Neurology Commons^™

Demographics And Paindetect As Predictors Of 24-Month Outcomes For 10 Khz Scs In Nonsurgical Refractory Back Pain, Leonardo Kapural, Chengyuan Wu, Aaron Calodney, Julie Pilitsis, Markus Bendel, Erika Petersen, Dawood Sayed, Colleen Kelly, Rose Province-Azalde, Naresh P. Patel

Department of Neurosurgery Faculty Papers

BACKGROUND: Nonsurgical refractory back pain (NSRBP) is broadly defined as chronic refractory back pain in patients who have not had previous spine surgery and, because they are deemed inappropriate candidates for surgery, are reliant on conventional medical management (CMM), which often provides poor long-term outcomes. High-frequency spinal cord stimulation (10kHz SCS) has demonstrated high rates of pain relief and improvements in functioning in patients with NSRBP. However, despite the use of temporary trial stimulation to select patients who will respond to therapy, some patients fail to achieve long-term therapy response with permanent implants. Prediction analysis founded on patients' baseline characteristics …

Novel Avenues Of Tau Research, Claire E Sexton, Gal Bitan, Kathryn R Bowles, Miroslaw Brys, Luc Buée, Mahmoud Bukar Maina, Claire D Clelland, Ann D Cohen, John F Crary, Jeffrey L Dage, Kristophe Diaz, Bess Frost, Li Gan, Alison M Goate, Lawrence I Golbe, Oskar Hansson, Celeste M Karch, Hartmuth C Kolb, Renaud La Joie, Suzee E Lee, Diana Matallana, Bruce L Miller, Chiadi U Onyike, Yakeel T Quiroz, Jessica E Rexach, Jonathan D Rohrer, Amy Rommel, Ghazaleh Sadri-Vakili, Suzanne E Schindler, Julie A Schneider, Reisa A Sperling, Charlotte E Teunissen, Stacie C Weninger, Susan L Worley, Hui Zheng, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years.

METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.

RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.

DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration …

Retinal Thickness In Essential Tremor And Early Parkinson Disease: Exploring Diagnostic Insights, Claudio Terravecchia, Giovanni Mostile, Clara G Chisari, Cristina Rascunà, Roberta Terranova, Calogero E Cicero, Loretta Giuliano, Giulia Donzuso, Giorgia Sciacca, Antonina Luca, Pierre-Marie Preux, Joseph Jankovic, Mario Zappia, Alessandra Nicoletti

Faculty, Staff and Students Publications

BACKGROUND: Essential tremor (ET) represents a heterogeneous condition which may overlap with Parkinson disease (PD) even at early stages, by sharing some subtle clinical aspects. Longstanding ET demonstrated also higher risk of developing PD, especially with a Tremor-dominant (TD-PD) phenotype. Therefore, differential diagnosis between ET and early PD could be quite challenging. Optical coherence tomography (OCT) has been recognized as a reliable tool to assess the retina as a proxy of neurodegeneration. We aimed to explore the possible role of retinal assessment in differential diagnosis between ET and early PD.

METHODS: Macular layers and peripapillary retinal nerve fiber layer (RNFL) …

Heterozygous Map3k20 Variants Cause Ectodermal Dysplasia, Craniosynostosis, Sensorineural Hearing Loss, And Limb Anomalies, Daniel Brooks, Elizabeth Burke, Sukyeong Lee, Tanya N Eble, Melanie O'Leary, Ikeoluwa Osei-Owusu, Heidi L Rehm, Shweta U Dhar, Lisa Emrick, David Bick, Michelle Nehrebecky, Ellen Macnamara, Dídac Casas-Alba, Judith Armstrong, Carolina Prat, Antonio F Martínez-Monseny, Francesc Palau, Pengfei Liu, David Adams, Undiagnosed Diseases Network, Seema Lalani, Jill A Rosenfeld, Lindsay C Burrage

Faculty, Staff and Students Publications

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. …

Severe Stiff-Person Syndrome After Covid: The First Video-Documented Covid Exacerbation And Viral Implications, Marinos C. Dalakas

Department of Neurology Faculty Papers

OBJECTIVES: To describe a patient with mild GAD-positive stiff-leg syndrome (SLS) who developed severely disabling stiff-person syndrome (SPS) 1 week after mild COVID-19 and discuss the impact of viral implications.

METHODS: Video-documented serial clinical observations at baseline, after acute COVID-19, and after IVIG treatments.

RESULTS: A 39-year-old man with left-SLS was stable during a 2-year follow-up with low-dose antispasmodics, working fully and functioning normally, even able to run. One week after mild COVID-19, he started to experience generalized SPS symptomatology that steadily worsened the following 2-3 weeks, becoming unable to walk, requiring a walker, with significant thoracolumbar and bilateral leg …

Association Of Plasma Ykl-40 With Mri, Csf, And Cognitive Markers Of Brain Health And Dementia, Matthew P Pase, Jayandra J Himali, Raquel Puerta, Alexa S Beiser, Mitzi M Gonzales, Claudia L Satizabal, Qiong Yang, Hugo J Aparicio, Daniel J Kojis, Charles S Decarli, Oscar L Lopez, Will Longstreth, Vilmundur Gudnason, Thomas H Mosley, Joshua C Bis, Alison Fohner, Bruce M Psaty, Mercè Boada, Pablo García-González, Sergi Valero, Marta Marquié, Russell Tracy, Lenore J Launer, Agustín Ruiz, Myriam Fornage, Sudha Seshadri

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk.

METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total …

Efficacy And Safety Of Daxibotulinumtoxina For Injection In Cervical Dystonia: Aspen-1 Phase 3 Randomized Controlled Trial, Cynthia L Comella, Joseph Jankovic, Robert A Hauser, Atul T Patel, Marta D Banach, Edvard Ehler, Domenico Vitarella, Roman G Rubio, Todd M Gross, Aspen-1 Study Group

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).

METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change …

Comparative Efficacy, Quality Of Life, Safety, And Tolerability Of Atogepant And Rimegepant In Migraine Prevention: A Matching-Adjusted Indirect Comparison Analysis, Cristina Tassorelli, Kateryna Onishchenko, Rashmi B. Halker Singh, Molly Duan, Laure Dupont-Benjamin, Matthew Hemstock, Corey Voller, Peter Mcallister, Stephanie J. Nahas, Pranav Gandhi, Jessica Ailani

Department of Neurology Faculty Papers

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice.

METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly …

Polyaminer-Bulk Is A Deep Learning-Based Algorithm That Decodes Alternative Polyadenylation Dynamics From Bulk Rna-Seq Data, Venkata Soumith Jonnakuti, Eric J Wagner, Mirjana Maletić-Savatić, Zhandong Liu, Hari Krishna Yalamanchili

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism; yet, its regulation and impact on human diseases remain understudied. Existing bulk RNA sequencing (RNA-seq)-based APA methods predominantly rely on predefined annotations, severely impacting their ability to decode novel tissue- and disease-specific APA changes. Furthermore, they only account for the most proximal and distal cleavage and polyadenylation sites (C/PASs). Deconvoluting overlapping C/PASs and the inherent noisy 3' UTR coverage in bulk RNA-seq data pose additional challenges. To overcome these limitations, we introduce PolyAMiner-Bulk, an attention-based deep learning algorithm that accurately recapitulates C/PAS sequence grammar, resolves overlapping C/PASs, captures non-proximal-to-distal APA changes, …

Progestin-Associated Meningiomatosis With Unusual Schwannoma-Like Morphology, Katherine A Krause, Jared K Woods, Alexandra J Golby, Eudocia Q Lee, Shyam Tanguturi, Zachary Spigelman, Azra H Ligon, Umberto De Girolami, Matthew Torre

Duncan NRI Faculty and Staff Publications

No abstract provided.

Uchl1 Is A Potential Molecular Indicator And Therapeutic Target For Neuroendocrine Carcinomas, Shiqin Liu, Timothy Chai, Fernando Garcia-Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Martin Shaw Toland, Abel Bermudez, Alifiani B Hartono, Christopher F Massey, Chung S Lee, Liwei Zheng, Maya Baron, Caden J Denning, Merve Aslan, Holly M Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian A Kunder, Brooke E Howitt, H Tom Soh, Irving L Weissman, Michael A Liss, Arnold I Chin, James D Brooks, Eva Corey, Sharon J Pitteri, Jiaoti Huang, Tanya Stoyanova

Faculty, Staff and Student Publications

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Duncan NRI Faculty and Staff Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Faculty, Staff and Students Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Development And Validation Of Parent-Reported Gastrointestinal Health Scale In Mecp2 Duplication Syndrome, Davut Pehlivan, Sukru Aras, Daniel G Glaze, Muharrem Ak, Bernhard Suter, Kathleen J Motil

Faculty, Staff and Students Publications

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.

METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale.

RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis …

Impact Of An Integrated Health, Nutrition, And Early Child Stimulation And Responsive Care Intervention Package Delivered To Preterm Or Term Small For Gestational Age Babies During Infancy On Growth And Neurodevelopment: Study Protocol Of An Individually Randomized Controlled Trial In India (Small Babies Trial), Ranadip Chowdhury, Rukman Manapurath, Ingvild Fossgard Sandøy, Ravi Prakash Upadhyay, Neeta Dhabhai, Saijuddin Shaikh, Harish Chellani, Tarun Shankar Choudhary, Abhinav Jain, Jose Martines, Nita Bhandari, Tor A Strand, Sunita Taneja

Faculty, Staff and Student Publications

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating.

METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata …

Endovascular Thrombectomy Treatment Effect In Direct Vs Transferred Patients With Large Ischemic Strokes: A Prespecified Analysis Of The Select2 Trial, Amrou Sarraj, Michael D Hill, M Shazam Hussain, Michael G Abraham, Santiago Ortega-Gutierrez, Michael Chen, Scott E Kasner, Leonid Churilov, Deep K Pujara, Hannah Johns, Spiros Blackburn, Sophia Sundararajan, Yin C Hu, Nabeel A Herial, Ronald F Budzik, William J Hicks, Juan F Arenillas, Jenny P Tsai, Osman Kozak, Dennis J Cordato, Ricardo A Hanel, Teddy Y Wu, Pere Cardona Portela, Chirag D Gandhi, Fawaz Al-Mufti, Laith Maali, Daniel Gibson, Natalia Pérez De La Ossa, Joanna D Schaafsma, Jordi Blasco, Navdeep Sangha, Steven Warach, Timothy J Kleinig, Faris Shaker, Clark W Sitton, Thanh Nguyen, Johanna T Fifi, Pascal Jabbour, Anthony Furlan, Maarten G Lansberg, Georgios Tsivgoulis, Cathy Sila, Nicholas Bambakidis, Stephen Davis, Lawrence Wechsler, Greg W Albers, James C Grotta, Marc Ribo, Bruce C Campbell, Ameer E Hassan, Nirav Vora, Nathan W Manning, Andrew Cheung, Amin N Aghaebrahim, Andres J Paipa Merchán, Daniel Sahlein, Manuel Requena Ruiz, Lucas Elijovich, Adam Arthur, Faisal Al-Shaibi, Edgar A Samaniego, Kelsey R Duncan, Amanda Opaskar, Abhishek Ray, Wei Xiong, Jeffery Sunshine, Michael Degeorgia, Stavropoula Tjoumakaris, Vitor Mendes Pereira

Faculty, Staff and Student Publications

Importance: Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT).

Objective: To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes.

Design, setting, and participants: This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as …

Discovery And Clinical Proof-Of-Concept Of Rly-2608, A First-In-Class Mutant-Selective Allosteric Pi3kα Inhibitor That Decouples Antitumor Activity From Hyperinsulinemia, Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Artemisa Bulku, Lucian Dipietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R Larochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H Mclean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, Hanmo Zhang, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp

Faculty, Staff and Student Publications

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor …

Benchmarking Signal Quality And Spatiotemporal Distribution Of Interictal Spikes In Prolonged Human Ieeg Recordings Using Cortec Wireless Brain Interchange, Amir Hossein Ayyoubi, Behrang Fazli Besheli, Michael M Quach, Jay R Gavvala, Alica M Goldman, Chandra Prakash Swamy, Eleonora Bartoli, Daniel J Curry, Sameer A Sheth, David J Francis, Nuri F Ince

Faculty, Staff and Student Publications

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit …

Longitudinal Single-Cell Transcriptional Dynamics Throughout Neurodegeneration In Sca1, Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S Mcloughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David Van Dijk, Janghoo Lim

Duncan NRI Faculty and Staff Publications

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a …

Insights Of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles, Andreas M Heilmann, Jonathan W Riess, Margaret Mclaughlin-Drubin, Richard S P Huang, Meghann Hjulstrom, James Creeden, Brian M Alexander, Rachel L Erlich

Faculty, Staff and Student Publications

BACKGROUND: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles.

MATERIALS AND METHODS: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, …

Neurologic Morbidity And Functional Independence In Adult Survivors Of Childhood Cancer, Stefanie C Vuotto, Mingjuan Wang, M Fatih Okcu, Daniel C Bowers, Nicole J Ullrich, Kirsten K Ness, Chenghong Li, Deo Kumar Srivastava, Rebecca M Howell, Todd M Gibson, Wendy M Leisenring, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies.

METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal …

Thrombectomy With The Preset Vs Solitaire Stent Retrievers As First-Line Large Vessel Occlusion Stroke Treatment: A Randomized Clinical Trial., Raul G Nogueira, Donald Lobsien, Joachim Klisch, Daniel Pielenz, Elmar Lobsien, Eric Sauvageau, Nima Aghaebrahim, Markus Möhlenbruch, Dominik Vollherbst, Christian Ulfert, Hormozd Bozorgchami, Wayne Clark, Ryan Priest, Edgar A Samaniego, Santiago Ortega-Gutierrez, Malik Ghannam, Demetrius Lopes, Joshua Billingsley, Kiffon Keigher, Diogo C Haussen, Alhamza R Al-Bayati, Adnan Siddiqui, Elad Levy, Michael Chen, Stephan Munich, Peter Schramm, Tobias Boppel, Sandra Narayanan, Bradley A Gross, Christian Roth, Tobias Boeckh-Behrens, Ameer Hassan, Johanna Fifi, Ron F Budzik, Jason Tarpley, Robert M Starke, Eytan Raz, Gary Brogan, David S Liebeskind, Ricardo A Hanel

Neuroscience Articles

IMPORTANCE: Stent retriever-based thrombectomy is highly beneficial in large vessel occlusion (LVO) strokes. Many stent retriever designs are currently available, but comparison of these technologies in well-conducted studies is lacking.

OBJECTIVE: To determine whether thrombectomy for LVO stroke with the pRESET stent retriever is noninferior to treatment with the Solitaire stent retriever.

DESIGN, SETTING, AND PARTICIPANTS: This study was a multicenter, prospective, randomized, controlled, open-label, adaptive, noninferiority trial with blinded primary end point evaluation. Between October 2019 and February 2022, multicenter participation occurred across 19 research hospitals and/or universities in the US and 5 in Germany. Patients with LVO stroke …

Trigeminal Neuralgia As A Primary Demyelinating Disease: Potential Multimodal Evidence And Remaining Controversies, Seyed H Mousavi, John W Lindsey, Karin N Westlund, Sascha R A Alles

Faculty, Staff and Student Publications

Trigeminal neuralgia is a heterogeneous disorder with likely multifactorial and complex etiology; however, trigeminal nerve demyelination and injury are observed in almost all patients with trigeminal neuralgia. The current management strategies for trigeminal neuralgia primarily involve anticonvulsants and surgical interventions, neither of which directly address demyelination, the pathological hallmark of trigeminal neuralgia, and treatments targeting demyelination are not available. Demyelination of the trigeminal nerve has been historically considered a secondary effect of vascular compression, and as a result, trigeminal neuralgia is not recognized nor treated as a primary demyelinating disorder. In this article, we review the evolution of our understanding …

Matr3 Pathogenic Variants Differentially Impair Its Cryptic Splicing Repression Function, Mashiat Khan, Xiao Xiao Lily Chen, Michelle Dias, Jhune Rizsan Santos, Sukhleen Kour, Justin You, Rebekah Van Bruggen, Mohieldin M M Youssef, Ying-Wooi Wan, Zhandong Liu, Jill A Rosenfeld, Qiumin Tan, Udai Bhan Pandey, Hari Krishna Yalamanchili, Jeehye Park

Duncan NRI Faculty and Staff Publications

Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research …

Generation Of Five Induced Pluripotent Stem Cell Lines From Patients With Mecp2 Duplication Syndrome, Danielle Mendonca, Gerarda Cappuccio, Jennifer Sheppard, Magdalena Delacruz, Jesse Bengtsson, Claudia M B Carvalho, Aleksandar Bajic, Hyekyung Park, Jean J Kim, Paymaan Jafar-Nejad, Christine Coquery, Davut Pehlivan, Bernhard Suter, Mirjana Maletic-Savatic

Faculty, Staff and Students Publications

MECP2 Duplication Syndrome (MDS) is a rare, severe neurodevelopmental disorder arising from duplications in the Xq28 region containing the MECP2 gene that predominantly affects males. We generated five human induced pluripotent stem cell (iPSC) lines from the fibroblasts of individuals carrying between 0.355 and 11.2 Mb size duplications in the chromosomal locus containing MECP2. All lines underwent extensive testing to confirm MECP2 duplication and iPSC-related features such as morphology, pluripotency markers, and trilineage differentiation potential. These lines are a valuable resource for molecular and functional studies of MDS as well as screening for a variety of therapeutic approaches.

Novel Hemizygous Single-Nucleotide Duplication In Rpgr In A Patient With Retinal Dystrophy And Sensorineural Hearing Loss, Ryan J German, Blake Vuocolo, Liesbeth Vossaert, Nichole Owen, Richard A Lewis, Lisa Saba, Texome Project, Michael F Wangler, Sandesh Nagamani

Duncan NRI Faculty and Staff Publications

Background: The RPGR gene has been associated with X-linked cone-rod dystrophy. This report describes a variant in RPGR detected with exome sequencing (ES). Genes like RPGR have not always been included in panel-based testing and thus genome-wide tests such as ES may be required for accurate diagnosis.

Methods: The Texome Project is studying the impact of ES in medically underserved patients who are in need of genomic testing to guide diagnosis and medical management. The hypothesis is that ES could uncover diagnoses not made by standard medical care.

Results: A 58-year-old male presented with retinitis pigmentosa, sensorineural hearing loss, and …

Study Design And Methods: Us Study To Protect Brain Health Through Lifestyle Intervention To Reduce Risk (Us Pointer), Laura D Baker, Heather M Snyder, Mark A Espeland, Rachel A Whitmer, Miia Kivipelto, Nancy Woolard, Jeffrey Katula, Kathryn V Papp, Jennifer Ventrelle, Sarah Graef, Marcus A Hill, Scott Rushing, Julia Spell, Laura Lovato, Deborah Felton, Benjamin J Williams, Mina Ghadimi Nouran, Rema Raman, Tiia Ngandu, Alina Solomon, Sharon Wilmoth, Maryjo L Cleveland, Jeff D Williamson, Katherine L Lambert, Sarah Tomaszewski Farias, Claire E Day, Christy C Tangney, Darren R Gitelman, Olivia Matongo, Terrianne Reynolds, Valory N Pavlik, Melissa M Yu, Ashley S Alexander, Richard Elbein, Ann Marie Mcdonald, Stephen Salloway, Rena R Wing, Susan Antkowiak, Martha Clare Morris, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans.

METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER.

RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and …

The Importance Of Considering Competing Risks In Recurrence Analysis Of Intracranial Meningioma, Christian Mirian, Lasse Rehné Jensen, Tareq A Juratli, Andrea Daniela Maier, Sverre H Torp, Helen A Shih, Ramin A Morshed, Jacob S Young, Stephen T Magill, Luca Bertero, Walter Stummer, Dorothee Cäcilia Spille, Benjamin Brokinkel, Soichi Oya, Satoru Miyawaki, Nobuhito Saito, Martin Proescholdt, Yasuhiro Kuroi, Konstantinos Gousias, Matthias Simon, Jennifer Moliterno, Ricardo Prat-Acin, Stéphane Goutagny, Vikram C Prabhu, John T Tsiang, Johannes Wach, Erdem Güresir, Junkoh Yamamoto, Young Zoon Kim, Joo Ho Lee, Matthew Koshy, Karthikeyan Perumal, Mustafa K Baskaya, Donald M Cannon, Dennis C Shrieve, Chang-Ok Suh, Jong Hee Chang, Maria Kamenova, Sven Straumann, Jehuda Soleman, Ilker Y Eyüpoglu, Tony Catalan, Austin Lui, Philip V Theodosopoulos, Michael W Mcdermott, Fang Wang, Fuyou Guo, Pedro Góes, Manoel Antonio De Paiva Neto, Aria Jamshidi, Ricardo Komotar, Michael Ivan, Evan Luther, Luis Souhami, Marie-Christine Guiot, Tamás Csonka, Toshiki Endo, Olivia Claire Barrett, Randy Jensen, Tejpal Gupta, Akash J Patel, Tiemo J Klisch, Jun Won Kim, Francesco Maiuri, Valeria Barresi, María Dolores Tabernero, Simon Skyrman, Anders Broechner, Mathias Jacobsen Bach, Ian Law, David Scheie, Bjarne Winther Kristensen, Tina Nørgaard Munch, Torstein Meling, Kåre Fugleholm, Paul Blanche, Tiit Mathiesen

Faculty, Staff and Students Publications

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated.

METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage …

Longitudinal Predictors Of Health-Related Quality Of Life In Isolated Dystonia, Johanna Junker, James Hall, Brian D Berman, Marie Vidailhet, Emmanuel Roze, Tobias Bäumer, Irene A Malaty, Aparna Wagle Shukla, Joseph Jankovic, Stephen G Reich, Alberto J Espay, Kevin R Duque, Neepa Patel, Joel S Perlmutter, H A Jinnah, Valerie Brandt, Norbert Brüggemann

Faculty, Staff and Students Publications

OBJECTIVE: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia.

METHODS: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year.

RESULTS: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). …

Isolated Abducens Nerve Palsy: A Rare Manifestation Of Recurrent Extramedullary Myeloma, Neal Joshi, Joy Li, Ajit Karambelkar, Payton Boere

Jefferson Hospital Staff Papers and Presentations

Multiple myeloma is a plasma cell neoplasm, which may present as a solitary plasmacytoma and, uncommonly, as an extramedullary plasmacytoma. Intracranial plasmacytomas may manifest in central nervous system involvement as cranial nerve palsies. Cranial nerve six palsy is the most common in cases of malignancy. However, isolated abducens palsy presenting as multiple myeloma recurrence is very uncommon. Here, we detail two cases in which intracranial plasmacytoma lesions were present within the region of the Dorello canal, resulting in acute isolated unilateral diplopia from disease recurrence in the absence of systemic marrow involvement.