Neurology Commons^™

Challenges In Traumatic Spinal Cord Injury Care In Developing Countries - A Scoping Review, Mohammad Hosein Ranjbar Hameghavandi, Elaheh Khodadoust, Mahgol Sadat Hassan Zadeh Tabatabaei, Farzin Farahbakhsh, Zahra Ghodsi, Sabra Rostamkhani, Shahryar Ghashghaie, Mahkame Abbaszade, Arash Arbabi, Seyedeh Maede Hossieni, Mohsen Sadeghi-Naini, Rasha Atlasi, Samuel Berchi Kankam, Alexander Vaccaro, James Guest, Michael Fehlings, Vafa Rahimi-Movaghar

Department of Neurosurgery Faculty Papers

OBJECTIVE: To evaluate the leading challenges in developing countries' traumatic spinal cord injury (TSCI) care.

METHODS: We conducted a systematic search in electronic databases of PubMed, SCOPUS, Web of Science, EMBASE, and Cochrane Library on 16 April 2023. Studies that investigated challenges associated with the management of TSCI in developing countries were eligible for review. We extracted related outcomes and categorized them into four distinct parts: injury prevention, pre-hospital care, in-hospital care, and post-hospital care.

RESULTS: We identified 82 articles that met the eligibility criteria including 13 studies on injury prevention, 25 on pre-hospital care, 32 on in-hospital care, and …

A Single-Cell Transcriptomic Map Of The Developing Atoh1 Lineage Identifies Neural Fate Decisions And Neuronal Diversity In The Hindbrain, Jessica C Butts, Sih-Rong Wu, Mark A Durham, Ryan S Dhindsa, Jean-Pierre Revelli, M Cecilia Ljungberg, Olivier Saulnier, Madison E Mclaren, Michael D Taylor, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for …

A Systematic Review Of Oral Vertical Dyskinesia ("Rabbit" Syndrome), Jamir Pitton Rissardo, Krish Kherajani, Nilofar Murtaza Vora, Venkatesh Yatakarla, Ana Letícia Fornari Caprara, Jeffrey Ratliff, Md, Stanley N Caroff

Department of Neurology Faculty Papers

Background and Objectives: Vertical rhythmic dyskinetic movements that are primarily drug-induced and affect solely the jaw, mouth, and lips without involving the tongue have been historically described as “rabbit” syndrome (RS). Evidence on the unique features and implications of this disorder remains limited. This literature review aims to evaluate the clinical–epidemiological profile, pathological mechanisms, and management of this movement disorder. Materials and Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction published between 1972 and 2024. Results: A total of 85 articles containing 146 cases of RS were found. The mean frequency of RS among …

Biological And Procedural Predictors Of Outcome In The Stroke Preclinical Assessment Network (Span) Trial, Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus Van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata

Faculty, Staff and Student Publications

BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.

METHODS: The study cohort included all mice enrolled and …

Clinical And Radiographic Outcomes After Mechanical Thrombectomy In Medium-Vessel Posterior Cerebral Artery Occlusions: Subgroup Analysis From Star, Eyad Almallouhi, Matthew C Findlay, Ilko Maier, Pascal Jabbour, Joon-Tae Kim, Stacey Quintero Wolfe, Ansaar Rai, Robert M Starke, Marios-Nikos Psychogios, Amir Shaban, Nitin Goyal, Shinichi Yoshimura, Hugo Cuellar, Brian Howard, Ali Alawieh, Ali Alaraj, Mohamad Ezzeldin, Daniele G Romano, Omar Tanweer, Justin Mascitelli, Isabel Fragata, Adam Polifka, Fazeel Siddiqui, Joshua Osbun, Roberto Crosa, Charles Matouk, Min S Park, Michael R Levitt, Waleed Brinjikji, Mark Moss, Ergun Daglioglu, Richard Williamson, Pedro Navia, Peter Kan, Reade De Leacy, Shakeel Chowdhry, David J Altschul, Alejandro Spiotta, Ramesh Grandhi

Faculty, Staff and Students Publications

BACKGROUND: Whereas mechanical thrombectomy (MT) has become standard-of-care treatment for patients with salvageable brain tissue after acute stroke caused by large-vessel occlusions, the results of MT in patients with medium-vessel occlusions (MEVOs), particularly in the posterior cerebral artery (PCA), are not well known.

METHODS: Using data from the international Stroke Thrombectomy and Aneurysm Registry (STAR), we assessed presenting characteristics and clinical outcomes for patients who underwent MT for primary occlusions in the P2 PCA segment. As a subanalysis, we compared the PCA MeVO outcomes with STAR's anterior circulation MeVO outcomes, namely middle cerebral artery (MCA) M2 and M3 segments.

RESULTS: …

Tfeb Activation Hallmarks Antigenic Experience Of B Lymphocytes And Directs Germinal Center Fate Decisions, Matthias Münchhalfen, Richard Görg, Michael Haberl, Jens Löber, Jakob Willenbrink, Laura Schwarzt, Charlotte Höltermann, Christian Ickes, Leonard Hammermann, Jan Kus, Björn Chapuy, Andrea Ballabio, Sybille D Reichardt, Alexander Flügel, Niklas Engels, Jürgen Wienands

Duncan NRI Faculty and Staff Publications

Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation …

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 …

Proximity Analysis Of Native Proteomes Reveals Phenotypic Modifiers In A Mouse Model Of Autism And Related Neurodevelopmental Conditions, Yudong Gao, Daichi Shonai, Matthew Trn, Jieqing Zhao, Erik J Soderblom, S Alexandra Garcia-Moreno, Charles A Gersbach, William C Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-Hui Jiang, Laura G Sloofman, Joseph D Buxbaum, Scott H Soderling

Faculty, Staff and Students Publications

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for …

Loss Of Transient Receptor Potential Channel 5 Causes Obesity And Postpartum Depression, Yongxiang Li, Tessa M Cacciottolo, Na Yin, Yang He, Hesong Liu, Hailan Liu, Yuxue Yang, Elana Henning, Julia M Keogh, Katherine Lawler, Edson Mendes De Oliveira, Eugene J Gardner, Katherine A Kentistou, Panayiotis Laouris, Rebecca Bounds, Ken K Ong, John R B Perry, Inês Barroso, Longlong Tu, Jonathan C Bean, Meng Yu, Kristine M Conde, Mengjie Wang, Olivia Ginnard, Xing Fang, Lydia Tong, Junying Han, Tia Darwich, Kevin W Williams, Yongjie Yang, Chunmei Wang, Shelagh Joss, Helen V Firth, Yong Xu, I Sadaf Farooqi

Duncan NRI Faculty and Staff Publications

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of …

Whole Genome Sequencing Based Analysis Of Inflammation Biomarkers In The Trans-Omics For Precision Medicine (Topmed) Consortium, Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Inflammation Working Group

Faculty, Staff and Student Publications

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant …

Case Report Of Unilateral Dysphagia In The Context Of A Classical Type Of Eagle Syndrome, Ryan Tam, Stephen D. Howard, Timothy Ehmann, Bryan Scott

Advances in Clinical Medical Research and Healthcare Delivery

A patient presents with unilateral, right-sided dysphagia and generalized facial symptoms following past surgical history of tonsillectomy that is consistent with an underdiagnosis of Eagle Syndrome. The elongation of the styloid process likely impinged on the glossopharyngeal and vagus nerves resulting in symptoms. Given the lack of recognition of the disease, this case report describes the presentation of Eagle Syndrome to encourage physicians to consider this disease as part of a broader differential diagnosis.

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 …

Associations Between Il-1Β, Il-6, And Tnfα Polymorphisms And Longitudinal Trajectories Of Cognitive Function In Non-Demented Older Adults, Karen A. Lawrence, Elana M. Gloger, Cristina N. Pinheiro, Frederick A. Schmitt, Suzanne C. Segerstrom

Neurology Faculty Publications

Inflammation is implicated in Alzheimer’s disease (AD), and specific single nucleotide polymorphisms (SNPs) in inflammatory cytokine genes are associated with increased AD risk. Whether the same polymorphisms also predict domain-specific cognitive change in cognitively healthy older adults is unclear. Specific SNPs in three cytokine genes, IL-1β (rs16944), IL-6 (rs1800795), and TNFα (rs1800629) were assessed for association with longitudinal trajectories spanning up to 16 years of global cognitive function, episodic memory, attention and working memory, and executive function in a sample of 324 non-demented older adults. Only rs1800629 (TNFα) was associated with significant change in global cognitive function over time [γ …

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 …

Emergency Care For Patients On Amyloid-Targeting Therapies In Alzheimer's Disease, Thomas K. Hagerman, Michelle Suh, Gayatri Devi, Jennifer Sutherland, Gloria Chiang, Don Melady, Kevin Biese, Maura Kennedy

Journal of Geriatric Emergency Medicine

The introduction of novel amyloid-targeting therapies for Alzheimer’s disease presents challenges for emergency clinicians. Patients on these therapies may present with amyloid related imaging abnormalities (ARIA) that are only detectable on magnetic resonance imaging and have significant implications for emergency department (ED) pathways, particularly for patients with stroke-like symptoms and those requiring anticoagulants. In this article, we highlight key considerations for the practicing clinician and ED administrators, including the identification of ARIA, protocols for imaging and treatment considerations, and strategies for interdisciplinary collaboration to ensure optimal care for this unique patient population.

Access To Medicines For Parkinson's Disease In Kenya: A Qualitative Exploration, Natasha Fothergill-Misbah, Juzar Hooker, Judith Kwasa, Richard Walker

Internal Medicine, East Africa

Background: The accessibility of Parkinson’s disease medicines is limited across sub-Saharan Africa,which can have negative health, social and financial consequences for people with Parkinson’s disease andtheir families. However, there is a stark gap in the literature regarding the impact of poor access to medicineson individuals.

Objectives: The study objective was to understand the accessibility of Parkinson’s disease medicines in Kenyafrom the perspective of people with Parkinson’s disease, their caregivers and neurologists.MethodsMethods: In-depth qualitative interviews were conducted with 55 people with Parkinson’s disease, 23 caregiversand 8 neurologists to understand their experience regarding challenges with accessing Parkinson’s diseasemedicines and the health, social …

Trends In Central Nervous System-Active Polypharmacy Among People With Multiple Sclerosis, Hayden Naizer, Joseph Wozny, Trudy Millard Krause, Ethan Huson, Leorah Freeman

Faculty, Staff and Student Publications

BACKGROUND: People with multiple sclerosis (pwMS) are at risk of concurrently using multiple central nervous system (CNS)-active drugs, yet the prevalence of CNS-active polypharmacy remains unmeasured in pwMS.

OBJECTIVE: The objective is to measure the prevalence of CNS-active polypharmacy in pwMS.

METHODS: This serial, cross-sectional study measured CNS-active polypharmacy in people with MS in the United States from 2008 to 2021 using insurance claims data. CNS-active polypharmacy was defined as the concurrent prescription of ⩾3 CNS-active drugs for >30 continuous days. CNS-active drugs included antidepressants, antiepileptics, antipsychotics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics, opioids, and skeletal muscle relaxants.

RESULTS: The …

Relationships Between Trauma Types And Psychotic Symptoms: A Network Analysis Of Patients With Psychotic Disorders In A Large, Multi-Country Study In East Africa, Anne Stevenson, Supriya Misra, Engida Girma, Adela-Maria Isvoranu, Dickens Akena, Melkam Alemayehu, Lukoye Atwoli, Bizu Gelaye, Stella Gichuru, Symon Kariuki

Internal Medicine, East Africa

Background: The link between trauma exposure and psychotic disorders is well-established. Further, specific types of trauma may be associated with specific psychotic symptoms. Network analysis is an approach that can advance our understanding of the associations across trauma types and psychotic symptoms. Methods: We conducted a network analysis with data from 16,628 adult participants (mean age [standard deviation] = 36.3 years [11.5]; 55.8% males) with psychotic disorders in East Africa recruited between 2018 and 2023. We used the Life Events Checklist and the Mini International Neuropsychiatric Interview to determine whether specific trauma types experienced over the life course and specific …

Nanoparticle-Based Approaches To Brain Injury And Studies For Improved Detectability Toward Better Delivery Characterization, Hunter A. Miller

Dissertations and Doctoral Documents, University of Nebraska-Lincoln, 2023–

The clinical translation of nanoparticle (NP) therapeutics for brain injury has been slow despite preclinical promise. The causes of disconnect between preclinical and clinical outcomes is multifactorial, but insufficient delivery is noteworthy. Preclinical delivery characterization often lacks, obscuring mechanisms of failure, slowing development. Multimodal imaging is a promising strategy to improve delivery characterization, combining the strengths of various modalities. Magnetic resonance imaging (MRI) and luminescence imaging are a suitable combination for multimodal imaging, expanding the spatial and temporal resolution of either alone, but further material development is needed to enhance detectability. One problem is the interference of cellular autofluorescence in …

African American Patients Have A Higher Probability Of Cognitive Impairment After Incident Stroke: An Analysis Of National Electronic Health Record Data, Alicia Zha, Chenguang Zhang, Gen Zhu, Xinran Huang, Sahar Anjum, Yashar Talebi, Sean Savitz, Hulin Wu

Faculty, Staff and Student Publications

Background: Cognitive impairment (CI) and stroke are diseases with significant disparities in race and geography. Post stroke cognitive impairment (PSCI) can be as high as 15-70 % but few studies have utilized large administrative or electronic health records (EHR) to evaluate trends in PSCI. We utilized an EHR database to evaluate for disparities in PSCI in a large sample of patients after first recorded stroke to evaluate for disparities in race.

Methods: This is a retrospective cohort analysis of Cerner Health Facts® EHR database, which is comprised of EHR data from hundreds of hospitals/clinics in the US from 2009-2018. We …

De-Escalation Of Disease-Modifying Therapy For People With Multiple Sclerosis Due To Safety Considerations: Characterizing 1-Year Outcomes In 25 People Who Switched From Ocrelizumab To Diroximel Fumarate., Mark Gudesblatt, Barbara Bumstead, Marijean Buhse, Myassar Zarif, Sarah A Morrow, Jacqueline A Nicholas, Laura M Hancock, Jeffrey Wilken, Joanna Weller, Nicole Scott, Anne Gocke, James B Lewin, Olivia Kaczmarek, Jason P Mendoza, Daniel Golan

Neuroscience Articles

INTRODUCTION: Switching disease-modifying therapy (DMT) may be considered for relapsing-remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic.

METHODS: Adults with RRMS were included if they had been clinically stable …

A Group 3 Medulloblastoma Stem Cell Program Is Maintained By Otx2-Mediated Alternative Splicing, Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D Hendrikse, Paul Layug, Victor Gordon, Kimberly A Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M Gonzales, Gareth Palidwor, Christopher J Porter, Stéphane Richard, Tanveer Sharif, Kathleen J Millen, Brad W Doble, Michael D Taylor, Tamra E Werbowetski-Ogilvie

Faculty, Staff and Students Publications

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among …

Parkinson’S Disease Variant Detection And Disclosure: Pd Generation, A North American Study, Lola Cook, Jennifer Verbrugge, Tae-Hwi Schwantes-An, Jeanine Schulze, Tatiana Foroud, Anne Hall, Karen S Marder, Ignacio F Mata, Niccolò E Mencacci, Martha A Nance, Michael A Schwarzschild, Tanya Simuni, Susan Bressman, Anne-Marie Wills, Hubert H Fernandez, Irene Litvan, Kelly E Lyons, Holly A Shill, Carlos Singer, Thomas F Tropea, Nora Vanegas Arroyave, Janfreisy Carbonell, Rossy Cruz Vicioso, Linn Katus, Joseph F Quinn, Priscila D Hodges, Yan Meng, Samuel P Strom, Cornelis Blauwendraat, Katja Lohmann, Cynthia Casaceli, Shilpa C Rao, Kamalini Ghosh Galvelis, Anna Naito, James C Beck, Roy N Alcalay

Faculty, Staff and Students Publications

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

Circuit-Specific Deep Brain Stimulation Provides Insights Into Movement Control., Aryn H Gittis, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Deep brain stimulation (DBS), a method in which electrical stimulation is delivered to specific areas of the brain, is an effective treatment for managing symptoms of a number of neurological and neuropsychiatric disorders. Clinical access to neural circuits during DBS provides an opportunity to study the functional link between neural circuits and behavior. This review discusses how the use of DBS in Parkinson's disease and dystonia has provided insights into the brain networks and physiological mechanisms that underlie motor control. In parallel, insights from basic science about how patterns of electrical stimulation impact plasticity and communication within neural circuits are …

Molecular And Physiological Changes In The Spacex Inspiration4 Civilian Crew, Christopher W Jones, Eliah G Overbey, Jerome Lacombe, Adrian J Ecker, Cem Meydan, Krista Ryon, Braden Tierney, Namita Damle, Matthew Mackay, Evan E Afshin, Jonathan Foox, Jiwoon Park, Theodore M Nelson, Mir Suhail Mohamad, Syed Gufran Ahmad Byhaqui, Burhan Aslam, Ummer Akbar Tali, Liaqun Nisa, Priya V Menon, Chintan O Patel, Sharib A Khan, Doug J Ebert, Aaron Everson, Michael C Schubert, Nabila N Ali, Mallika S Sarma, Jangkeun Kim, Nadia Houerbi, Kirill Grigorev, J Sebastian Garcia Medina, Alexander J Summers, Jian Gu, John A Altin, Ali Fattahi, Mohammad I Hirzallah, Jimmy H Wu, Alexander C Stahn, Afshin Beheshti, Remi Klotz, Veronica Ortiz, Min Yu, Laura Patras, Irina Matei, David Lyden, Ari Melnick, Neil Banerjee, Sean Mullane, Ashley S Kleinman, Michael Loesche, Anil S Menon, Dorit B Donoviel, Emmanuel Urquieta, Jaime Mateus, Ashot E Sargsyan, Mark Shelhamer, Frederic Zenhausern, Eric M Bershad, Mathias Basner, Christopher E Mason

Faculty, Staff and Students Publications

Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular …

Extrapyramidal System/Symptoms/Signs Should Be Retired, Abhishek Lenka, Joseph Jankovic

Faculty, Staff and Students Publications

The term "extrapyramidal system/symptoms/signs" and the acronym "EPS" have been abundantly used in neurology and psychiatry literature for more than a century. However, EPS has been increasingly criticized, especially by movement disorder neurologists, for its lack of clinical, anatomical, and physiologic definition. Contrary to traditional assumptions, pyramidal and extrapyramidal systems are not mutually exclusive. The acronym EPS, commonly used to denote drug-induced movement disorders, lacks specificity in conveying the nature and severity of these and other movement disorders. Consequently, we propose that the term is retired from scientific literature and that clinicians use specific phenomenologic descriptors for the various hypokinetc …

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 …