-p532D3A8+), in 375 plasma samples derived from InveCe.Ab and PharmaCog/E-ADNI longitudinal studies. A machine learning approach is used to combine U-p532D3A8+ plasma levels with Mini-Mental State Examination (MMSE) and apolipoprotein E …

New Approaches To Symptomatic Treatments For Alzheimer’S Disease, Jeffrey Cummings

School of Medicine Faculty Publications

Background: Successful development of agents that improve cognition and behavior in Alzheimer’s disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder. Discussion: There have been no recent approvals of cognitive enhancing agents for AD. There are currently 6 cognitive enhancers in Phase 2 trials and 4 in phase 3. They represent a variety of novel mechanisms. There has been progress in developing new treatments for neuropsychiatric symptoms in AD with advances in treatment of insomnia, psychosis, apathy, and agitation in AD. There are currently 4 AD-related psychotropic agents in Phase 2 trials …

The Interplay Of Progestins, Matrix Metalloproteinases, And The Aging Brain, Keyana Nicole Porter

Graduate Theses, Dissertations, and Problem Reports

Progestins are synthetic hormones that are designed to mimic the biological actions of progesterone. They, however, possess other pharmacological actions and properties, in addition to their progestational activities. Medroxyprogesterone Acetate (MPA) is a progestin used globally in the hormonal contraceptive, Depo Provera®, by women in their reproductive prime and is a major compound found in hormone therapy (HT) formulations used by menopausal women. MPA is used by approximately 1 in 5 adolescents and adult women in the United States who are sexually active. Globally, nearly 48 million women utilize injectable contraceptives to prevent pregnancy, with most users utilizing MPA as …

Resedent Study- Reducing Sedentary Behaviour May Slow Cognitive Decline In Older Adults With Mild Cognitive Impairment: A Pilot Study, Kirsten B. Dillon

Electronic Thesis and Dissertation Repository

Physical activity (PA) has been shown to slow down dementia. Unfortunately, older adults spend most of their day in sedentary behaviours (SB). Breaking up prolonged bouts of sitting with intermittent bouts of light intensity PA may reduce glycemic variability in the brain; potentially mitigating cognitive decline. This study investigated how interrupting SB with 10 min bouts of light intensity PA 3x a day would affect mild to moderate cognitive impairment progression (primary outcome) in older adults residing in an assisted living facility. Participants (n=25) were assigned in clusters into a two arm 10-week single site pilot randomized controlled trial. Secondary …

Visual And Verbal Serial List Learning In Patients With Statistically-Determined Mild Cognitive Impairment., Victor Wasserman, Sheina Emrani, Emily F Matusz, David Miller, Kelly Davis Garrett, Katherine A Gifford, Timothy J Hohman, Angela L Jefferson, Rhoda Au, Rod Swenson, David J Libon, Consortium For Clinical And Epidemiological Neuropsychological Data Analysis (Cenda).

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Background and Objective: Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes.

Research Design and Methods: Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively.

Results: BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored …

Astrocyte Activation And The Calcineurin/Nfat Pathway In Cerebrovascular Disease, Susan D. Kraner, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Calcineurin (CN) is a Ca²⁺/calmodulin-dependent protein phosphatase with high abundance in nervous tissue. Though enriched in neurons, CN can become strongly induced in subsets of activated astrocytes under different pathological conditions where it interacts extensively with the nuclear factor of activated T cells (NFATs). Recent work has shown that regions of small vessel damage are associated with the upregulation of a proteolized, highly active form of CN in nearby astrocytes, suggesting a link between the CN/NFAT pathway and chronic cerebrovascular disease. In this Mini Review article, we discuss CN/NFAT signaling properties in the context of vascular disease and …

Ca2+, Astrocyte Activation And Calcineurin/Nfat Signaling In Age-Related Neurodegenerative Diseases, Pradoldej Sompol, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Mounting evidence supports a fundamental role for Ca²⁺ dysregulation in astrocyte activation. Though the activated astrocyte phenotype is complex, cell-type targeting approaches have revealed a number of detrimental roles of activated astrocytes involving neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation. Work from our lab and others has suggested that the Ca²⁺/calmodulin dependent protein phosphatase, calcineurin (CN), provides a critical link between Ca²⁺ dysregulation and the activated astrocyte phenotype. A proteolyzed, hyperactivated form of CN appears at high levels in activated astrocytes in both human tissue and rodent tissue around regions of amyloid and …

Combined Mnemonic Strategy Training And High-Definition Transcranial Direct Current Stimulation For Memory Deficits In Mild Cognitive Impairment, Benjamin M. Hampstead, Krishnankutty Sathian, Marom Bikson, Anthony Y. Stringer

Publications and Research

Introduction: Memory deficits characterize Alzheimer’s dementia and the clinical precursor stage known as mild cognitive impairment. Nonpharmacologic interventions hold promise for enhancing functioning in these patients, potentially delaying functional impairment that denotes transition to dementia. Previous findings revealed that mnemonic strategy training (MST) enhances long-term retention of trained stimuli and is accompanied by increased blood oxygen level–dependent signal in the lateral frontal and parietal cortices as well as in the hippocampus. The present study was designed to enhance MST generalization, and the range of patients who benefit, via concurrent delivery of transcranial direct current stimulation (tDCS).

Methods: This protocol describes …

Contribution Of Trpm2 To Memory Loss In An Alzheimer's Mouse Model, Megan M. Chen

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive deterioration of memory and other intellectual abilities. Accumulation of amyloid-β (Aβ) peptide, the major contributor to the senile plaques central to AD, is thought to mediate neurotoxicity by inducing oxidative stress and calcium dysregulation. Transient Receptor Potential Melastatin type 2 (TRPM2) is a calcium permeable, non-selective cation channel activated under oxidative stress and ultimately induces cell death. The APPSWE/PSEN1ΔE9 double transgenic mouse model carries the human APPswe (Swedish mutations K594N/M595L) and PS1 mutations with a deletion in exon 9 (PS1-dE9), and is one of the most commonly used AD …