Neurology Commons^™

Multiomic And Clinical Analysis Of Multiply Recurrent Meningiomas Reveals Risk Factors, Underlying Biology, And Insights Into Evolution, Sangami Pugazenthi, Bhuvic Patel, Collin W English, William A Leidig, Kyle P Mcgeehan, Colin R Mccornack, Shinghei Mok, Markus Anzaldua-Campos, Shervin Hosseingholi Nouri, Kaleigh Roberts, Ajay Chatrath, A Khan, Ron Gadot, Hiroko Yano, Tiemo J Klisch, Akdes S Harmanci, Akash J Patel, Albert H Kim

Faculty, Staff and Students Publications

An important subset of meningiomas behaves aggressively and is characterized by multiple recurrences. We identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and evaluate the evolution of these meningiomas in patient-matched samples. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P = 0.012), subtotal resection (P = 0.001), higher number of meningiomas on presentation (P = 0.017), and histopathological sheeting (P = 0.002). Multiomic analysis of primary meningiomas revealed that MRMs have greater copy number losses (P = 0.0313) and increased DNA methylation (P = 0.0155). In …

Characterizing The Progression From Mild Cognitive Impairment To Dementia: A Network Analysis Of Longitudinal Clinical Visits, Muskan Garg, Sara Hejazi, Sunyang Fu, Maria Vassilaki, Ronald C Petersen, Jennifer St Sauver, Sunghwan Sohn

Faculty, Staff and Student Publications

Background: With the recent surge in the utilization of electronic health records for cognitive decline, the research community has turned its attention to conducting fine-grained analyses of dementia onset using advanced techniques. Previous works have mostly focused on machine learning-based prediction of dementia, lacking the analysis of dementia progression and its associations with risk factors over time. The black box nature of machine learning models has also raised concerns regarding their uncertainty and safety in decision making, particularly in sensitive domains like healthcare.

Objective: We aimed to characterize the progression of health conditions, such as chronic diseases and neuropsychiatric symptoms, …

Clonal Hematopoiesis Of Indeterminate Potential Is Associated With Reduced Risk Of Cognitive Impairment In Patients With Chronic Kidney Disease, Cissy Xiao, Manjula Kurella Tamura, Yang Pan, Varun Rao, Celestin Missikpode, Caitlyn Vlasschaert, Tetsushi Nakao, Xiao Sun, Changwei Li, Zhijie Huang, Amanda Anderson, Md Mesbah Uddin, Do-Kyun Kim, Jonathan Taliercio, Rajat Deo, Zeenat Bhat, Dawei Xie, Panduranga Rao, Jing Chen, James P Lash, Jiang He, Pradeep Natarajan, James E Hixson, Kristine Yaffe, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Student Publications

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown.

Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean.

Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted …

Long-Term Dementia Risk In Parkinson Disease, Julia Gallagher, Caroline Gochanour, Chelsea Caspell-Garcia, Roseanne D Dobkin, Dag Aarsland, Roy N Alcalay, Matthew J Barrett, Lana Chahine, Alice S Chen-Plotkin, Christopher S Coffey, Nabila Dahodwala, Jamie L Eberling, Alberto J Espay, James B Leverenz, Irene Litvan, Eugenia Mamikonyan, James Morley, Irene H Richard, Liana Rosenthal, Andrew D Siderowf, Tatyana Simuni, Michele K York, Allison W Willis, Sharon X Xie, Daniel Weintraub, Parkinson's Progression Markers Initiative

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.

METHODS: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated …

Predictors Of Outcome And Symptomatic Intracranial Hemorrhage In Acute Basilar Artery Occlusions: Analysis Of The Pc-Search Thrombectomy Registry., Adam T Mierzwa, Ashley Nelson, Sami Al Kasab, Santiago Ortega Gutierrez, Juan Vivanco-Suarez, Mudassir Farooqui, Ashutosh P Jadhav, Shashvat Desai, Gabor Toth, Anas Alrohimi, Thanh N Nguyen, Piers Klein, Mohamad Abdalkader, Hisham Salahuddin, Aditya Pandey, Zachary Wilseck, Sravanthi Koduri, Niraj Vora, Nameer Aladamat, Khaled Gharaibeh, Ehad Afreen, Hisham Al-Hajala, Julie Shawver, Syed Zaidi, Mouhammad Jumaa

Neuroscience Articles

INTRODUCTION: Recent randomized controlled trials demonstrated superiority of mechanical thrombectomy compared to medical therapy in acute basilar artery occlusions, however, little data is available to guide clinicians in functional prognosis and risk stratification.

PATIENTS AND METHODS: Data from the retrospectively established PC-SEARCH Thrombectomy registry, which included patients with basilar artery occlusion from eight sites from January 2015 to December 2021, was interrogated. Outcomes were dichotomized into 90-day favorable (mRS ⩽ 3) and unfavorable (mRS > 3). Multivariate logistic regression analysis was performed with respect to the outcome groups and were adjusted for potential confounding baseline characteristics.

RESULTS: Four-hundred-forty-four patients were included …

Treatment Response To Onabotulinumtoxina In Cervical Dystonia Patients With Anterocollis And Retrocollis, Khashayar Dashtipour, Marjan Sadeghi, David Charles, Shyamal Mehta, Hubert H Fernandez, Marc Schwartz, Joseph Jankovic

Faculty, Staff and Students Publications

Anterocollis (AC) and retrocollis (RC) are less common cervical dystonia (CD) subtypes that are often under-represented in CD clinical trials. Herein we describe real-world demographics, disease characteristics, and treatment response to onabotulinumtoxinA (onabotA) in AC or RC patients from an observational, multicenter, prospective registry, CD PROBE. After three onabotA treatments, outcomes (CDIP-58, PGIC, CGIC, CD severity, TWSTRS) in patients with predominant AC or RC were compared to torticollis (TC) and all CD subtypes combined. The mean dosages at each treatment ranged from 153.5 to 195.4 U (AC) to 184.0-213.4 U (RC). After treatment, AC and RC patients reported improvements in …

Milvexian Vs Apixaban For Stroke Prevention In Atrial Fibrillation: The Librexia Atrial Fibrillation Trial Rationale And Design, Sneha S Jain, Kenneth W Mahaffey, Karen S Pieper, Wataru Shimizu, Tatjana Potpara, Christian T Ruff, Hooman Kamel, Basil S Lewis, Jan H Cornel, Peter R. Kowey, Jay Horrow, John Strony, Alexei N Plotnikov, Danshi Li, Stephen Weng, Julia Donahue, C Michael Gibson, P Gabriel Steg, Roxana Mehran, Jeffrey I Weitz, S Claiborne Johnston, Graeme J Hankey, Robert A Harrington, Carolyn S P Lam

Department of Medicine Faculty Papers

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk.

METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to …

Evaluating The Impact Of Laboratory-Based Eligibility Criteria By Race/Ethnicity In First-Line Clinical Trials Of Dlbcl, Arushi Khurana, Raphael Mwangi, Loretta J Nastoupil, Patrick M Reagan, Umar Farooq, Jason T Romancik, Timothy J Mcdonnell, Shaun M Riska, Lzidore S Lossos, Brad S Kahl, Peter Martin, Thomas E Witzig, James R Cerhan, Christopher R Flowers, Grzegorz S Nowakowski, Matthew J Maurer

Faculty, Staff and Student Publications

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, …

Clinical Features And Disease Progression In Older Individuals With Rett Syndrome, Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Bernhard Suter, Cary Fu, Robin C Ryther, Steven A Skinner, David N Lieberman, Timothy Feyma, Arthur Beisang, Peter Heydemann, Sarika U Peters, Amitha Ananth, Alan K Percy

Faculty, Staff and Students Publications

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different …

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

Neurology Faculty Publications

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

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

Faculty, Staff and Student Publications

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

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

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

RESULTS: The …

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

Faculty, Staff and Student Publications

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

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

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

Faculty, Staff and Students Publications

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

Clear Thrombectomy Score: An Index To Estimate The Probability Of Good Functional Outcome With Or Without Endovascular Treatment In The Late Window For Anterior Circulation Occlusion, James E Siegler, Manisha Koneru, Muhammad M Qureshi, Mohamed Doheim, Raul G Nogueira, Nicolas Martinez-Majander, Simon Nagel, Mary Penckofer, Jelle Demeestere, Volker Puetz, Marc Ribo, Mohamad Abdalkader, João Pedro Marto, Alhamza R Al-Bayati, Hiroshi Yamagami, Diogo C Haussen, Marta Olive-Gadea, Simon Winzer, Mahmoud H Mohammaden, Robin Lemmens, Kanta Tanaka, Pekka Virtanen, Anne Dusart, Flavio Bellante, Daniel P O Kaiser, Francois Caparros, Hilde Henon, João Nuno Ramos, Santiago Ortega-Gutierrez, Sunil A Sheth, Stefania Nannoni, Lieselotte Vandewalle, Johannes Kaesmacher, Sergio Salazar-Marioni, Liisa Tomppo, Rita Ventura, Syed F Zaidi, Mouhammad Jumaa, Alicia C Castonguay, Milagros Galecio-Castillo, Ajit S Puri, Adnan Mujanovic, Piers Klein, Liqi Shu, Behzad Farzin, Hannah Moomey, Hesham E Masoud, Jessica Jesser, Markus A Möhlenbruch, Peter A Ringleb, Daniel Strbian, Osama O Zaidat, Shadi Yaghi, Davide Strambo, Patrik Michel, Daniel Roy, Shinichi Yoshimura, Kazutaka Uchida, Jean Raymond, Thanh N Nguyen

Faculty, Staff and Student Publications

Background: With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6-24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management.

Methods and results: A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014-2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9-point score for predicting good functional outcome (modified Rankin Scale score 0-2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity …

Home Blood Pressure Telemonitoring And Nurse Case Management In Black And Hispanic Patients With Stroke: A Randomized Clinical Trial, Gbenga Ogedegbe, Jeanne A Teresi, Stephen K Williams, Adebayo Ogunlade, Chigozirim Izeogu, Joseph P Eimicke, Jian Kong, Stephanie A Silver, Olajide Williams, Helen Valsamis, Susan Law, Steven R Levine, Salina P Waddy, Tanya M Spruill

Faculty, Staff and Student Publications

Importance: Black and Hispanic patients have high rates of recurrent stroke and uncontrolled hypertension in the US. The effectiveness of home blood pressure telemonitoring (HBPTM) and telephonic nurse case management (NCM) among low-income Black and Hispanic patients with stroke is unknown.

Objective: To determine whether NCM plus HBPTM results in greater systolic blood pressure (SBP) reduction at 12 months and lower rate of stroke recurrence at 24 months than HBPTM alone among Black and Hispanic stroke survivors with uncontrolled hypertension.

Design, setting, and participants: Practice-based, multicenter, randomized clinical trial in 8 stroke centers and ambulatory practices in New York City. …

Reliable Detection Of Generalized Convulsive Seizures Using An Off-The-Shelf Digital Watch: A Multisite Phase 2 Study, Yash Shashank Vakilna, Xiaojin Li, Jaison S Hampson, Yan Huang, John C Mosher, Yuri Dabaghian, Xi Luo, Blanca Talavera, Sandipan Pati, Masel Todd, Ryan Hays, Charles Akos Szabo, Guo-Qiang Zhang, Samden D Lhatoo

Faculty, Staff and Student Publications

Objective: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy.

Methods: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of …

Endovascular Versus Medical Therapy In Posterior Cerebral Artery Stroke: Role Of Baseline Nihss Score And Occlusion Site, Davide Strambo, Patrik Michel, Thanh N Nguyen, Mohamad Abdalkader, Muhammad M Qureshi, Daniel Strbian, Christian Herweh, Markus A Möhlenbruch, Silja Räty, Marta Olivé-Gadea, Marc Ribo, Marios Psychogios, Urs Fischer, Anh Nguyen, Joji B Kuramatsu, David Haupenthal, Martin Köhrmann, Cornelius Deuschl, Jordi Kühne Escolà, Jelle Demeestere, Robin Lemmens, Lieselotte Vandewalle, Shadi Yaghi, Liqi Shu, Volker Puetz, Daniel P O Kaiser, Johannes Kaesmacher, Adnan Mujanovic, Dominique Cornelius Marterstock, Tobias Engelhorn, Manuel Requena, Hormuzdiyar H Dasenbrock, Piers Klein, Diogo C Haussen, Mahmoud H Mohammaden, Hend Abdelhamid, Lorena Souza Viana, Bruno Cunha, Isabel Fragata, Michele Romoli, Francesco Diana, Wei Hu, Chao Zhang, Pekka Virtanen, Riikka Lauha, Jessica Jesser, Judith Clark, Stavros Matsoukas, Johanna T Fifi, Sunil A Sheth, Sergio Salazar-Marioni, João Pedro Marto, João Nuno Ramos, Milena Miszczuk, Christoph Riegler, Sven Poli, Khouloud Poli, Ashutosh P Jadhav, Shashvat M Desai, Volker Maus, Maximilian Kaeder, Adnan H Siddiqui, Andre Monteiro, Hesham E Masoud, Neil Suryadareva, Maxim Mokin, Shail Thanki, Kemal Alpay, Pauli Ylikotila, James E Siegler, Italo Linfante, Guilherme Dabus, Negar Asdaghi, Vasu Saini, Christian H Nolte, Eberhard Siebert, Bettina L Serrallach, Charlotte S Weyland, Uta Hanning, Lukas Meyer, Anne Berberich, Peter A Ringleb, Raul G Nogueira, Simon Nagel

Faculty, Staff and Student Publications

Background: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site.

Methods: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site …

Thoracic Canal Morphology On Preoperative Magnetic Resonance Imaging In Spinal Cord Stimulation Patients, Kevin Hines, Christian Tran, Anusha Koka, Nikolaos Mouchtouris, Karim Hafazalla, Ellina Hattar, Chengyuan Wu, Ashwini Sharan

Department of Neurosurgery Faculty Papers

INTRODUCTION: In high-frequency spinal cord stimulation anatomic placement targeting of the T9-10 disc space is based on "empiric" results that are best replicated with coverage broadly from T8 to T10. This study contains the largest cohort of patients evaluating low thoracic morphology and seeks to address the lack of MRI morphological analysis in literature.

METHODS: This study was a retrospective review of a database of 101 consecutive patients undergoing permanent implant of thoracic SCS for chronic pain. Measurements were carried out on preoperative MRI imaging. Anteroposterior (AP) and lateral dimensions of the spinal cord as well as dural sac were …

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 …

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 …

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 …

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 …

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 …

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 …

Montelukast As A Repurposable Additive Drug For Standard-Efficacy Multiple Sclerosis Treatment: Emulating Clinical Trials With Retrospective Administrative Health Claims Data, Astrid M Manuel, Assaf Gottlieb, Leorah Freeman, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach.

OBJECTIVE: The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS).

METHODS: In this retrospective case-control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18-65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum's Clinformatics

RESULTS: pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared …

Treatments Perceived To Be Helpful For Neuropathic Pain After Traumatic Spinal Cord Injury: A Multicenter Cross-Sectional Survey Study, Thomas N Bryce, Chung-Ying Tsai, Andrew D Delgado, Sara J Mulroy, Abigail Welch, Diana D Cardenas, Heather B Taylor, Elizabeth R Felix

Faculty, Staff and Student Publications

DESIGN: Cross-sectional survey.

OBJECTIVE: To evaluate the perceived helpfulness of pharmacological and non-pharmacological interventions and their combinations for neuropathic pain (NeuP) and subcategories of NeuP after spinal cord injury (SCI).

SETTING: Six Spinal Cord Injury Model System Centers.

METHODS: Three hundred ninety one individuals at least one year post traumatic SCI were enrolled. A telephone survey was conducted to determine the pharmacologic and non-pharmacologic treatments used in the last 12 months for each participant's three worst pains, whether these treatments were "helpful", and if currently used, each treatments' effectiveness.

RESULTS: Two hundred twenty participants (56%) reported 354 distinct NeuPs. Pharmacological …

Examining The Effect Of Genes On Depression As Mediated By Smoking And Modified By Sex, Kirsten Voorhies, Julian Hecker, Sanghun Lee, Georg Hahn, Dmitry Prokopenko, Merry-Lynn Mcdonald, Alexander C Wu, Ann Wu, John E Hokanson, Michael H Cho, Christoph Lange, Karin F Hoth, Sharon M Lutz

Faculty, Staff and Student Publications

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted …

The Dementia Care Study (D-Care): Recruitment Strategies And Demographic Characteristics Of Participants In A Pragmatic Randomized Trial Of Dementia Care, Mia Yang, Rafael Samper-Ternent, Elena Volpi, Aval-Na'ree Green, Maya Lichtenstein, Katy Araujo, Pamela Borek, Peter Charpentier, James Dziura, Thomas M Gill, Rebecca Galloway, Erich J Greene, Kristin Lenoir, Peter Peduzzi, Can Meng, Jordan Reese, Amy Shelton, Eleni A Skokos, Jenny Summapund, Erin Unger, David B Reuben, Jeff D Williamson, Alan B Stevens

Faculty, Staff and Student Publications

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare.

METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients.

RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), …