Neurology Commons^™

Metabolic Bioactivation Of Antidepressants: Advance And Underlying Hepatotoxicity, Saleh M Khalil, Kevin R Mackenzie, Mirjana Maletic-Savatic, Feng Li

Faculty, Staff and Students Publications

Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which …

Delivering Multidisciplinary Rehabilitation Care In Parkinson's Disease: An International Consensus Statement, Jennifer G Goldman, Daniele Volpe, Terry D Ellis, Mark A Hirsch, Julia Johnson, Julia Wood, Ana Aragon, Roberta Biundo, Alessandro Di Rocco, Glenn S Kasman, Robert Iansek, Janis Miyasaki, Victor M Mcconvey, Marten Munneke, Serge Pinto, Karen A St Clair, Santiago Toledo, Michele K York, Ronnie Todaro, Nicole Yarab, Kristin Wallock

Faculty, Staff and Students Publications

BACKGROUND: Parkinson's disease (PD) is a complex neurodegenerative disorder impacting everyday function and quality of life. Rehabilitation plays a crucial role in improving symptoms, function, and quality of life and reducing disability, particularly given the lack of disease-modifying agents and limitations of medications and surgical therapies. However, rehabilitative care is under-recognized and under-utilized in PD and often only utilized in later disease stages, despite research and guidelines demonstrating its positive effects. Currently, there is a lack of consensus regarding fundamental topics related to rehabilitative services in PD.

OBJECTIVE: The goal of the international Parkinson's Foundation Rehabilitation Medicine Task Force was …

Screening For Adhd In Adult Patients With Epilepsy: Prevalence Of Symptoms And Challenges To Diagnosis, Trung Nguyen, Emily Xiao, Allison Clark, Afroz Shamim, Atul Maheshwari

Faculty, Staff and Students Publications

OBJECTIVE: Given the complex nature of seizure disorders and their treatments, ADHD may be underdiagnosed in this population. We hypothesized that a higher percentage of patients presenting to a seizure clinic would endorse ADHD symptoms compared to rates reported in the general population and that formal screening for ADHD symptoms would identify patients with previously undiagnosed comorbid ADHD.

METHODS: In this study, we surveyed 312 adults in a seizure clinic using the Adult ADHD Self-Report Scale (ASRS-v1.1).

RESULTS: We found that 90 patients (28.8%) screened positive with the ASRS-v1.1, but only nine of these patients were able to complete neuropsychological …

Rragd-Associated Autosomal Dominant Kidney Hypomagnesemia With Cardiomyopathy: A Review On The Clinical Manifestations And Therapeutic Options, Francesco Trepiccione, Irene Sambri, Barbara Ruggiero, Francesco Emma, Andrea Ballabio, Giulia Florio, Ines Vanderheyden, Anna Iervolino, François Jouret

Duncan NRI Faculty and Staff Publications

Background: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function.

Summary: All identified RRAGD variants compromise …

Functional Genomics And Small Molecules In Mitochondrial Neurodevelopmental Disorders, Daniel G Calame, Lisa T Emrick

Faculty, Staff and Students Publications

Mitochondria are critical for brain development and homeostasis. Therefore, pathogenic variation in the mitochondrial or nuclear genome which disrupts mitochondrial function frequently results in developmental disorders and neurodegeneration at the organismal level. Large-scale application of genome-wide technologies to individuals with mitochondrial diseases has dramatically accelerated identification of mitochondrial disease-gene associations in humans. Multi-omic and high-throughput studies involving transcriptomics, proteomics, metabolomics, and saturation genome editing are providing deeper insights into the functional consequence of mitochondrial genomic variation. Integration of deep phenotypic and genomic data through allelic series continues to uncover novel mitochondrial functions and permit mitochondrial gene function dissection on an …

Researching Covid To Enhance Recovery (Recover) Pediatric Study Protocol: Rationale, Objectives And Design, Rachel S Gross, Tanayott Thaweethai, Erika B Rosenzweig, James Chan, Lori B Chibnik, Mine S Cicek, Amy J Elliott, Valerie J Flaherman, Andrea S Foulkes, Margot Gage Witvliet, Richard Gallagher, Maria Laura Gennaro, Terry L Jernigan, Elizabeth W Karlson, Stuart D Katz, Patricia A Kinser, Lawrence C Kleinman, Michelle F Lamendola-Essel, Joshua D Milner, Sindhu Mohandas, Praveen C Mudumbi, Jane W Newburger, Kyung E Rhee, Amy L Salisbury, Jessica N Snowden, Cheryl R Stein, Melissa S Stockwell, Kelan G Tantisira, Moriah E Thomason, Dongngan T Truong, David Warburton, John C Wood, Shifa Ahmed, Almary Akerlundh, Akram N Alshawabkeh, Brett R Anderson, Judy L Aschner, Andrew M Atz, Robin L Aupperle, Fiona C Baker, Venkataraman Balaraman, Dithi Banerjee, Deanna M Barch, Arielle Baskin-Sommers, Sultana Bhuiyan, Marie-Abele C Bind, Amanda L Bogie, Tamara Bradford, Natalie C Buchbinder, Elliott Bueler, Hülya Bükülmez, B J Casey, Linda Chang, Maryanne Chrisant, Duncan B Clark, Rebecca G Clifton, Katharine N Clouser, Lesley Cottrell, Kelly Cowan, Viren D'Sa, Mirella Dapretto, Soham Dasgupta, Walter Dehority, Audrey Dionne, Kirsten B Dummer, Matthew D Elias, Shari Esquenazi-Karonika, Danielle N Evans, E Vincent S Faustino, Alexander G Fiks, Daniel Forsha, John J Foxe, Naomi P Friedman, Greta Fry, Sunanda Gaur, Dylan G Gee, Kevin M Gray, Stephanie Handler, Ashraf S Harahsheh, Keren Hasbani, Andrew C Heath, Camden Hebson, Mary M Heitzeg, Christina M Hester, Sophia Hill, Laura Hobart-Porter, Travis K F Hong, Carol R Horowitz, Daniel S Hsia, Matthew Huentelman, Kathy D Hummel, Katherine Irby, Joanna Jacobus, Vanessa L Jacoby, Pei-Ni Jone, David C Kaelber, Tyler J Kasmarcak, Matthew J Kluko, Jessica S Kosut, Angela R Laird, Jeremy Landeo-Gutierrez, Sean M Lang, Christine L Larson, Peter Paul C Lim, Krista M Lisdahl, Brian W Mccrindle, Russell J Mcculloh, Kimberly Mchugh, Alan L Mendelsohn, Torri D Metz, Julie Miller, Elizabeth C Mitchell, Lerraughn M Morgan, Eva M Müller-Oehring, Erica R Nahin, Michael C Neale, Manette Ness-Cochinwala, Sheila M Nolan, Carlos R Oliveira, Onyekachukwu Osakwe, Matthew E Oster, R Mark Payne, Michael A Portman, Hengameh Raissy, Isabelle G Randall, Suchitra Rao, Harrison T Reeder, Johana M Rosas, Mark W Russell, Arash A Sabati, Yamuna Sanil, Alice I Sato, Michael S Schechter, Rangaraj Selvarangan, S Kristen Sexson Tejtel, Divya Shakti, Kavita Sharma, Lindsay M Squeglia, Shubika Srivastava, Michelle D Stevenson, Jacqueline Szmuszkovicz, Maria M Talavera-Barber, Ronald J Teufel, Deepika Thacker, Felicia Trachtenberg, Mmekom M Udosen, Megan R Warner, Sara E Watson, Alan Werzberger, Jordan C Weyer, Marion J Wood, H Shonna Yin, William T Zempsky, Emily Zimmerman, Benard P Dreyer, Recover-Pediatric Consortium

Faculty, Staff and Students Publications

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.

OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of …

De Novo Missense Variants In Zbtb47 Are Associated With Developmental Delays, Hypotonia, Seizures, Gait Abnormalities, And Variable Movement Abnormalities, Scott K Ward, Alexandrea Wadley, Chun-Hui Anne Tsai, Paul J Benke, Lisa Emrick, Kristen Fisher, Kimberly M Houck, Hongzheng Dai, Undiagnosed Diseases Network, Maria J Guillen Sacoto, William Craigen, Kimberly Glaser, David R Murdock, Luis Rohena, Karin E M Diderich, Hennie T Bruggenwirth, Brendan Lee, Carlos Bacino, Lindsay C Burrage, Jill A Rosenfeld

Faculty, Staff and Students Publications

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected …

Parkinson's Disease And Other Alzheimer's Disease And Related Dementia Pathologies And The Progression Of Parkinsonism In Older Adults, Aron S Buchman, Lei Yu, Shahram Oveisgharan, Andrea R Zammit, Tianhao Wang, Joshua M Shulman, Veronique Vanderhorst, Sukrit Nag, David A Bennett

Faculty, Staff and Students Publications

BACKGROUND: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear.

OBJECTIVE: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies.

METHODS: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). In decedents, we examined …

Validation Of A New Patient-Reported Outcome Measure Of The Functional Impact Of Essential Tremor On Activities Of Daily Living, Ludy C Shih, Michael T Stevenson, Steven Bellows, Alfonso Fasano, Sheng-Han Kuo, Kelly E Lyons, Henry Moore, Holly A Shill, Aparna Wagle Shukla, Carlos Singer, Rodger J Elble

Faculty, Staff and Students Publications

BACKGROUND: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines.

OBJECTIVE: Develop and validate a TETRAS PRO subscale.

METHODS: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for …

Altered Outer Retinal Structure, Electrophysiology And Visual Perception In Parkinson's Disease, Katie K N Tran, Pei Ying Lee, David I Finkelstein, Allison M Mckendrick, Bao N Nguyen, Bang V Bui, Christine T O Nguyen

Faculty, Staff and Student Publications

BACKGROUND: Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation.

OBJECTIVE: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing.

METHODS: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = …

Para-Infectious Brain Injury In Covid-19 Persists At Follow-Up Despite Attenuated Cytokine And Autoantibody Responses, Benedict D Michael, Cordelia Dunai, Edward J Needham, Kukatharmini Tharmaratnam, Robyn Williams, Yun Huang, Sarah A Boardman, Jordan J Clark, Parul Sharma, Krishanthi Subramaniam, Greta K Wood, Ceryce Collie, Richard Digby, Alexander Ren, Emma Norton, Maya Leibowitz, Soraya Ebrahimi, Andrew Fower, Hannah Fox, Esteban Tato, Mark A Ellul, Geraint Sunderland, Marie Held, Claire Hetherington, Franklyn N Egbe, Alish Palmos, Kathy Stirrups, Alexander Grundmann, Anne-Cecile Chiollaz, Jean-Charles Sanchez, James P Stewart, Michael Griffiths, Tom Solomon, Gerome Breen, Alasdair J Coles, Nathalie Kingston, John R Bradley, Patrick F Chinnery, Jonathan Cavanagh, Sarosh R Irani, Angela Vincent, J Kenneth Baillie, Peter J Openshaw, Malcolm G Semple, Covid-Cns Consortium, Isaric4c Investigators, Leonie S Taams, David K Menon

Faculty, Staff and Student Publications

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common …

Drivers Of Chronic Pathology Following Ischemic Stroke: A Descriptive Review, Grant W Goodman, Trang H Do, Chunfeng Tan, Rodney M Ritzel

Faculty, Staff and Student Publications

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an …

Mirna-211 Maintains Metabolic Homeostasis In Medulloblastoma Through Its Target Gene Long-Chain Acyl-Coa Synthetase 4, Menglang Yuan, Iqbal Mahmud, Keisuke Katsushima, Kandarp Joshi, Olivier Saulnier, Rudramani Pokhrel, Bongyong Lee, Wathsala Liyanage, Haritha Kunhiraman, Stacie Stapleton, Ignacio Gonzalez-Gomez, Rangaramanujam M Kannan, Tanja Eisemann, Elayaraja Kolanthai, Sudipta Seal, Timothy J Garrett, Saed Abbasi, Kimberly Bockley, Justin Hanes, Prem Chapagain, George Jallo, Robert J Wechsler-Reya, Michael D Taylor, Charles G Eberhart, Animesh Ray, Ranjan J Perera

Faculty, Staff and Students Publications

The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected …

Bayesian Longitudinal Tensor Response Regression For Modeling Neuroplasticity, Suprateek Kundu, Alec Reinhardt, Serena Song, Joo Han, M Lawson Meadows, Bruce Crosson, Venkatagiri Krishnamurthy

Faculty, Staff and Student Publications

A major interest in longitudinal neuroimaging studies involves investigating voxel-level neuroplasticity due to treatment and other factors across visits. However, traditional voxel-wise methods are beset with several pitfalls, which can compromise the accuracy of these approaches. We propose a novel Bayesian tensor response regression approach for longitudinal imaging data, which pools information across spatially distributed voxels to infer significant changes while adjusting for covariates. The proposed method, which is implemented using Markov chain Monte Carlo (MCMC) sampling, utilizes low-rank decomposition to reduce dimensionality and preserve spatial configurations of voxels when estimating coefficients. It also enables feature selection via joint credible …

Variations Of The Trapezius Branch Of The Accessory Nerve: An Anatomic Study, Matthew E Lin, Celeste Kim, Adam Howard, Niels Kokot

Faculty, Staff and Student Publications

Although modified radical neck dissections have increased in popularity to reduce morbidity secondary to intraoperative accessory nerve damage, inadvertent injury still often occurs. As this phenomenon is thought to be due to anatomic variation in the trapezius branch of the accessory nerve, it is imperative to better understand the nuances of these anatomic variations to better inform surgical decision-making. A total of 24 accessory nerves were dissected, exposed, and traced in 15 cadavers. Three aspects of the accessory nerve were identified and recorded: the course of the trapezius branch in relation to the sternocleidomastoid, the number of trapezius branches at …

Detection Of Prions In The Urine Of Patients Affected By Sporadic Creutzfeldt-Jakob Disease, M Talke

Faculty, Staff and Student Publications

Objective

Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt–Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter‐individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD.

Methods

Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were …

Capacity Assessment And Spatial Analysis Of Cervical Cancer Services In The Gambia, Meghan E Mali, Ousman Sanyang, Katherine L Harris, Justin Sorensen, Mustapha Bittaye, Jonathan Nellermoe, Raymond R Price, Edward K Sutherland

Faculty, Staff and Student Publications

Background

Cervical cancer is the most common cancer and the leading cause of cancer-related death in Gambian women. The Gambian Ministry of Health is striving to improve access to screening, diagnostic, and treatment services for cervical cancer, but comprehensive data on currently available services is limited making it challenging to appropriately prioritize the ideal next steps for expanding care. This study aims to describe the current services available for the prevention, screening, and treatment of cervical cancer in The Gambia and provide suggestions for expanding geographic access to care.

Methods

A survey aimed at assessing the availability of key cervical …

Novel Sox10 Indel Mutations Drive Schwannomas Through Impaired Transactivation Of Myelination Gene Programs, Erik A Williams, Ajay Ravindranathan, Rohit Gupta, Nicholas O Stevers, Abigail K Suwala, Chibo Hong, Somang Kim, Jimmy Bo Yuan, Jasper Wu, Jairo Barreto, Calixto-Hope G Lucas, Emily Chan, Melike Pekmezci, Philip E Leboit, Thaddeus Mully, Arie Perry, Andrew Bollen, Jessica Van Ziffle, W Patrick Devine, Alyssa T Reddy, Nalin Gupta, Kristen M Basnet, Robert J B Macaulay, Patrick Malafronte, Han Lee, William H Yong, Kevin Jon Williams, Tareq A Juratli, Douglas A Mata, Richard S P Huang, Matthew C Hiemenz, Dean C Pavlick, Garrett M Frampton, Tyler Janovitz, Jeffrey S Ross, Susan M Chang, Mitchel S Berger, Line Jacques, Jun S Song, Joseph F Costello, David A Solomon

Faculty, Staff and Student Publications

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a …

Agreement Between Published Reference Resources For Neurofilament Light Chain Levels In People With Multiple Sclerosis., Elias S Sotirchos, Chen Hu, Matthew D Smith, Hannah-Noelle Lord, Anna L Duval, Georgina Arrambide, Xavier Montalban, Katja Akgün, Tjalf Ziemssen, Robert T Naismith, Carrie M Hersh, Megan Hyland, Lauren B Krupp, Jacqueline A Nicholas, Robert A Bermel, Ellen M Mowry, Peter A Calabresi, Kathryn C Fitzgerald

Neuroscience Articles

OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS).

METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL

RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 …

Functional And Anatomical Connectivity Predict Brain Stimulation’S Mnemonic Effects, Youssef Ezzyat, James E> Kragel, Ethan A. Solomon, Bradley C. Lega, Joshua P. Aronson, Barbara C. Jobst, Robert E. Gross, Michael R. Sperling, Gregory A. Worrell, Sameer A. Sheth, Paul A. Wanda, Daniel S. Rizzuto, Michael J. Kahana

Department of Neurology Faculty Papers

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC …

Isoform-Level Transcriptome-Wide Association Uncovers Genetic Risk Mechanisms For Neuropsychiatric Disorders In The Human Brain, Arjun Bhattacharya, Daniel D Vo, Connor Jops, Minsoo Kim, Cindy Wen, Jonatan L Hervoso, Bogdan Pasaniuc, Michael J Gandal

Faculty, Staff and Student Publications

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power …

Altered Amygdala Volumes And Microstructure In Focal Epilepsy Patients With Tonic-Clonic Seizures, Ictal, And Post-Convulsive Central Apnea, Claudia Zeicu, Antoine Legouhy, Catherine A Scott, Joana F A Oliveira, Gavin P Winston, John S Duncan, Sjoerd B Vos, Maria Thom, Samden Lhatoo, Hui Zhang, Ronald M Harper, Beate Diehl

Faculty, Staff and Student Publications

Objectives

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal‐to‐bilateral tonic–clonic seizures (FBTCS) are a major risk factor, and centrally‐mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post‐convulsive central apnea (PCCA).

Methods

Seventy‐three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during …

Relapse Recovery In Relapsing-Remitting Multiple Sclerosis: An Analysis Of The Combirx Dataset, Marcus W Koch, Ester Moral, Luis Brieva, Jop Mostert, Eva Mm Strijbis, Jacynthe Comtois, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Gary Cutter

Faculty, Staff and Student Publications

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery.

OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS).

METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to …

Genomic Profiles And Clinical Outcomes Of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden, Andrea Necchi, Philippe E Spiess, Tiago Costa De Padua, Roger Li, Petros Grivas, Richard S P Huang, Douglas I Lin, Natalie Danziger, Jeffrey S Ross, Joseph M Jacob, Rebecca A Sager, Alina Basnet, Gerald Li, Ryon P Graf, Dean C Pavlick, Gennady Bratslavsky

Faculty, Staff and Student Publications

IMPORTANCE: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC).

OBJECTIVE: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low ([mut/Mb]), high (10-19 mut/Mb), or very high …

Behavioral Or Neuropsychiatric Symptoms Of Alzheimer’S Disease: From Psychopathology To Pharmacological Management, Antonio Lucio Teixeira, Natalia Pessoa Rocha, Jennifer Gatchel

Faculty, Staff and Student Publications

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this …

Shift From Older- To Newer-Generation Antiseizure Medications In People With Acute Ischemic Stroke In Australia: A Population-Based Study, Stella Jung-Hyun Kim, Stephen Wood, Clara Marquina, Emma Foster, J Simon Bell, Jenni Ilomäki

Faculty, Staff and Student Publications

OBJECTIVE: To investigate the trends in antiseizure medications (ASMs) use following ischemic stroke and to examine factors associated with use of newer- and older-generation ASMs.

METHODS: A retrospective cohort study was conducted using state-wide linked health datasets. Patients who were hospitalized with a first-ever ischemic stroke between 2013 and 2017 and were dispensed ASM within 12 months from discharge were included. Logistic regression was used to examine the predictors of receiving newer-generation ASMs. Generalized linear modeling was used to identify factors associated with ASM use after ischemic stroke.

RESULTS: Of 19 601 people hospitalized with a first-ever ischemic stroke, 989 …

Sleep Duration, Sleep Quality, And Weapon Carrying In A Sample Of Adolescents From Texas, Arthur Stefanski, Eduardo Pérez-Palma, Tobias Brünger, Ludovica Montanucci, Cornelius Gati, Chiara Klöckner, Katrine M Johannesen, Kimberly Goodspeed, Marie Macnee, Alexander T Deng, Ángel Aledo-Serrano, Artem Borovikov, Maina Kava, Arjan M Bouman, M J Hajianpour, Deb K Pal, Marc Engelen, Eveline E O Hagebeuk, Marwan Shinawi, Alexis R Heidlebaugh, Kathryn Oetjens, Trevor L Hoffman, Pasquale Striano, Amanda S Freed, Line Futtrup, Thomas Balslev, Anna Abulí, Leslie Danvoye, Damien Lederer, Tugce Balci, Maryam Nabavi Nouri, Elizabeth Butler, Sarah Drewes, Kalene Van Engelen, Katherine B Howell, Jean Khoury, Patrick May, Marena Trinidad, Steven Froelich, Johannes R Lemke, Jacob Tiller, Amber N Freed, Jing-Qiong Kang, Arthur Wuster, Rikke S Møller, Dennis Lal

Faculty, Staff and Student Publications

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.

We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches.

The GAT1 transmembrane domains …

Management Strategies Of Unanticipated Intracranial Stenosis During Mechanical Thrombectomy For Acute Stroke: A Survey Of Academic Neurointerventionalists, Tyler T Lazaro, Alex N Hoang, Patrick C Cotton, Huy Q Dang, Omar Tanweer, Daniel M S Raper

Faculty, Staff and Students Publications

BACKGROUND: The optimal approach to the management of intracranial atherosclerotic disease (ICAD) at the time of mechanical thrombectomy (MT) for large vessel occlusion (LVO) remains controversial. The goal of this study is to characterize current practices concerning this challenging clinical situation in a survey of practicing neurointerventionalists.

METHODS: An electronic questionnaire was sent to a cross-section of North American academic neurointerventionalists using publicly available contact information and departmental websites. Prior to analysis, responses were anonymized and categorized by region.

RESULTS: A total of 136/360 responses were recorded from the U.S. and Canada. The mean number of years of practicing as …

Impact Of Routine Urine Cultures On Antibiotic Usage In Those Undergoing A Routine Annual Spinal Cord Injury Evaluation, Sarah May, Annette Walder, Casey Hines-Munson, Ivy Poon, S Ann Holmes, Charlesnika T Evans, Barbara W Trautner, Felicia Skelton

Faculty, Staff and Students Publications

OBJECTIVE: The Veterans Health Administration (VHA), the largest single provider of spinal cord injury and disorder (SCI/D) care in the United States, currently mandates that every patient receives a screening urine culture during the annual evaluation, a yearly comprehensive history and physical examination. This testing has shown in a small subset of patients to overidentify asymptomatic bacteriuria that is then inappropriately treated with antibiotics. The objective of the current analysis was to assess the association of the annual evaluation on urine testing and antibiotic treatment in a national sample of Veterans with SCI/D.

DESIGN/METHOD: A retrospective cohort study using national …

Precision Therapy For A Medically Actionable Atp1a3 Variant From A Genomic Medicine Program In An Underserved Population, Cara P Ford, Rebecca O Littlejohn, Ryan German, Blake Vuocolo, Jose Aceves, Liesbeth Vossaert, Nichole Owen, Michael Wangler, Carrie A Schmid

Duncan NRI Faculty and Staff Publications

Background: Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7-year-old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance.

Methods: After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG …