Neurology Commons^™

Endovascular Management Of A Ruptured Aneurysm On A Posterior Inferior Cerebellar Artery With Extradural C2-Origin: Case Report And Literature Review, Rasmus Holmboe Dahl, Gary Lloyd Horn, Zeyad Metwalli, Shankar Prakash Gopinath, Goetz Benndorf

Faculty, Staff and Students Publications

Extracranial vascular pathology uncommonly causes intracranial subarachnoid hemorrhage (SAH). Among possible lesions are aneurysms at the craniocervical junction arising from a posterior inferior cerebellar artery (PICA) with an extradural origin. We describe a case of a 55-year-old female presenting with a sudden and severe headache. A computed tomography scan revealed a SAH within the fourth ventricle and cervical spinal canal, and a ruptured saccular aneurysm on a PICA with extradural C2-origin. Despite difficult access anatomy, endovascular treatment was feasible and resulted in subtotal initial occlusion and preservation of distal PICA flow. Upon 3-month follow-up, the aneurysm was completely occluded with …

Neuroimaging Of Vermiform Giant Arachnoid Granulations In Children, Oswaldo A Guevara Tirado, Livja Mertiri, Stephen F Kralik, Nilesh K Desai, Thierry A G M Huisman, Maarten H Lequin, Huy Brandon D Tran

Faculty, Staff and Students Publications

Arachnoid granulations (AGs) are generally benign structures within the subarachnoid space that extend into the dural sinuses and calvarial bone. They can present in a variety of sizes but are termed 'giant' arachnoid granulations (GAGs) when they are larger than 1 cm in diameter or take up a significant portion of the dural sinus' lumen. Vermiform giant arachnoid granulations are a specific type of GAG that are known for their worm-like appearance. Specifically, these vermiform GAGs can be challenging to diagnose as they can mimic other pathologies like dural sinus thrombosis, sinus cavernomas, or brain tumors. In this case series, …

Protocol For Preclinical Evaluation Of Locoregionally Delivered Car T Cells In Patient-Derived Xenograft Models Of Brain Tumors, Benjamin Draper, Chantelle Bowers, Eleni Vassalou, Ailsa Greppi, John Anderson, Nabil Ahmed, Michael D Taylor, Laura K Donovan

Faculty, Staff and Students Publications

Here, we present a protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of primary, metastatic, and recurrent brain tumors. We provide instructions for isolating peripheral blood mononuclear cells (PBMCs), producing CAR T cells in conjunction with locoregional delivery, and preclinical trial design and analysis involving CAR T cells. Additionally, we describe comprehensive preclinical readouts and guidelines for critical endpoint sample collections. In line with clinical trial procedures, our protocol broadens available treatment modalities for direct clinical translation. For complete details on the use and execution of this protocol, please refer to Donovan et al …

Fate-Mapping And Functional Dissection Reveal Perilous Influence Of Type I Interferon Signaling In Mouse Brain Aging, Ethan R Roy, Sanming Li, Sepideh Saroukhani, Yanyu Wang, Wei Cao

Faculty, Staff and Student Publications

Background: Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.

Methods: To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- …

Small-Molecule Inhibition Of Kras Through Conformational Selection, Bharti Manwani, Nivetha Brathaban, Abiya Baqai, Yashee Munshi, Hilda W Ahnstedt, Mengqi Zhang, Kajsa Arkelius, Ted Llera, Edilberto Amorim, Fanny M Elahi, Neel S Singhal

Faculty, Staff and Student Publications

L1CAM-positive extracellular vesicles (L1EV) are an emerging biomarker that may better reflect ongoing neuronal damage than other blood-based biomarkers. The physiological roles and regulation of L1EVs and their small RNA cargoes following stroke is unknown. We sought to characterize L1EV small RNAs following stroke and assess L1EV RNA signatures for diagnosing stroke using weighted gene co-expression network analysis and random forest (RF) machine learning algorithms. Interestingly, small RNA sequencing of plasma L1EVs from patients with stroke and control patients (n = 28) identified micro(mi)RNAs known to be enriched in the brain. Weighted gene co-expression network analysis (WGCNA) revealed small RNA …

Meningioma Transcriptomic Landscape Demonstrates Novel Subtypes With Regional Associated Biology And Patient Outcome, H Nayanga Thirimanne, Damian Almiron-Bonnin, Nicholas Nuechterlein, Sonali Arora, Matt Jensen, Carolina A Parada, Chengxiang Qiu, Frank Szulzewsky, Collin W English, William C Chen, Philipp Sievers, Farshad Nassiri, Justin Z Wang, Tiemo J Klisch, Kenneth D Aldape, Akash J Patel, Patrick J Cimino, Gelareh Zadeh, Felix Sahm, David R Raleigh, Jay Shendure, Manuel Ferreira, Eric C Holland

Faculty, Staff and Students Publications

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest …

Hemojuvelin-Mediated Hepcidin Induction Requires Both Bone Morphogenetic Protein Type I Receptors Alk2 And Alk3, Deniz Y Dogan, Eugen I Urzica, Isabelle Hornung, Philipp Kastl, David Oguama, Franca M Fette, Lien H Nguyen, Frank Rosenbauer, Kai Zacharowski, Ursula Klingmüller, Elise Gradhand, Andreas Von Knethen, Rüdiger Popp, Ingrid Fleming, Lisa Schrader, Andrea U Steinbicker

Faculty, Staff and Student Publications

Hemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) …

Rigor And Reproducibility In Human Brain Organoid Research: Where We Are And Where We Need To Go, Soraya O Sandoval, Gerarda Cappuccio, Karina Kruth, Sivan Osenberg, Saleh M Khalil, Natasha M Méndez-Albelo, Krishnan Padmanabhan, Daifeng Wang, Mark J Niciu, Anita Bhattacharyya, Jason L Stein, André M M Sousa, Elisa A Waxman, Elizabeth D Buttermore, Dosh Whye, Carissa L Sirois, Cross-Iddrc Human Stem Cell Consortium, Aislinn Williams, Mirjana Maletic-Savatic, Xinyu Zhao

Faculty, Staff and Students Publications

Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.

Feasibility Of Achieving Nutritional Adequacy In Critically Ill Children With Critical Neurological Illnesses (Cnis)?-A Quaternary Hospital Experience, Marwa Mansour, Nicole Knebusch, Jennifer Daughtry, Thomas P Fogarty, Fong Wilson Lam, Renan A Orellana, Yi-Chen Lai, Jennifer Erklauer, Jorge A Coss-Bu

Faculty, Staff and Students Publications

The literature on the nutritional needs and outcomes of critically ill children is scarce, especially on those with critical neurological illnesses (CNIs). Current evidence shows a lower mortality in patients who achieve two-thirds of their nutritional needs during the first week of pediatric intensive care unit (PICU) admission. We hypothesized that achieving 60% of the recommended dietary intake during the first week of a PICU stay is not feasible in patients with CNI. We designed an observational retrospective cohort study where we included all index admissions to the PICU in our institution of children (1 month to 18 years) with …

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

Faculty, Staff and Student Publications

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

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

Cost-Effectiveness And Threshold Analysis Of Deep Brain Stimulation Vs Treatment-As-Usual For Treatment-Resistant Depression, Katherine E Kabotyanski, Ricardo A Najera, Garrett P Banks, Himanshu Sharma, Nicole R Provenza, Benjamin Y Hayden, Sanjay J Mathew, Sameer A Sheth

Faculty, Staff and Students Publications

Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare …

A Process To Reanalyze Clinical Dna Sequencing Data For Biomarker Matching In The Lung-Map Master Protocol, Joel W Neal, Katherine Minichiello, Ryan Brennick, Richard S P Huang, Matthew C Hiemenz, Cornel Amler, Jyoti Patel, Roy Herbst, Karen L Reckamp, Hossein Borghaei, Louise Highleyman, Mary W Redman, Lincoln W Pasquina, David E Kozono

Faculty, Staff and Student Publications

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) …

Methylthioadenosine Phosphorylase Genomic Loss In Advanced Gastrointestinal Cancers, Natalie Y L Ngoi, Tin-Yun Tang, Catia F Gaspar, Dean C Pavlick, Gregory M Buchold, Emma L Scholefield, Vamsi Parimi, Richard S P Huang, Tyler Janovitz, Natalie Danziger, Mia A Levy, Shubham Pant, Anaemy Danner De Armas, David Kumpula, Jeffrey S Ross, Milind Javle, Jordi Rodon Ahnert

Faculty, Staff and Student Publications

BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker.

MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI …

Polygenic Liability For Anxiety In Association With Comorbid Anxiety In Multiple Sclerosis, Kaarina Kowalec, Arvid Harder, Casandra Dolovich, Kathryn C Fitzgerald, Amber Salter, Yi Lu, Charles N Bernstein, James M Bolton, Gary Cutter, John D Fisk, Joel Gelernter, Lesley A Graff, Sara Hägg, Carol A Hitchon, Daniel F Levey, Fred D Lublin, Kyla A Mckay, Scott Patten, Amit Patki, Murray B Stein, Hemant K Tiwari, Jerry S Wolinsky, Ruth A Marrie

Faculty, Staff and Student Publications

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS.

METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed …

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

Faculty, Staff and Student Publications

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

STUDY DESIGN: Retrospective.

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

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

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

A Novel Missense Variant Located Within The Zinc Finger Domain Of The Gli3 Gene Was Identified In A Vietnamese Pedigree With Index Finger Polydactyly, Thy Ngoc Nguyen, Giang Son Tran, Hai Duc Hoang, Long Giang Nguyen

Faculty, Staff and Student Publications

BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly.

METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.

RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. …

Incidence And Clinical Outcomes Of Perforations During Mechanical Thrombectomy For Medium Vessel Occlusion In Acute Ischemic Stroke: A Retrospective, Multicenter, And Multinational Study, Adam A Dmytriw, Basel Musmar, Hamza Salim, Sherief Ghozy, James E Siegler, Hassan Kobeissi, Hamza Shaikh, Jane Khalife, Mohamad Abdalkader, Piers Klein, Thanh N Nguyen, Jeremy J Heit, Robert W Regenhardt, Nicole M Cancelliere, Joshua D Bernstock, Kareem El Naamani, Abdelaziz Amllay, Lukas Meyer, Anne Dusart, Flavio Bellante, Géraud Forestier, Aymeric Rouchaud, Suzana Saleme, Charbel Mounayer, Jens Fiehler, Anna Luisa Kühn, Ajit S Puri, Christian Dyzmann, Peter T Kan, Marco Colasurdo, Gaultier Marnat, Jérôme Berge, Xavier Barreau, Igor Sibon, Simona Nedelcu, Nils Henninger, Thomas R Marotta, Christopher J Stapleton, James D Rabinov, Takahiro Ota, Shogo Dofuku, Leonard Ll Yeo, Benjamin Yq Tan, Anil Gopinathan, Juan Carlos Martinez-Gutierrez, Sergio Salazar-Marioni, Sunil Sheth, Leonardo Renieri, Carolina Capirossi, Ashkan Mowla, Lina Chervak, Achala Vagal, Nimer Adeeb, Hugo H Cuellar-Saenz, Stavropoula I Tjoumakaris, Pascal Jabbour, Priyank Khandelwal, Arundhati Biswas, Frédéric Clarençon, Mahmoud Elhorany, Kevin Premat, Iacopo Valente, Alessandro Pedicelli, João Pedro Filipe, Ricardo Varela, Miguel Quintero-Consuegra, Nestor R Gonzalez, Markus A Möhlenbruch, Jessica Jesser, Vincent Costalat, Adrien Ter Schiphorst, Vivek Yedavalli, Pablo Harker, Yasmin Aziz, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Ramanathan Kadirvel, Monika Killer-Oberpfalzer, Christoph J Griessenauer, Ajith J Thomas, Cheng-Yang Hsieh, David S Liebeskind, Răzvan Alexandru Radu, Andrea M Alexandre, Illario Tancredi, Tobias D Faizy, Robert Fahed, Charlotte Weyland, Boris Lubicz, Aman B Patel, Vitor Mendes Pereira, Adrien Guenego, Mad-Mt Consortium

Faculty, Staff and Student Publications

Background: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO.

Methods: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed. …

Endovascular Treatment Of Acute Ischemic Stroke Patients With Tandem Lesions: Antegrade Versus Retrograde Approach, Milagros Galecio-Castillo, Michael Abraham, Mudassir Farooqui, Ameer E Hassan, Afshin A Divani, Mouhammad A Jumaa, Marc Ribo, Nils Petersen, Johanna Fifi, Waldo R Guerrero, Amer M Malik, James E Siegler, Thanh N Nguyen, Sunil A Sheth, Albert J Yoo, Guillermo Linares, Nazli Janjua, Darko Quispe-Orozco, Abid Qureshi, Wondwossen G Tekle, Asad Ikram, Syed F Zaidi, Cynthia B Zevallos, Belen Taborda, Alex Devarajan, Linda Zhang, Mohamad Abdalkader, Sergio Salazar-Marioni, Jazba Soomro, Weston Gordon, Aaron Rodriguez-Calienes, Juan Vivanco-Suarez, Katrina Woolfolk, Maxim Mokin, Dileep R Yavagal, Santiago Ortega-Gutierrez

Faculty, Staff and Student Publications

Objective: The optimal technique for treating tandem lesions (TLs) with endovascular therapy is debatable. The authors evaluated the functional, safety, and procedural outcomes of different approaches in a multicenter study.

Methods: Anterior circulation TL patients treated from January 2015 to December 2020 were divided on the basis of antegrade versus retrograde approach and included. The evaluated outcomes were favorable modified Rankin Scale (mRS) score (mRS score 0-2) at 3 months, ordinal shift in mRS score, successful recanalization, excellent recanalization, first-pass effect (FPE), time from groin puncture to successful recanalization, symptomatic intracranial hemorrhage (sICH), and 90-day mortality.

Results: Among 691 patients …

Adaptive, Behavioral, And Emotional Outcomes Following Postoperative Pediatric Cerebellar Mutism Syndrome In Survivors Treated For Medulloblastoma, Kimberly P Raghubar, Andrew M Heitzer, Fatema Malbari, Jason Gill, Roy V Sillitoe, Livia Merrill, Johanna Escalante, M Fatih Okcu, Guillermo Aldave, Avner Meoded, Stephen Kralik, Kimberly Davis, Marina Ma, Emily A H Warren, Mark D Mccurdy, Howard L Weiner, William Whitehead, Michael E Scheurer, Lisa Rodriguez, Amy Daigle, Murali Chintagumpala, Lisa S Kahalley

Faculty, Staff and Students Publications

OBJECTIVE: Patients who experience postoperative pediatric cerebellar mutism syndrome (CMS) during treatment for medulloblastoma have long-term deficits in neurocognitive functioning; however, the consequences on functional or adaptive outcomes are unknown. The purpose of the present study was to compare adaptive, behavioral, and emotional functioning between survivors with and those without a history of CMS.

METHODS: The authors examined outcomes in 45 survivors (15 with CMS and 30 without CMS). Comprehensive neuropsychological evaluations, which included parent-report measures of adaptive, behavioral, and emotional functioning, were completed at a median of 2.90 years following craniospinal irradiation.

RESULTS: Adaptive functioning was significantly worse in …

Purkinje Cell Dysfunction Causes Disrupted Sleep In Ataxic Mice, Luis E Salazar Leon, Amanda M Brown, Heet Kaku, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, …

Atp1a3 Disease Spectrum Includes Paroxysmal Weakness And Encephalopathy Not Triggered By Fever, Chetan Immanneni, Daniel Calame, Song Jiao, Lisa T Emrick, Miguel Holmgren, Sho T Yano

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: Heterozygous pathogenic variants in ATP1A3, which encodes the catalytic alpha subunit of neuronal Na+/K+-ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3-related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function.

METHODS: We …

Presynaptic Nanoscale Components Of Retrograde Synaptic Signaling, Benjámin Barti, Barna Dudok, Kata Kenesei, Miklós Zöldi, Vivien Miczán, Gyula Y Balla, Diana Zala, Mariana Tasso, Claudia Sagheddu, Máté Kisfali, Blanka Tóth, Marco Ledri, E Sylvester Vizi, Miriam Melis, László Barna, Zsolt Lenkei, Iván Soltész, István Katona

Faculty, Staff and Students Publications

While our understanding of the nanoscale architecture of anterograde synaptic transmission is rapidly expanding, the qualitative and quantitative molecular principles underlying distinct mechanisms of retrograde synaptic communication remain elusive. We show that a particular form of tonic cannabinoid signaling is essential for setting target cell–dependent synaptic variability. It does not require the activity of the two major endocannabinoid-producing enzymes. Instead, by developing a workflow for physiological, anatomical, and molecular measurements at the same unitary synapse, we demonstrate that the nanoscale stoichiometric ratio of type 1 cannabinoid receptors (CB1Rs) to the release machinery is sufficient to predict synapse-specific release probability. Accordingly, …

Neurorehabilitation With Vagus Nerve Stimulation: A Systematic Review, Radha Korupolu, Alyssa Miller, Andrew Park, Nuray Yozbatiran

Faculty, Staff and Student Publications

OBJECTIVE: To systematically review vagus nerve stimulation (VNS) studies to present data on the safety and efficacy on motor recovery following stroke, traumatic brain injury (TBI), and spinal cord injury (SCI).

METHODS: Data sources: PubMed, EMBASE, SCOPUS, and Cochrane.

STUDY SELECTION: Clinical trials of VNS in animal models and humans with TBI and SCI were included to evaluate the effects of pairing VNS with rehabilitation therapy on motor recovery.

DATA EXTRACTION: Two reviewers independently assessed articles according to the evaluation criteria and extracted relevant data electronically.

DATA SYNTHESIS: Twenty-nine studies were included; 11 were animal models of stroke, TBI, and …

Noncontrast Ct Selected Thrombectomy Vs Medical Management For Late-Window Anterior Large Vessel Occlusion, Thanh N Nguyen, Raul G Nogueira, Muhammad M Qureshi, Simon Nagel, Jean Raymond, Mohamad Abdalkader, Jelle Demeestere, João Pedro Marto, Sunil A Sheth, Volker Puetz, Anne Dusart, Patrik Michel, Marc Ribo, Osama O Zaidat, James E Siegler, Diogo C Haussen, Daniel Strbian, Hilde Henon, Mahmoud H Mohammaden, Markus A Möhlenbruch, Marta Olive-Gadea, Ajit S Puri, Simon Winzer, Johannes Kaesmacher, Piers Klein, Liisa Tomppo, Francois Caparros, João Nuno Ramos, Mouhammad A Jumaa, Syed F Zaidi, Nicolas Martinez-Majander, Stefania Nannoni, Lieselotte Vandewalle, Flavio Bellante, Mudassir Farooqui, Sergio Salazar-Marioni, Pekka Virtanen, Daniel P O Kaiser, Anke Wouters, Rita Ventura, Jessica Jesser, Adnan Mujanovic, Liqi Shu, Alicia C Castonguay, Zain Mansoor, Zhongming Qiu, Hesham E Masoud, Manuel Requena, Erno Peltola, Wei Hu, Eugene Lin, Kanta Tanaka, Charlotte Cordonnier, Daniel Roy, Shadi Yaghi, Davide Strambo, Hiroshi Yamagami, Urs Fischer, Tudor G Jovin, Robin Lemmens, Peter A Ringleb, Santiago Ortega-Gutierrez

Faculty, Staff and Student Publications

Background and objectives: There is uncertainty whether patients with large vessel occlusion (LVO) presenting in the late 6-hour to 24-hour time window can be selected for endovascular therapy (EVT) by noncontrast CT (NCCT) and CT angiography (CTA) for LVO detection. We evaluated the clinical outcomes of patients selected for EVT by NCCT compared with those medically managed in the extended time window.

Methods: This multinational cohort study was conducted at 66 sites across 10 countries. Consecutive patients with proximal anterior LVO stroke selected for EVT by NCCT or medically managed and presenting within 6-24 hours of time last seen well …

Glioblastoma Disrupts Cortical Network Activity At Multiple Spatial And Temporal Scales, Jochen Meyer, Kwanha Yu, Estefania Luna-Figueroa, Benjamin Deneen, Jeffrey Noebels

Faculty, Staff and Students Publications

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and …

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

Faculty, Staff and Student Publications

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

Incidence And Characteristics Of Cerebellar Atrophy/Volume Loss In Children With Confirmed Diagnosis Of Tuberous Sclerosis Complex, Livja Mertiri, Eugen Boltshauser, Stephen F Kralik, Nilesh K Desai, Maarten H Lequin, Thierry A G M Huisman

Faculty, Staff and Students Publications

Objectives: The goal of our study was to determine the incidence of cerebellar atrophy, assess the imaging findings in the posterior fossa and determine the incidence of hippocampal sclerosis in a cohort of pediatric patients with confirmed tuberous sclerosis complex (TSC).

Material and methods: MRI studies of 98 TSC pediatric patients (mean age 7.67 years) were evaluated for cerebellar atrophy, cerebral/cerebellar tubers, white matter lesions, subependymal nodules, subependymal giant cell astrocytomas, ventriculomegaly, and hippocampal sclerosis. Clinical charts were revisited for clinical symptoms suggesting cerebellar involvement, for seizures and treatment for seizures, behavioral disorders and autism.

Results: Cerebral tubers were present …

Prediction Of Disease-Free Survival For Precision Medicine Using Cooperative Learning On Multi-Omic Data, Georg Hahn, Dmitry Prokopenko, Julian Hecker, Sharon M Lutz, Kristina Mullin, Leinal Sejour, Winston Hide, Ioannis Vlachos, Stacia Desantis, Rudolph E Tanzi, Christoph Lange

Faculty, Staff and Student Publications

In precision medicine, both predicting the disease susceptibility of an individual and forecasting its disease-free survival are areas of key research. Besides the classical epidemiological predictor variables, data from multiple (omic) platforms are increasingly available. To integrate this wealth of information, we propose new methodology to combine both cooperative learning, a recent approach to leverage the predictive power of several datasets, and polygenic hazard score models. Polygenic hazard score models provide a practitioner with a more differentiated view of the predicted disease-free survival than the one given by merely a point estimate, for instance computed with a polygenic risk score. …

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

Faculty, Staff and Student Publications

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

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

Astrocytes Remember Inflammation, Michael R Williamson, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes respond to all forms of central nervous system maladies. In a recent issue of Nature, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.