Developmental Neuroscience Commons^™

Data Reporting Quality And Semantic Interoperability Increase With Community-Based Data Elements (Codes). Analysis Of The Open Data Commons For Spinal Cord Injury (Odc-Sci), Anushka Sheoran, Kenneth A. Fond, Lex Maliga Davis, J. R. Huie, Romana Vavrek, P. J. Axtman, Vance P. Lemmon, John L. Bixby, Ubbo Visser, John C. Gensel, Karim Fouad, Adam R. Ferguson, Jeffrey S. Grethe, Anita Bandrowski, Maryann E. Martone, Abel Torres-Espin

Neurology Faculty Publications

Data interoperability is crucial for effectively combining data for scientific inquiry. To facilitate interoperability, data standards such as a common definition of variables are often developed. The Open Data Commons for Spinal Cord Injury (odc-sci.org) has established an initial set of community-based data elements (CoDEs)—a minimal set of variables for sharing—to promote data interoperability in SCI research, aligning with FAIR (Findable, Accessible, Interoperable, and Reusable) data principles. We sought to understand the use of CoDEs by the SCI community to inform current standards adherence and future standards development. We systematically analyzed 39 public datasets in relation to 17 required CoDEs …

Plasma S100Β Is A Predictor For Pathology And Cognitive Decline In Alzheimer’S Disease, Geetika Nehra, Bryan J. Maloney, Rebecca Smith, Wijitra Chumboatong, Erin L. Abner, Peter T. Nelson, Björn Bauer, Anika M. S. Hartz

UK CARES Faculty Publications

Background Blood–brain barrier dysfunction is one characteristic of Alzheimer’s disease (AD) and is recognized as both a cause and consequence of the pathological cascade leading to cognitive decline. The goal of this study was to assess markers for barrier dysfunction in postmortem tissue samples from research participants who were either cognitively normal individuals (CNI) or diagnosed with AD at the time of autopsy and determine to what extent these markers are associated with AD neuropathologic changes (ADNC) and cognitive impairment.

Methods We used postmortem brain tissue and plasma samples from 19 participants: 9 CNI and 10 AD dementia patients who …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer’S Disease Detection And Monitoring, Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O’Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg

Neurology Faculty Publications

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer’s Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Weighted Family History Density Of Substance Use: Influence On Participant Substance Use Onset, Escalation, And Duration, Carleigh A. Litteral

Theses and Dissertations--Psychology

Substance use disorders impose a staggering toll on the United States (U.S.), straining healthcare systems, destabilizing communities, and profoundly impacting both individuals and families. Approximately one in six Americans aged 12 and older had a past-year substance use disorder in 2022 (Key Substance Use, 2022), and nearly one-third of adults experience a substance use disorder in their lifetime (Wu, 2010), contributing to an economic burden exceeding $400 billion annually (National Drug Threat Assessment, 2011). Family history of substance use disorders is a key predictor of vulnerability, with individuals who have affected relatives being 2–8 times more …

Parallel Electrophysiological Abnormalities Due To Covid-19 Infection And To Alzheimer’S Disease And Related Dementia, Yang Jiang, Jennifer Neal, Pradoldej Sompol, Görsev Yener, Xianghong Arakaki, Christopher M. Norris, Francesca R. Farina, Agustin Ibanez, Susanna Lopez, Abdulhakim Al-Ezzi, Voyko Kavcic, Bahar Güntekin, Claudio Babiloni, Mihály Hajós

Neurology Faculty Publications

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting “brain fog” and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer’s disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients resemble those observed in early stages of neurodegenerative diseases, particularly ADRD. It is proposed that similar EEG abnormalities in …

Cerebrovascular Reactivity Mri As A Biomarker For Cerebral Small Vessel Disease–Related Cognitive Decline: Multi-Site Validation In The Markvcid Consortium, Peiying Liu, Zixuan Lin, Kaisha Hazel, George Pottanat, Cuimei Xu, Dengrong Jiang, Jay J. Pillai, Emma Lucke, Christopher E. Bauer, Brian T. Gold, Steven M. Greenburg, Karl G. Helmer, Kay Jann, Gregory Jicha, Joel Kramer, Pauline Maillard, Rachel M. Mulavelil, Pavel Rodriguez, Claudia L. Satizabal, Kristin Schwab, Sudha Seshadri, Herpreet Singh, Ángel G. Velarde Dediós, Danny J. J. Wang, Rita R. Kalyani, Abhay Moghekar, Paul B. Rosenberg, Sevil Yasar, Marilyn Albert, Hanzhang Lu

Neurology Faculty Publications

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis.

METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes.

RESULTS: CVR …

Decentralized Clinical Trials For Medications To Reduce The Risk Of Dementia: Consensus Report And Guidance, Leanne Howard, Carla Abdelnour, Erin Abner, Ricardo F. Allegri, Hiroko H. Dodge, Serge Gauthier, Camilla M. Hoyos, Gregory Jicha, Patrick G. Kehoe, Catherine J. Mummery, Adesola Ogunniyi, Nikolaos Scarmeas, Xiaoying Chen, Jodie R. Titiner, Christopher R. Weber, Ruth Peters

Neurology Faculty Publications

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field.

METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations.

RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention …

Alzheimer’S Disease And Inflammatory Biomarkers Positively Correlate In Plasma In The Uk-Adrc Cohort, Kate E. Foley, Zachary Winder, Tiffany L. Sudduth, Barbara J. Martin, Peter T. Nelson, Gregory Jicha, Jordan P. Harp, Erica M. Weekman, Donna M. Wilcock

Neurology Faculty Publications

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer’s Disease Research Center cohort. We evaluated six Alzheimer’s disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p- tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory …

Azithromycin Reduces Hemoglobin-Induced Innate Neuroimmune Activation, Chirayu D. Pandya, Hemendra J. Vekaria, Miriam Zamorano, Amanda L. Trout, Rodney M. Ritzel, Gary Guzman, Christopher Bolden, Patrick G. Sullivan

Neurology Faculty Publications

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to …

Different Cohort, Disparate Results: Selection Bias Is A Key Factor In Autopsy Cohorts, Kathryn Gauthreaux, Walter A. Kukull, Karin B. Nelson, Charles Mock, Yen-Chi Chen, Kwun C. G. Chan, David W. Fardo, Yuriko Katsumata, Erin L. Abner, Peter T. Nelson

Neurology Faculty Publications

INTRODUCTION: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences.

METHODS: The National Alzheimer’s Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit.

RESULTS: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who …

Cognitive Decline, Aβ Pathology, And Blood–Brain Barrier Function In Aged 5xfad Mice, Geetika Nehra, Sasivimon Promsan, Ruedeemars Yubolphan, Wijitra Chumboatong, Pornpun Vivithanaporn, Bryan J. Maloney, Anusorn Lungkaphin, Bjoern Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background

Patients with Alzheimer’s disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time.

Methods

5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the …

Oxidative Stress Alters Mitochondrial Homeostasis In Isolated Brain Capillaries, Gopal V. Velmurugan, Hemendra J. Vekaria, Anika M. S. Hartz, Björn Bauer, William Brad Hubbard

Markey Cancer Center Faculty Publications

Background

Neurovascular deficits and blood-brain barrier (BBB) dysfunction are major hallmarks of brain trauma and neurodegenerative diseases. Oxidative stress is a prominent contributor to neurovascular unit (NVU) dysfunction and can propagate BBB disruption. Oxidative damage results in an imbalance of mitochondrial homeostasis, which can further drive functional impairment of brain capillaries. To this end, we developed a method to track mitochondrial-related changes after oxidative stress in the context of neurovascular pathophysiology as a critical endophenotype of neurodegenerative diseases.

Methods

To study brain capillary-specific mitochondrial function and dynamics in response to oxidative stress, we developed an ex vivo model in which …

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …

Her9/Hes4 Is Required For Retinal Photoreceptor Development, Maintenance, And Survival, Cagney E. Coomer, Stephen G. Wilson, Kayla F. Titialii-Torres, Jessica D. Bills, Laura A. Krueger, Rebecca A. Petersen, Evelyn M. Turnbaugh, Eden L. Janesch, Ann C. Morris

Biology Faculty Publications

The intrinsic and extrinsic factors that regulate vertebrate photoreceptor specification and differentiation are complex, and our understanding of all the players is far from complete. Her9, the zebrafish ortholog of human HES4, is a basic helix-loop-helix-orange transcriptional repressor that regulates neurogenesis in several developmental contexts. We have previously shown that her9 is upregulated during chronic rod photoreceptor degeneration and regeneration in adult zebrafish, but little is known about the role of her9 during retinal development. To better understand the function of Her9 in the retina, we generated zebrafish her9 CRISPR mutants. Her9 homozygous mutants displayed striking retinal phenotypes, including decreased …

Insulin-Like Growth Factor-1 Overexpression Mediates Hippocampal Remodeling And Plasticity Following Tbi, Erica Latrice Littlejohn

Theses and Dissertations--Physiology

Every year over 2.5 million traumatic brain injuries (TBI) occur and are the leading cause of death and disability among adolescents. There are no approved treatments for TBI. Survivors suffer from persistent cognitive impairment due to posttraumatic tissue damage and disruption of neural networks which significantly detract from their quality of life. Posttraumatic cognitive impairment depends in part on the brain's limited ability to repair or replace damaged cells. Immature neurons in the hippocampus dentate gyrus, a brain region required for learning and memory, are particularly vulnerable to TBI. Insulin-like growth factor-1 (IGF1) is a potential therapeutic for TBI because …

Type 2 Neural Progenitor Cell Activation Drives Reactive Neurogenesis After Binge-Like Alcohol Exposure In Adolescent Male Rats, Chelsea Rhea Geil Nickell, Hui Peng, Dayna M. Hayes, Kevin Y. Chen, Justin A. Mcclain, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Excessive alcohol consumption during adolescence remains a significant health concern as alcohol drinking during adolescence increases the likelihood of an alcohol use disorder in adulthood by fourfold. Binge drinking in adolescence is a particular problem as binge-pattern consumption is the biggest predictor of neurodegeneration from alcohol and adolescents are particularly susceptible to the damaging effects of alcohol. The adolescent hippocampus, in particular, is highly susceptible to alcohol-induced structural and functional effects, including volume and neuron loss. However, hippocampal structure and function may recover with abstinence and, like in adults, a reactive burst in hippocampal neurogenesis in abstinence may contribute to …

Effects Of Chromium On Mouse Splenic T Lymphocytes And Effects Of Ethanol Exposure During Early Neurodevelopment On Behaviors In Mice, Lu Dai

Theses and Dissertations--Toxicology and Cancer Biology

The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.

Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro …

Role Of Sox11 During Vertebrate Ocular Morphogenesis And Retinal Neurogenesis, Lakshmi Shashidharan Pillai

Theses and Dissertations--Biology

Microphthalmia, anophthalmia, and coloboma (MAC) are distinct abnormalities demonstrating a continuum of developmental eye defects that contribute to 15-20% of blindness and severe vision deficiencies in children worldwide. The genetic etiology of MAC is large, complex and encompasses the whole developmental biology of the eye. Understanding how the eye develops will aid in identifying genes and developmental pathways involved in MAC. Although investigation of the genetic architecture of congenital anomalies is growing exponentially, much work remains to be accomplished to understand the complex, genetically heterogeneous congenital anomalies, which significantly impact childhood vision.

With an interest in elucidating the mechanisms that …

Dual Functions For Insulinoma-Associated 1 In Retinal Development, Marie A. Forbes-Osborne

Theses and Dissertations--Biology

Proper visual system function requires tightly controlled proliferation of a pool of relatively homogeneous retinal progenitor cells, followed by the stepwise specification and differentiation of multiple distinct cell types. These retinal cells, both neuronal and glial, must be generated in the correct numbers, and the correct laminar location to permit the formation of synaptic connections between individual cell types. After synapses are made, constant signaling is required as part of normal retinal function, and to maintain cellular identity and connectivity. These processes rely on both extrinsic and intrinsic signaling, with regulation of gene expression by cascades of transcription factors having …