Neurology Commons^™

Targeting Tiam1 Enhances Hippocampal-Dependent Learning And Memory In The Adult Brain And Promotes Nmda Receptor-Mediated Synaptic Plasticity And Function, Francisco A Blanco, Md Ali Bin Saifullah, Jinxuan X Cheng, Carlota Abella, Federico Scala, Karen Firozi, Sanyong Niu, Jin Park, Jeannie Chin, Kimberley F Tolias

Faculty, Staff and Students Publications

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO) and assessed …

Anatomy And Variations Of The Carina And Its Cartilaginous Makeup: A Cadaveric Study, Chung Yoh Kim, Kristen Rizzuto, Daniel Tahan, Devendra Shekhawat, Rarinthorn Samrid, Yoko Tabira, Stephen J. Bordes, Joe Iwanaga, R. Shane Tubbs

School of Medicine Faculty Publications

Purpose: The carina, located at the bifurcation of the trachea, has been regarded as a part of the trachea. Although clinically useful as an anatomical landmark, studies of its detailed morphology are lacking in the literature. Methods: The distal trachea and left and right main bronchi were harvested from 32 cadavers and the carina studied using microsurgical dissection, endoscopy, micro-CT, and histology. Results: The right bronchial cartilages were most commonly involved in forming the carina (72.41%), and the left bronchial cartilages were the second most commonly involved (37.93%). The carinal cartilages were slightly deviated to the left of midline in …

Understanding Pediatric Bipolar Disorder Through The Investigation Of Clinical, Neuroanatomic, Neurophysiological And Neurocognitive Dimensions: A Pilot Study, Alessio Simonetti, Evelina Bernardi, Sherin Kurian, Antonio Restaino, Claudia Calderoni, Emanuela De Chiara, Francesca Bardi, Gabriele Sani, Jair C Soares, Kirti Saxena

Faculty, Staff and Student Publications

Background: Pathophysiological models of pediatric bipolar disorder (PBD) are lacking. Multimodal approaches may provide a comprehensive description of the complex relationship between the brain and behavior. Aim: To assess behavioral, neuropsychological, neurophysiological, and neuroanatomical alterations in youth with PBD.

Methods: Subjects with PBD (n = 23) and healthy controls (HCs, n = 23) underwent (a) clinical assessments encompassing the severity of psychiatric symptoms, (b) neuropsychological evaluation, (c) analyses of event-related potentials (related to the passive viewing of fearful, neutral, and happy faces during electroencephalography recording, and (d) cortical thickness and deep gray matter volume measurement using magnetic …

From Bench To Bedside: Murine Models Of Inherited And Sporadic Brain Arteriovenous Malformations, Ashely R Ricciardelli, Gael Genet, Nafiisha Genet, Samuel T Mcclugage, Peter T Kan, Karen K Hirschi, Jason E Fish, Joshua D Wythe

Faculty, Staff and Students Publications

Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in …

Investigating The In Vivo Effects Of Anti-Prion Protein Nanobodies On Prion Disease With Aav Vector, Jingjing Zhang, Mengfei Wang, Dan Wang, Xiangyi Zhang, Yue Ma, Els Pardon, Jan Steyaert, Romany Abskharon, Fei Wang, Jiyan Ma

Faculty, Staff and Student Publications

Prion diseases are fatal neurodegenerative disorders affecting humans and animals, and the central pathogenic event is the conversion of normal prion protein (PrPC) into the pathogenic PrPSc isoform. Previous studies have identified nanobodies that specifically recognize PrPC and inhibit the PrPC to PrPSc conversion in vitro. In this study, we investigated the potential for in vivo expression of anti-PrPC nanobodies and evaluated their impact on prion disease. The coding sequences of three nanobodies were packaged into recombinant adeno-associated virus (rAAV) and were administered via intracerebroventricular (ICV) injection in newborn mice. We found that the expression of these nanobodies remained robust …

The Global Epidemiology And Health Burden Of The Autism Spectrum: Findings From The Global Burden Of Disease Study 2021, Global Burden Of Disease Study 2021 Autism Spectrum Collaborators, Lourdes Bernadette Tanchanco, Angel Belle Dy

Ateneo School of Medicine and Public Health Publications

Background

High-quality estimates of the epidemiology of the autism spectrum and the health needs of autistic people are necessary for service planners and resource allocators. Here we present the global prevalence and health burden of autism spectrum disorder from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 following improvements to the epidemiological data and burden estimation methods.

Methods

For GBD 2021, a systematic literature review involving searches in PubMed, Embase, PsycINFO, the Global Health Data Exchange, and consultation with experts identified data on the epidemiology of autism spectrum disorder. Eligible data were used to estimate prevalence …

Evidence For Alpha-Synuclein Aggregation In Older Individuals With Hyposmia: A Cross-Sectional Study, Kenneth Marek, David S Russell, Luis Concha-Marambio, Seung Ho Choi, Danna Jennings, Michael C Brumm, Christopher S Coffey, Ethan Brown, John Seibyl, Matthew Stern, Claudio Soto, Andrew Siderowf

Faculty, Staff and Student Publications

Background: Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (α-syn SAA) may detect aggregated synuclein before symptoms occur.

Methods: Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. α-syn aggregates in CSF were measured in 100 PARS participants using α-syn SAA.

Findings: CSF α-syn SAA was positive in 48% …

Plasma Proteomic Characterization Of Motoric Cognitive Risk And Mild Cognitive Impairment, Gabriela T Gomez, Sanish Sathyan, Jingsha Chen, Myriam Fornage, Pascal Schlosser, Zhongsheng Peng, Jenifer Cordon, Priya Palta, Kevin J Sullivan, Adrienne Tin, B Gwen Windham, Rebecca F Gottesman, Nir Barzilai, Sofiya Milman, Joe Verghese, Josef Coresh, Keenan A Walker

Faculty, Staff and Student Publications

INTRODUCTION: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI).

METHODS: Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort.

RESULTS: Proteome-wide analysis (n = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR …

Psychiatric Manifestations Of Encephalitis, Paris Bean, Ashley Heck, Ralph Habis, Swathi Sowmitran, Zoe Cartaina, Rajesh Gupta, John Probasco, Rodrigo Hasbun, Arun Venkatesan

Faculty, Staff and Student Publications

Objective: Encephalitis is a serious and potentially life-threatening condition of infectious or autoimmune cause. We aim to characterize the frequency and clinical spectrum of presenting psychiatric symptoms in encephalitis in order to inform earlier recognition and initiation of treatment.

Methods: This was a retrospective study of adult patients who met the 2013 International Encephalitis Consortium (IEC) and/or 2016 Graus criteria between February 2005 and February 2023. The study included two hospital systems in Houston, Texas, and Baltimore, Maryland and included a total of 642 patients. Psychiatric manifestations were grouped into five high-level categories: behavior, psychosis, mood, sleep disturbances, and catatonia. …

Protein Arginine Methyltransferases As Regulators Of Cellular Stress, Julia Zaccarelli-Magalhães, Cristiane Teresinha Citadin, Julia Langman, Drew James Smith, Luiz Henrique Matuguma, Hung Wen Lin, Mariana Sayuri Berto Udo

Faculty, Staff and Student Publications

Arginine modification can be a "switch" to regulate DNA transcription and a post-translational modification via methylation of a variety of cellular targets involved in signal transduction, gene transcription, DNA repair, and mRNA alterations. This consequently can turn downstream biological effectors "on" and "off". Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs 1-9) in both the nucleus and cytoplasm, and is thought to be involved in many disease processes. However, PRMTs have not been well-documented in the brain and their function as it relates to metabolism, circulation, functional learning and memory are understudied. In this review, we provide a comprehensive …

Synaptic Alterations In Pyramidal Cells Following Genetic Manipulation Of Neuronal Excitability In Monkey Prefrontal Cortex, Guillermo Gonzalez-Burgos, Takeaki Miyamae, Yosuke Nishihata, Olga L Krimer, Kirsten Wade, Kenneth N Fish, Dominique Arion, Zhao-Lin Cai, Mingshan Xue, William R Stauffer, David A Lewis

Duncan NRI Faculty and Staff Publications

The primate dorsolateral prefrontal cortex (DLPFC) displays unique in vivo activity patterns, but how in vivo activity regulates DLPFC pyramidal neuron (PN) properties remains unclear. We assessed the effects of in vivo Kir2.1 overexpression, a genetic silencing tool, on synapses in monkey DLPFC PNs. We show for the first time that recombinant ion channel expression successfully modifies the excitability of primate cortex neurons, producing effects on synaptic properties apparently different from those in the rodent cortex.

Comprehensive Assessment Reveals Numerous Clinical And Neurophysiological Differences Between Mecp2-Allelic Disorders, Davut Pehlivan, Chengjun Huang, Holly K Harris, Christine Coquery, Aditya Mahat, Mirjana Maletic-Savatic, Laurence Mignon, Sukru Aras, Daniel G Glaze, Charles S Layne, Leonardo Sahelijo, Huda Y Zoghbi, Matthew J Mcginley, Bernhard Suter

Faculty, Staff and Students Publications

OBJECTIVE: Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) result from under- and overexpression of MECP2, respectively. Preclinical studies using genetic-based treatment showed robust phenotype recovery for both MDS and RTT. However, there is a risk of converting MDS to RTT, or vice versa, if accurate MeCP2 levels are not achieved. The aim of this study was to identify biomarkers distinguishing RTT from MDS.

MATERIALS AND METHODS: We prospectively enrolled 11 MDS and 6 male RTT like (MRL) individuals for a panel of clinical and neurophysiological assessments over two visits, 8-10 months apart.

RESULTS: We identified numerous clinical and physiological …

Defining Neonatal Status Epilepticus: A Scoping Review From The Ilaee Neonatal Task Force, Magda L Nunes, Elissa G Yozawitz, Courtney J Wusthoff, Renée A Shellhaas, Efraín Olivas-Peña, Jo M Wilmshurst, Ronit M Pressler, Chahnez C Triki, Hans Hartmann, Terrie Inder, Geraldine B Boylan, Kette Valente, Solomon L Moshe, Eli M Mizrahi, Nicholas S Abend

Faculty, Staff and Students Publications

Objective: To review the available literature concerning the definition of neonatal status epilepticus (SE) and/or seizure burden.

Methods: The International League Against Epilepsy Neonatal Task Force performed a scoping review of the definitions of neonatal SE. Following a systematic literature review, articles were screened and data were abstracted regarding: (1) article characteristics (author identification, publication year, journal name, digital object identifier, title, objective, and study design); (2) cohort characteristics (sample size, gestational age, seizure etiology); (3) definition of SE and/or seizure burden; and (4) the method used to identify and classify SE, including routine EEG (EEG), continuous EEG monitoring (cEEG), …

Magnesium Sulfate In The Management Of Acute Ischemic Stroke: A Review Of The Literature And Future Directions, Maximillian S Feygin, Alex Brenner, Omar Tanweer

Faculty, Staff and Students Publications

Background: The management of acute ischemic stroke (AIS) was revolutionized within the last 15 years with the introduction of mechanical thrombectomy (MT) to standard of care. Despite the success of mechanical thrombectomy (MT) in achieving high recanalization rates for large vessel occlusion, functional independence post-treatment remains suboptimal. The current limitations of MT prompt evaluation of the role of adjunctive pharmacologic neuroprotective therapies to prevent excitotoxicity, cellular apoptosis, and inflammation that cause irreversible neuronal damage during AIS. Magnesium (MgSO4) provides an attractive neuroprotectant profile, having many different effects, and is inexpensive, readily available, and has a long-established safety and tolerability profile …

Exploring Individual Differences In Amygdala-Mediated Memory Modulation, Martina K Hollearn, Joseph R Manns, Lou T Blanpain, Stephan B Hamann, Kelly Bijanki, Robert E Gross, Daniel L Drane, Justin M Campbell, Krista L Wahlstrom, Griffin F Light, Aydin Tasevac, Phillip Demarest, Peter Brunner, Jon T Willie, Cory S Inman

Faculty, Staff and Students Publications

Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without …

Ligand Distances As Key Predictors Of Pathogenicity And Function In Nmda Receptors, Ludovica Montanucci, Tobias Brünger, Nisha Bhattarai, Christian M Boßelmann, Sukhan Kim, James P Allen, Jing Zhang, Chiara Klöckner, Ilona Krey, Piero Fariselli, Patrick May, Johannes R Lemke, Scott J Myers, Hongjie Yuan, Stephen F Traynelis, Dennis Lal

Faculty, Staff and Student Publications

Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by …

Robust Cluster Prediction Across Data Types Validates Association Of Sex And Therapy Response In Gbm, David L Gibbs, Gino Cioffi, Boris Aguilar, Kristin A Waite, Edward Pan, Jacob Mandel, Yoshie Umemura, Jingqin Luo, Joshua B Rubin, David Pot, Jill Barnholtz-Sloan

Faculty, Staff and Students Publications

Background: Previous studies have described sex-specific patient subtyping in glioblastoma. The cluster labels associated with these "legacy data" were used to train a predictive model capable of recapitulating this clustering in contemporary contexts.

Methods: We used robust ensemble machine learning to train a model using gene microarray data to perform multi-platform predictions including RNA-seq and potentially scRNA-seq.

Results: The engineered feature set was composed of many previously reported genes that are associated with patient prognosis. Interestingly, these well-known genes formed a predictive signature only for female patients, and the application of the predictive signature to male patients produced unexpected results. …

Atm Expression And Activation In Ataxia Telangiectasia Patients With And Without Class Switch Recombination Defects, Fereshte Salami, Tannaz Moeini Shad, Nazanin Fathi, Hanieh Mojtahedi, Marzie Esmaeili, Sepideh Shahkarami, Ladan Gol Mohammad Pour Afrakoti, Parisa Amirifar, Samaneh Delavari, Hassan Nosrati, Azadehsadat Razavi, Mohammad Reza Ranjouri, Mahsa Yousefpour, Zahra Hamidi Esfahani, Gholamreza Azizi, Mahmoudreza Ashrafi, Nima Rezaei, Reza Yazdani, Hassan Abolhassani

Department of Neurology Faculty Papers

BACKGROUND: Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.

METHODS: A-T patients with defined genetic diagnoses were classified based on CSR and based on the severity of their medical complications. Isolated peripheral blood mononuclear cells from any patient were evaluated before and after exposure to 0.5 Gy ionizing radiation for one minute. Western blotting was performed to identify the expression …

A Randomized, Placebo-Controlled, Cross-Over Trial Of Ketamine In Rett Syndrome, Kathleen Campbell, Jeffrey L Neul, David N Lieberman, Elizabeth Berry-Kravis, Tim A Benke, Cary Fu, Alan Percy, Bernhard Suter, David Morris, Randall L Carpenter, Eric D Marsh, Jana Von Hehn

Faculty, Staff and Students Publications

BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.

DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.

METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite …

The Biological Intersection Between Chemotherapy-Related Cognitive Impairment And Alzheimer Disease, Matthew Torre, Camila A Zanella, Mel B Feany

Duncan NRI Faculty and Staff Publications

Alzheimer disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with the number of patients with AD, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment. This review discusses biologically plausible pathways underlying both disorders, with the goal of …

Advances In Multiple Sclerosis, Victor M Rivera

Faculty, Staff and Students Publications

Multiple sclerosis (MS) is the most common demyelinating and inflammatory disease of the CNS; it has a global distribution with increasing prevalence [...].

High Cellular Plasticity State Of Medulloblastoma Local Recurrence And Distant Dissemination, Hailong Liu, Jing Zhang, Ziwei Wang, Wei Wang, Dongming Han, Xuan Chen, Yu Su, Jiao Zhang, Craig Daniels, Olivier Saulnier, Zeyuan John Wang, Chunyu Gu, Fei Liu, Kaiwen Deng, Dongyang Wang, Zhaoyang Feng, Yahui Zhao, Yifei Jiang, Yu Gao, Zijia Liu, Mingxu Ma, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yanfeng Shi, Tao Yang, Wenxing Li, Xueling Qi, Zejun Duan, Junping Zhang, Mingshan Zhang, Chunjiang Yu, Wei Jin, Xinguang Yu, Yu Tian, Shuaicheng Li, Chunde Li, Michael D Taylor, Jiankang Li, Yong-Qiang Liu, Xiaoguang Qiu, Tao Jiang

Faculty, Staff and Students Publications

Medulloblastoma (MB), a heterogeneous pediatric brain tumor, poses challenges in the treatment of tumor recurrence and dissemination. To characterize cellular diversity and genetic features, we comprehensively analyzed single-cell/nucleus RNA sequencing (sc/snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and spatial transcriptomics profiles and identified distinct cellular populations in SHH (sonic hedgehog) and Group_3 subgroups, with varying proportions in local recurrence or dissemination. Local recurrence showed higher cycling tumor cell enrichment, whereas disseminated lesions had a relatively notable presence of differentiated subsets. Chromosomal alteration evaluation revealed distinct genetic subclones during MB progression, such as chr7q gain and chr11 loss in Group_3 …

Real-World Satisfaction And Experience With Injection And Autoinjector Device For Ofatumumab Indicated For Multiple Sclerosis., Amy Perrin Ross, Jacqueline Nicholas, Ming-Hui Tai, Stephen Yeung, Nazneen Fatima Shaikh, Helen Chen, Mariana Fernandes, Aaron Cortright, Kevin Hawkins

Neuroscience Articles

BACKGROUND: To evaluate the overall satisfaction, device usability, and injection experience of MS patients self-administering ofatumumab using the Sensoready

METHODS: This US-based, cross-sectional survey study included patients with MS (≥ 18 years) who self-administered ofatumumab using the Sensoready device within the previous 12 months of the survey. Eligible patients were administered a 30-item de novo questionnaire that focused on overall device satisfaction, device usability, convenience/flexibility for travel with the device, user confidence, injection experience, and time to administer the injection. Ratings were measured on Likert and numeric rating scales, with higher scores indicating positive responses.

RESULTS: Overall, 105 patients with …

A Potential Vegf-Driven Hypothesis Of Calvarial Centripetal Proliferation In Cerebral Proliferative Angiopathy, Shigeta Miyake, Timo Krings, Tze Phei Kee, Thierry A G M Huisman

Faculty, Staff and Students Publications

Cerebral proliferative angiopathy (CPA) is a rare subtype of cerebral arteriovenous malformation, characterized by unique angiographic features and clinical presentations. Although the clinical and angiographic characteristics of CPA have been well described, their impact on the surrounding tissues remains underexplored. Herein, we investigated the presence of calvarial thickening in patients with CPA, and discuss its potential pathogenesis. This retrospective multicenter cohort study enrolled 16 CPA patients from our institutions. Patients were identified by a search of the hospital medical records for key words related to "cerebral proliferative angiopathy." Data on demographics, CPA characteristics, clinical symptoms, and calvarial thickening were collected …

Associations Between Deficit Accumulation Frailty And Baseline Markers Of Lifestyle In The Us Pointer Trial, Mark A Espeland, Yitbarek N Demesie, Kayloni Olson, Samuel N Lockhart, Sarah E Tomaszewski Farias, Maryjo L Cleveland, Christy C Tangney, Lucia Crivelli, Heather M Snyder, Michele K York, Laura D Baker, Rachel A Whitmer, Rena R Wing, Katelyn R Garcia, Kathryn E Callahan

Faculty, Staff and Students Publications

BACKGROUND: Multidomain lifestyle interventions may have the potential to slow biological aging as captured by deficit accumulation frailty indices. We describe the distribution and composition of the 49-component frailty index developed by the U.S. POINTER clinical trial team of investigators and assess its cross-sectional associations with sociodemographic factors and markers chosen to be representative of behaviors targeted by the trial's multidomain interventions.

METHODS: We draw baseline data from the 2 111 volunteers enrolled in U.S. POINTER who were ages 60-79 years and at increased risk for cognitive decline. Frailty components were grouped into 9 domains. Associations that frailty index scores …

Discontiguous Recurrences Of Idh-Wildtype Glioblastoma Share A Common Origin With The Initial Tumor And Are Frequently Hypermutated, Malcolm F Mcdonald, Sricharan Gopakumar, Tareq A Juratli, Ilker Y Eyüpoglu, Ganesh Rao, Jacob J Mandel, Ali Jalali

Faculty, Staff and Students Publications

Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences …

Detection Of Elder Abuse Through Emergency Care Technicians Screening Tool Revision For Home-Based Primary Care (Detect-Rpc): A Cluster Randomised Controlled Trial Study Protocol, Brad Cannell, Nicholas Sevey, Melvin D Livingston, Jason Burnett, Kristin Lees Haggerty, Carolyn Pickering

Faculty, Staff and Student Publications

Introduction: The annual prevalence of elder mistreatment (EM) in cognitively intact older adults is estimated to be 11%, yet the annual prevalence in older adults with Alzheimer's disease and related dementias (AD/ADRD) is estimated to be as high as 75%. Associated with a decrease in quality of life and increase in risk of mortality, EM represents a significant public health burden. Home-based primary care (HBPC) providers are uniquely positioned to address the critical need for robust EM screening and reporting, especially among individuals with AD/ADRD. This protocol seeks to adapt the Detection of Elder mistreatment Through Emergency Care Technicians (DETECT) …

Foxr2 Targets Lhx6+/Dlx+ Neural Lineages To Drive Central Nervous System Neuroblastoma, Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael Mcnicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W Tsai, Andrey Korshunov, Timothy N Phoenix, Benjamin Ellezam, David T W Jones, Michael D Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, Claudia L Kleinman

Faculty, Staff and Students Publications

Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal …

Is Modulation Of Immune Checkpoints On Glioblastoma-Infiltrating Myeloid Cells A Viable Therapeutic Strategy?, Ruochen Du, Jianzhong Zhang, Rimas V Lukas, Shashwat Tripathi, Jared T Ahrendsen, Michael A Curran, Crismita Dmello, Peng Zhang, Roger Stupp, Ganesh Rao, Amy B Heimberger

Faculty, Staff and Students Publications

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, …

Alzheimer’S Disease: Relationship Of Cognition And Behavior To Neurochemistry, Peter J. Whitehouse

Faculty Scholarship

Alzheimer’s disease is characterized by loss of cells and synapses in specific neural systems. The development of more effective therapies will depend on understanding the relationships between this pathology and the cognitive and behavioral impairments. In this review, focusing primarily on work in our laboratory, we will examine both classic and neuropeptide neurotransmitter systems and will discuss conceptual and methodological problems in relating clinical and biological measures.