Neurology Commons^™

Considerations For Widespread Implementation Of Blood-Based Biomarkers Of Alzheimer's Disease, Michelle Mielke, Matthew Anderson, Wesson Ashford, Andreas Jeromin, Pei-Jung Lin, Allyson Rosen, Jamie Tyrone, Lawren Vandevrede, Deanna Willis, Zul Merali

Brain and Mind Institute

Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges …

Recommendations For Clinical Implementation Of Blood-Based Biomarkers For Alzheimer's Disease, Michelle Mielke, Matthew Anderson, Wesson Ashford, Andreas Jeromin, Pei-Jung Lin, Allyson Rosen, Jamie Tyrone, Lawren Vandevrede, Deanna Willis, Zul Merali, Chinedu Momoh

Brain and Mind Institute

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational …

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 …

Cortisol And Alpha-Synuclein Stability In Saliva Under Varying Storage And Handling Conditions, Mo Zheng, Sujata Srikanth, Jeremiah Carpenter, Delphine Dean

Journal of the South Carolina Academy of Science

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor impairments and non-motor symptoms, significantly impacting patients' quality of life. Currently, cerebrospinal fluid (CSF) is the primary biofluid used for PD biomarker studies, notably α-synuclein, despite the invasive nature of lumbar puncture procedures. Recent work has shown that some of these PD biomarkers have been measured in saliva. As an alternative to CSF, saliva can be non-invasively self-collected by patients repeatedly over time to monitor biomarker levels. However, the stability of these biomarkers in saliva needs to be evaluated before saliva can be considered for patient self-collection studies. Therefore, …

Targeting Igf2 To Reprogram The Tumor Microenvironment For Enhanced Viro-Immunotherapy, Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Faculty, Staff and Student Publications

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. …

The Seattle Amyotrophic Lateral Sclerosis (Als) Patient Project Database: Observational, Longitudinal, Dyadic Characterization Of People With Als And Their Partners, Suzanne C. Segerstrom, Edward J. Kasarskis

Neurology Faculty Publications

Introduction: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.

Methods: The SALSPPD is a longitudinal dataset of people with ALS (n = …

Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere

Faculty, Staff and Students Publications

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and …

Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere

Faculty, Staff and Students Publications

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and …

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

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 …

Transcriptomics Analysis Reveals Potential Regulatory Role Of Nsmase2 (Smpd3) In Nervous System Development And Function Of Middle-Aged Mouse Brains, Zhihui Zhu, Timothy S. Mcclintock, Erhard Bieberich

Markey Cancer Center Faculty Publications

Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid cer- amide. The function of nSMase2 in the brain is still controversial. To better under- stand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annota- tion terms among transcripts increased in fro/fro mice included synaptogenesis, syn- apse development, synaptic signaling, axon development, and …

Differential Effect Of An Evolving Amyloid And Tau Pathology On Brain Phospholipids And Bioactive Lipid Mediators In Rat Models Of Alzheimer-Like Pathology, Sonia Do Carmo, Marie Audrey I. Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T. Emmerson, Janice C. Malcolm, Quentin Bonomo, Nicolas G. Bazan, A. Claudio Cuello

School of Graduate Studies Faculty Publications

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive …

Antitumor Activity Of A Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting Lgr5 In Preclinical Models Of Neuroblastoma, Jianghua Tu, Yukimatsu Toh, Adela M Aldana, Jake J Wen, Ling Wu, Joan Jacob, Li Li, Sheng Pan, Kendra S Carmon, Qingyun J Liu

Faculty, Staff and Student Publications

Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody-drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads …

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 …

Type-2 Diabetes, Pancreatic Amylin, And Neuronal Metabolic Remodeling In Alzheimer's Disease, Noah Leibold, James R. Bain, Florin Despa

Neurology Faculty Publications

Type-2 diabetes raises the risk for Alzheimer’s disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic 𝜷-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid 𝜷 (A𝜷) pathology, in both sporadic and familial Alzheimer’s disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, …

A Pathologic Study Of Perivascular Ptdp-43 Lin Bodies In Late-Nc, Ryan K. Shahidehpour, Peter T. Nelson, Adam D. Bachstetter

Neurology Faculty Publications

Background TAR DNA-Binding Protein 43 (TDP-43) pathological inclusions are a distinctive feature in dozens of neurodegenerative pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Prior investigations identified vascular-associated TDP-43-positive micro-lesions, known as “Lin bodies,” located on or near the brain capillaries of some individuals with LATE-NC. This study aimed to investigate the relationship between the accumulation of Lin bodies and glial cells in LATE-NC and the potential co-localization with ferritin, a protein associated with iron storage. Using multiplexed immunohistochemistry and digital pathology tools, we conducted pathological analyses to investigate the relationship between Lin bodies and glial markers (GFAP for …

Cholesterol-Dependent Lxr Transcription Factor Activity Represses Pronociceptive Effects Of Estrogen In Sensory Neurons And Pain Induced By Myelin Basic Protein Fragments, Swathi K Hullugundi, Jennifer Dolkas, Andrei V Chernov, Tony L Yaksh, Kelly A Eddinger, Mila Angert, Glaucilene Ferreira Catroli, Alex Y Strongin, Patrick M Dougherty, Yan Li, Oswal Quehenberger, Aaron Armando, Veronica I Shubayev

Faculty, Staff and Student Publications

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP

METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP

RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP

CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of …

Reliable Detection Of Generalized Convulsive Seizures Using An Off-The-Shelf Digital Watch: A Multisite Phase 2 Study, Yash Shashank Vakilna, Xiaojin Li, Jaison S Hampson, Yan Huang, John C Mosher, Yuri Dabaghian, Xi Luo, Blanca Talavera, Sandipan Pati, Masel Todd, Ryan Hays, Charles Akos Szabo, Guo-Qiang Zhang, Samden D Lhatoo

Faculty, Staff and Student Publications

Objective: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy.

Methods: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of …

Improved Liver Disease Prediction From Clinical Data Through An Evaluation Of Ensemble Learning Approaches, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

PURPOSE: Liver disease causes two million deaths annually, accounting for 4% of all deaths globally. Prediction or early detection of the disease via machine learning algorithms on large clinical data have become promising and potentially powerful, but such methods often have some limitations due to the complexity of the data. In this regard, ensemble learning has shown promising results. There is an urgent need to evaluate different algorithms and then suggest a robust ensemble algorithm in liver disease prediction.

METHOD: Three ensemble approaches with nine algorithms are evaluated on a large dataset of liver patients comprising 30,691 samples with 11 …

Neural Mechanisms Of Respiratory Interoception, Pei-Ying Sarah Chan, Lu-Yuan Lee, Paul W. Davenport

UK CARES Faculty Publications

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. …

Comprehensive Assessment Of Tdp‑43 Neuropathology Data In The National Alzheimer’S Coordinating Center Database, Davis C. Woodworth, Katelynn M. Nguyen, Lorena Sordo, Kiana A. Scambray, Elizabeth Head, Claudia H. Kawas, María M. Corrada, Peter T. Nelson, S. Ahmad Sajjadi

Neurology Faculty Publications

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer’s Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by …

Increased Incidence Of Vestibular Disorders In Patients With Sars-Cov-2, Lawrance Lee, Evan French, Daniel H Coelho, Nauman F Manzoor, Adam B Wilcox, Adam M Lee, Alexis Graves, Alfred Anzalone, Amin Manna, Amit Saha, Amy Olex, Andrea Zhou, Andrew E Williams, Andrew Southerland, Andrew T Girvin, Anita Walden, Anjali A Sharathkumar, Benjamin Amor, Benjamin Bates, Brian Hendricks, Brijesh Patel, Caleb Alexander, Carolyn Bramante, Cavin Ward-Caviness, Charisse Madlock-Brown, Christine Suver, Christopher Chute, Christopher Dillon, Chunlei Wu, Clare Schmitt, Cliff Takemoto, Dan Housman, Davera Gabriel, David A Eichmann, Diego Mazzotti, Don Brown, Eilis Boudreau, Elaine Hill, Elizabeth Zampino, Emily Carlson Marti, Emily R Pfaff, Evan French, Farrukh M Koraishy, Federico Mariona, Fred Prior, George Sokos, Greg Martin, Harold Lehmann, Heidi Spratt, Hemalkumar Mehta, Hongfang Liu, Hythem Sidky, J W Awori Hayanga, Jami Pincavitch, Jaylyn Clark, Jeremy Richard Harper, Jessica Islam, Jin Ge, Joel Gagnier, Joel H Saltz, Joel Saltz, Johanna Loomba, John Buse, Jomol Mathew, Joni L Rutter, Julie A Mcmurry, Justin Guinney, Justin Starren, Karen Crowley, Katie Rebecca Bradwell, Kellie M Walters, Ken Wilkins, Kenneth R Gersing, Kenrick Dwain Cato, Kimberly Murray, Kristin Kostka, Lavance Northington, Lee Allan Pyles, Leonie Misquitta, Lesley Cottrell, Lili Portilla, Mariam Deacy, Mark M Bissell, Marshall Clark, Mary Emmett, Mary Morrison Saltz, Matvey B Palchuk, Melissa A Haendel, Meredith Adams, Meredith Temple-O'Connor, Michael G Kurilla, Michele Morris, Nabeel Qureshi, Nasia Safdar, Nicole Garbarini, Noha Sharafeldin, Ofer Sadan, Patricia A Francis, Penny Wung Burgoon, Peter Robinson, Philip R O Payne, Rafael Fuentes, Randeep Jawa, Rebecca Erwin-Cohen, Rena Patel, Richard A Moffitt, Richard L Zhu, Rishi Kamaleswaran, Robert Hurley, Robert T Miller, Saiju Pyarajan, Sam G Michael, Samuel Bozzette, Sandeep Mallipattu, Satyanarayana Vedula, Scott Chapman, Shawn T O'Neil, Soko Setoguchi, Stephanie S Hong, Steve Johnson, Tellen D Bennett, Tiffany Callahan, Umit Topaloglu, Usman Sheikh, Valery Gordon, Vignesh Subbian, Warren A Kibbe, Wenndy Hernandez, Will Beasley, Will Cooper, William Hillegass, Xiaohan Tanner Zhang

Faculty, Staff and Student Publications

OBJECTIVE: Determine the incidence of vestibular disorders in patients with SARS-CoV-2 compared to the control population.

STUDY DESIGN: Retrospective.

SETTING: Clinical data in the National COVID Cohort Collaborative database (N3C).

METHODS: Deidentified patient data from the National COVID Cohort Collaborative database (N3C) were queried based on variant peak prevalence (untyped, alpha, delta, omicron 21K, and omicron 23A) from covariants.org to retrospectively analyze the incidence of vestibular disorders in patients with SARS-CoV-2 compared to control population, consisting of patients without documented evidence of COVID infection during the same period.

RESULTS: Patients testing positive for COVID-19 were significantly more likely to have …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Faculty, Staff and Student Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …

Generalizing Parkinson’S Disease Detection Using Keystroke Dynamics: A Self-Supervised Approach, Shikha Tripathi, Alejandro Acien, Ashley A Holmes, Teresa Arroyo-Gallego, Luca Giancardo

Faculty, Staff and Student Publications

Objective: Passive monitoring of touchscreen interactions generates keystroke dynamic signals that can be used to detect and track neurological conditions such as Parkinson's disease (PD) and psychomotor impairment with minimal burden on the user. However, this typically requires datasets with clinically confirmed labels collected in standardized environments, which is challenging, especially for a large subject pool. This study validates the efficacy of a self-supervised learning method in reducing the reliance on labels and evaluates its generalizability.

Materials and methods: We propose a new type of self-supervised loss combining Barlow Twins loss, which attempts to create similar feature representations with reduced …

Interactions Between Repetitive Mild Traumatic Brain Injury And Methylphenidate Administration On Catecholamine Transporter Protein Levels Within The Rodent Prefrontal Cortex, Anna Abrimian, Eleni Papadopoulos, Christopher P. Knapp, J. Loweth, Barry Waterhouse, Rachel Navarra

Rowan-Virtua Research Day

It is theorized that low concentrations of dopamine (DA) and norepinephrine (NE) within in the prefrontal cortex (PFC) following traumatic brain injury (TBI) leads to increased risky behavior. Our lab has shown that repeated mild TBI (rmTBI) sex-differentially increases risky behavior in a rodent model. Methylphenidate (MPH) is a psychostimulant drug used to treat symptoms of Attention-Deficit Hyperactivity Disorder (ADHD), also driven by a hypo-catecholaminergic PFC. MPH elevates catecholamine levels by blocking DA and NE transporters, DAT and NET. While the potential of psychostimulants to treat post-TBI symptoms have been explored, the effects of sub-chronic MPH on transporter levels following …

A Preliminary Report On The Role Of Lipoxin A4 In Reinstating The Blood-Brain Barrier Integrity In A Rodent Model Of Acute Inflammation With Impaired Cerebrovasculature, Minjal Patel, Shruti Varshney, Ananya Nethikunta, George G. Godsey, Mary C. Kosciuk, Ana Rodriguez, Bernd Spur, Kingsley Yin, Randel L. Swanson, Venkat Venkataraman, Robert G. Nagele, Nimish Acharya

Rowan-Virtua Research Day

Background: The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis and ultimately proper neuronal function. Disruption of the BBB, leading to increased BBB permeability, has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Lipoxins (LXs) are a class of arachidonate-derived eicosanoids, which are a class of specialized pro-resolving lipid mediators (SPMs). SPMs are known to inhibit immune response through inhibition of cellular infiltration, downregulation of pro-inflammatory mediators and upregulation of anti-inflammatory mediators. Hence, LXs are recognized as “breaking signals” in the inflammatory process. One form of LXs, Lipoxin A4 (LXA4) …

The Impact Of Traumatic Brain Injury On Noradrenergic Innervation Of The Prefrontal Cortex, Jil P. Modi, Christopher P. Knapp, Rachel L. Navarra

Rowan-Virtua Research Day

Traumatic Brain Injury (TBI) is a common cause of death and disability in the United States, and it can occur due to varied reasons including motor vehicle accidents, gunshot wounds, and falls. Following TBIs, patients are often left with lifelong disabilities and cognitive problems that can lead to increased risk-taking behaviors. The main goal of my research was to understand the neural mechanisms that drive increased risk-taking behaviors due to TBIs. The specific areas of the brain I was interested in looking at were the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and/or anterior cingulate cortex (ACC) of the prefrontal …

Effect Of Dosage On Severity Of Dysphagia In A Toxicological Rat Model Of Parkinson's Disease, Shivam Patel, Taylor Good, Nicholas Zanghi, Francois Gould

Rowan-Virtua Research Day

Parkinson’s Disease (PD) is a prevalent and devastating neurodegenerative disorder that causes progressively worsening motor symptoms affecting locomotor and oropharyngeal function. There is limited research in animal models on swallowing dysfunction in PD. To examine how neurodegeneration in PD produces progressive impairment in the oropharyngeal and locomotor processes, rotenone, a type II mitochondrial inhibitor, was injected into Lewis rat models to reproduce a parkinsonian phenotype. We hypothesized that the animal models injected with the rotenone will exhibit both oropharyngeal dysfunction and locomotor deficiency with an increased deficit that correlates with prolonged treatment. We utilized 18 rats receiving either 2.75 mg/kg …

Plant Model Of Α-Synucleinopathy: Expression Of Α-Synuclein A53t Variant In Hairy Root Cultures Leads To Proteostatic Stress And Dysregulation Of Iron Metabolism, Jasmina Kurepa, Kristen A. Bruce, Greg A. Gerhardt, Jan A. Smalle

Neurology Faculty Publications

Synucleinopathies, typified by Parkinson’s disease (PD), entail the accumulation of α- synuclein (αSyn) aggregates in nerve cells. Various αSyn mutants, including the αSyn A53T variant linked to early-onset PD, increase the propensity for αSyn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of αSyn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of αSyn A53T expression in transgenic hairy roots of four medicinal plants (Lobelia cardinalis, Artemisia annua, Salvia miltiorrhiza, and Polygonum multiflorum). In all …

Montelukast As A Repurposable Additive Drug For Standard-Efficacy Multiple Sclerosis Treatment: Emulating Clinical Trials With Retrospective Administrative Health Claims Data, Astrid M Manuel, Assaf Gottlieb, Leorah Freeman, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach.

OBJECTIVE: The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS).

METHODS: In this retrospective case-control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18-65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum's Clinformatics

RESULTS: pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared …