Neurosciences Commons^™

A Model To Address Healthcare Gaps And Poor Research Participation In Hispanic Patients With Parkinson’S Disease, M Felice Ghilardi, Alessandro Di Rocco, Jennifer Fearday, Donna Sperlakis, Maria Lima, Nora Vanegas-Arroyave, Elisa Tatti, Marcelo Arroyave, Evelyn Stevens, Denise Hernandez, Paulina Latapi-Gonzalez, Meri-Margaret Deoudes, Christiana Evers

Faculty, Staff and Students Publications

Parkinson's disease (PD), a progressive neurodegenerative disorder, manifests with motor and non-motor symptoms. Despite similar incidence, in the US, disease management of Hispanic patients with PD is poorer than that of White non-Hispanics, and their participation in clinical trials does not reflect expected values (well below 5% vs. expected values around 20%). Together with other evidence, these observations are expressions of poor healthcare in Hispanic patients with PD, suggesting underutilization of proper healthcare, social and economic disadvantage, and other factors. The scant participation of Hispanic patients in clinical trials further exacerbates care inadequacy. In this paper, after reviewing evidence of …

Validation Of The Polish Version Of The Movement Disorder Society Non-Motor Rating Scale (Mds-Nms), Joanna Siuda, Mateusz Toś, Tomasz Chmiela, Andrzej Bogucki, Barbara Borodziuk, Sławomir Budrewicz, Marek Dąbrowski, Marceli Gacan, Agata Gajos, Justyna Gawryluk, Piotr Janik, Justyna Kaczyńska, Ewa Koziorowska-Gawron, Jakub Malkiewicz, Ewa Papuć, Paulina Kaczmarska, Monika Rudzińska-Bar, Jarosław Sławek, Magdalena Wójcik-Pędziwiatr, Luowen Yu, Sheng Luo, Christopher Goetz, Glenn Stebbins, Pablo Martinez-Martin, Tiago Mestre, Alvaro Sanchez-Ferro, Monika Kurtis, Michelle Hyczy De Siqueira Tosin, Roberta Balestrino, Chi-Ying Roy Lin, Carmen Gasca-Salas

Faculty, Staff and Students Publications

Aim of the study: We aimed to translate and validate the Polish version of the MDS-NMS and compare it with the original English version.

Clinical rationale for the study: Non-motor symptoms (NMS) affect a significant portion of the Parkinson's disease (PD) patient population and may negatively impact their quality of life. Non-motor symptoms may contribute to an increased sense of illness among patients and to a greater burden upon their caregivers. It is therefore advisable to develop a Polish validation of a reference scale for diagnosing and assessing the severity of NMS.

Material and methods: The MDS-NMS was translated into …

Inferred Developmental Origins Of Brain Tumors From Single-Cell Rna-Sequencing Data, Su Wang, Rachel Naomi Curry, Malcolm F Mcdonald, Hyun Yong Koh, Anders W Erickson, Claudia L Kleinman, Michael D Taylor, Ganesh Rao, Benjamin Deneen, Arif O Harmanci, Akdes Serin Harmanci

Faculty, Staff and Students Publications

Background: The reactivation of neurodevelopmental programs in cancer highlights parallel biological processes that occur in both normal development and brain tumors. Achieving a deeper understanding of how dysregulated developmental factors play a role in the progression of brain tumors is therefore crucial for identifying potential targets for therapeutic interventions. Single-cell RNA-sequencing (scRNA-Seq) provides an opportunity to understand how developmental programs are dysregulated and reinitiated in brain tumors at single-cell resolution. The aim of this study is to identify the developmental origins of brain tumors using scRNA-Seq data.

Methods: Here, we introduce COORS (Cell Of ORigin like CellS), a computational tool …

Glutamatergic Lateral Habenula Neurons Modulate Consolidation Of Associative Memories, Snigdha Srivastava, I-Ching Wang, Mikhail Y Kochukov, Jessica L Swanson, Mauro Costa-Mattioli, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

INTRODUCTION: Despite the rise in psychiatric disorders worldwide, the underlying brain circuits responsible for these devastating conditions remain elusive. The lateral habenula (LHb) has emerged as a key brain structure in depression studies due to its hyperactive state in both patients and animal models. While this aligns with known roles in driving aversive states and regulating serotonin release, it is still unclear how acute and transient activity changes in the LHb can influence higher order cognitive processes such as learning, memory, and behavioral adaptation. Given the importance of these processes to psychiatric conditions, understanding how LHb activity impacts cognitive function …

Resort Enhances Reference-Based Cell Type Deconvolution For Spatial Transcriptomics Through Regional Information Integration, Linhua Wang, Ling Wu, Guantong Qi, Chaozhong Liu, Wanli Wang, Xiang H-F Zhang, Zhandong Liu

Duncan NRI Faculty and Staff Publications

Motivation: Spatial transcriptomics (ST) captures positional gene expression within tissues but lacks single-cell resolution. Reference-based cell type deconvolution methods were developed to understand cell type distributions for ST. However, batch/platform discrepancies between references and ST impact their accuracy.

Results: We present Region-based Cell Sorting (ReSort), which utilizes ST's region-level data to lessen reliance on reference data and alleviate these technical issues. In simulation studies, ReSort enhances reference-based deconvolution methods. Applying ReSort to a mouse breast cancer model highlights macrophages M0 and M2 enrichment in the epithelial clone, revealing insights into epithelial-mesenchymal transition and immune infiltration.

Availability and implementation: Source codes …

Recurrent Carotid Paragangliomas In A Syndromic Patient With A Heterozygous Missense Variant In Dna Methyltransferase 3 Alpha, Ryan J German, Blake Vuocolo, Liesbeth Vossaert, Lisa Saba, Robin Fletcher, Matthew L Tedder, Bekim Sadikovic, Jennifer Kerkhof, Michael Wangler, Carlos A Bacino

Duncan NRI Faculty and Staff Publications

We report a 40-year-old African American female with a novel variant in exon 8 of DNA methyltransferase 3 alpha (DNMT3A), (NM_022552.4: c.905G>C, p.G302A) who presented with a history of recurrent carotid paragangliomas, mediastinal mass, intellectual disability, dysarthria, cholelithiasis, diabetes mellitus, hypertension, and dysmorphic features. We interpret this novel variant as likely pathogenic and causative for the patient's syndromic features of Heyn-Sproul-Jackson syndrome. Heyn-Sproul-Jackson syndrome is a condition caused by gain-of-function genetic changes in DNMT3A. Paragangliomas have also been observed in non-syndromic patients with genetic alterations in DNMT3A. We describe a patient with clinical features of Heyn-Sproul-Jackson syndrome such as …

Analysis Of 1,25-Dihydroxyvitamin D Genomic Action In Human Enteroids And Colonoids Reveals Multiple Regulatory Effects Of Vitamin D In Human Intestinal Physiology, Zachary K Criss, Kali Deans-Fielder, James C Fleet, Sylvia Christakos, Noah Shroyer

Faculty, Staff and Students Publications

Introduction: The intestine has molecular and functional diversity across the proximal-distal and the crypt-villus axes, so it is imperative to determine the common and compartment-specific molecular actions of vitamin D. However, very little work on vitamin D mediated gene regulation has been done in normal human intestine. Here, we examined the impact of 1,25-dihydroxyvitamin D (1,25(OH)2D3) on cultures of human intestinal epithelium derived from duodenum (Dd) and distal colon (Co) biopsies of 6 subjects per tissue.

Methods: Human enteroids and colonoids were cultured for 3 days to promote a stem cell phenotype (undifferentiated, Un) or to induce differentiation (Diff) and …

Predictive Equation Derived From 6,497 Doubly Labelled Water Measurements Enables The Detection Of Erroneous Self-Reported Energy Intake, Rania Bajunaid, Chaoqun Niu, Catherine Hambly, Zongfang Liu, Yosuke Yamada, Heliodoro Aleman-Mateo, Liam J Anderson, Lenore Arab, Issad Baddou, Linda Bandini, Kweku Bedu-Addo, Ellen E Blaak, Carlijn V C Bouten, Soren Brage, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Regina Casper, Graeme L Close, Jamie A Cooper, Richard Cooper, Sai Krupa Das, Peter S W Davies, Prasangi Dabare, Lara R Dugas, Simon Eaton, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Melanie Gillingham, Annelies H Goris, Michael Gurven, Asmaa El Hamdouchi, Hinke H Haisma, Daniel Hoffman, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Misaka Kimura, William E Kraus, Wantanee Kriengsinyos, Rebecca Kuriyan, Robert F Kushner, Estelle V Lambert, Pulani Lanerolle, Christel L Larsson, William R Leonard, Nader Lessan, Marie Löf, Corby K Martin, Eric Matsiko, Anine C Medin, James C Morehen, James P Morton, Aviva Must, Marian L Neuhouser, Theresa A Nicklas, Christine D Nyström, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Susan B Racette, David A Raichlen, Eric Ravussin, Leanne M Redman, John J Reilly, Rebecca Reynolds, Susan B Roberts, Dulani Samaranayakem, Luis B Sardinha, Analiza M Silva, Anders M Sjödin, Marina Stamatiou, Eric Stice, Samuel S Urlacher, Ludo M Van Etten, Edgar G A H Van Mil, George Wilson, Jack A Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Srishti Sinha, Cornelia U Loechl, Amy H Luke, Herman Pontzer, Jennifer Rood, Hiroyuki Sagayama, Dale A Schoeller, Klaas R Westerterp, William W Wong, John R Speakman

Faculty, Staff and Students Publications

Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96 years. The resultant regression equation predicts expected TEE from easily acquired variables, such as body weight, age and sex, with 95% predictive limits that can be used …

Survey And Improvement Strategies For Gene Prioritization With Large Language Models, Matthew B Neeley, Guantong Qi, Guanchu Wang, Ruixiang Tang, Dongxue Mao, Chaozhong Liu, Sasidhar Pasupuleti, Bo Yuan, Fan Xia, Pengfei Liu, Zhandong Liu, Xia Hu

Duncan NRI Faculty and Staff Publications

Motivation: Rare diseases remain difficult to diagnose due to limited patient data and genetic diversity, with many cases remaining undiagnosed despite advances in variant prioritization tools. While large language models have shown promise in medical applications, their optimal application for trustworthy and accurate gene prioritization downstream of modern prioritization tools has not been systematically evaluated.

Results: We benchmarked various language models for gene prioritization using multi-agent and Human Phenotype Ontology classification approaches to categorize patient cases by phenotype-based solvability levels. To address language model limitations in ranking large gene sets, we implemented a divide-and-conquer strategy with mini-batching and token limiting …

Drosophila Models Uncover Substrate Channeling Effects On Phospholipids And Sphingolipids In Peroxisomal Biogenesis Disorders, Michael F Wangler, Yu-Hsin Chao, Mary Roth, Ruth Welti, James A Mcnew

Duncan NRI Faculty and Staff Publications

Peroxisomal Biogenesis Disorders Zellweger Spectrum (PBD-ZSD) disorders are a group of autosomal recessive defects in peroxisome formation that produce a multi-systemic disease presenting at birth or in childhood. Well documented clinical biomarkers such as elevated very long chain fatty acids (VLCFA) are key biochemical diagnostic findings in these conditions. Additional, secondary biochemical alterations such as elevated very long chain lysophosphatidylcholines are allowing newborn screening for peroxisomal disease. In addition, a more widespread impact on metabolism and lipids is increasingly being documented by metabolomic and lipidomic studies. Here we utilize Drosophila models of pex2 and pex16 as well as human plasma …

Comparing Guillain-Barré Syndrome Outcomes Between Rural And Urban Hospitals In The United States: A Retrospective Cohort Study, Anudeep Surendranath, Rahul Damani, Anushareddy Muddasani, Anupam Kumar Gupta

Faculty, Staff and Students Publications

Background and purpose: Rural-urban disparities in neurological care have been well documented, but limited data exist regarding Guillain-Barré Syndrome (GBS). This study examines differences in patient demographics, hospital characteristics, and outcomes among GBS admissions to rural versus urban hospitals in the United States.

Methods: Using the 2021 National Inpatient Sample, we conducted a retrospective cohort study of adult hospitalizations with a principal diagnosis of GBS. Hospitals were classified as rural or urban based on U.S. census designations. Multivariate logistic and linear regression models were used to assess associations between hospital location and outcomes, adjusting for demographic, clinical, and hospital-level factors. …

Affective Bias Predicts Changes In Depression During Deep Brain Stimulation Therapy, Brian Cui, Madaline M Mocchi, Brian A Metzger, Prathik Kalva, John F Magnotti, Jess G Fiedorowicz, Allison Waters, Christopher K Kovach, Yvonne Y Reed, Raissa K Mathura, Camille Steger, Bailey Pascuzzi, Kourtney Kanja, Ashan Veerakumar, Vineet Tiruvadi, Andrea Crowell, Lydia Denison, Christopher J Rozell, Nader Pouratian, Wayne Goodman, Patricio Riva Posse, Helen S Mayberg, Kelly Rowe Bijanki

Faculty, Staff and Students Publications

Introduction: Deep brain stimulation (DBS) is a promising treatment for refractory depression, utilizing surgically implanted electrodes to stimulate specific anatomical targets within the brain. However, limitations of patient-reported and clinician-administered mood assessments pose obstacles in evaluating DBS treatment efficacy. In this study, we investigated whether an affective bias task, which leverages the inherent negative interpretation bias seen in individuals with depression, could serve as a reliable measure of mood changes during DBS therapy in patients with treatment-resistant depression.

Methods: Two cohorts of patients (n = 8, n = 2) undergoing DBS for treatment-resistant depression at different academic medical centers …

Orthogonal And Multiplexable Genetic Perturbations With An Engineered Prime Editor And A Diverse Rna Array, Qichen Yuan, Hongzhi Zeng, Tyler C Daniel, Qingzhuo Liu, Yongjie Yang, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M Abramson, Boyang Zhang, Yong Xu, Xue Gao

Faculty, Staff and Students Publications

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation. mvGPT can precisely edit human genome via PE coupled with a prime editing guide RNA and a nicking guide RNA, activate endogenous gene expression …

Role Of Nf2 Mutation In The Development Of Eleven Different Cancers, Shervin Hosseingholi Nouri, Vijay Nitturi, Elizabeth Ledbetter, Collin W English, Sean Lau, Tiemo J Klisch, Akash J Patel

Faculty, Staff and Students Publications

Background/Objectives: With the rise in prevalence of diagnostic genetic techniques like RNA sequencing and whole exome sequencing (WES), as well as biological treatment regiments for cancer therapy, several genes have been implicated in carcinogenesis. This review aims to update our understanding of the Neurofibromatosis 2 (NF2) gene and its role in the pathogenesis of various cancers. Methods: A comprehensive search of five online databases yielded 43 studies that highlighted the effect of sporadic NF2 mutations on several cancers, including sporadic meningioma, ependymoma, schwannoma, mesothelioma, breast cancer, hepatocellular carcinoma, prostate cancer, glioblastoma, thyroid cancer, and melanoma. Of note were key biological …

Aperiodic Spectral Slope Tracks The Effects Of Brain State On Saliency Responses In The Human Auditory Cortex, Madaline Mocchi, Eleonora Bartoli, John Magnotti, Jan Willem De Gee, Brian Metzger, Bailey Pascuzzi, Raissa Mathura, Suhruthaa Pulapaka, Wayne Goodman, Sameer Sheth, Matthew J Mcginley, Kelly Bijanki

Faculty, Staff and Students Publications

Alteration of responses to salient stimuli occurs in a wide range of brain disorders and may be rooted in pathophysiological brain state dynamics. Specifically, tonic and phasic modes of activity in the reticular activating system (RAS) influence, and are influenced by, salient stimuli, respectively. The RAS influences the spectral characteristics of activity in the neocortex, shifting the balance between low- and high-frequency fluctuations. Aperiodic '1/f slope' has emerged as a promising composite measure of these brain state dynamics. However, the relationship of 1/f slope to state-dependent processes, such as saliency, is less explored, particularly intracranially in humans. Here, we record …

International Workshop: What Is Needed To Ensure Outcome Measures For Rett Syndrome Are Fit-For-Purpose For Clinical Trials? June 7, 2023, Nashville, Usa, Jenny Downs, Dominique C Pichard, Walter E Kaufmann, Joseph P Horrigan, Melissa Raspa, Gillian Townend, Eric D Marsh, Helen Leonard, Kathleen Motil, Andrew C Dietz, Nupur Garg, Amitha Ananth, Breanne Byiers, Sarika Peters, Christopher Beatty, Frank Symons, Aleksandra Jacobs, James Youakim, Bernhard Suter, Paramola Santosh, Jeffrey L Neul, Tim A Benke

Faculty, Staff and Students Publications

INTRODUCTION: The clinical, research and advocacy communities for Rett syndrome are striving to achieve clinical trial readiness, including having fit-for-purpose clinical outcome assessments. This study aimed to (1) describe psychometric properties of clinical outcome assessment for Rett syndrome and (2) identify what is needed to ensure that fit-for-purpose clinical outcome assessments are available for clinical trials.

METHODS: Clinical outcome assessments for the top 10 priority domains identified in the Voice of the Patient Report for Rett syndrome were compiled and available psychometric data were extracted. The clinical outcome assessments measured clinical severity, functional abilities, comorbidities and quality of life, and …

Irregular Assessment Times In Pragmatic Randomized Clinical Trials, Andrea Apter, Frances K Barg, Sanjib Basu, Alex Federman, Winifred J Hamilton, Jerry A Krishnan, Tianjing Li, Russell Localio, Christine Pindle, Daniel O Scharfstein, Justin D Smith, Kaharu Sumino

Faculty, Staff and Students Publications

Deviation from protocolized assessment times is commonplace in pragmatic randomized clinical trials. Working with a stakeholder advisory board for a Patient-Centered Outcomes Research Institute®-funded project on statistical methods for handling potential biases introduced by irregular assessment times, we identified reasons for off-schedule or missed assessments. We used the Consolidated Framework for Implementation Research 2.0 to organize our findings. We conjectured that timely completion of outcome assessments is a function of multiple determinants, only some related to participants' health status. We identified potential determinants that can be modified during the protocol design stage and can be reassessed and mitigated during trial …

Age-Related Tfeb Downregulation In Proximal Tubules Causes Systemic Metabolic Disorders And Occasional Apolipoprotein A4-Related Amyloidosis, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB …

Macrowire For Intracranial Thrombectomy: An Early Experience Of A New Device And Technique For Anterior Circulation Large Vessel Occlusion Stroke, Kaustubh Limaye, Sami Al Kasab, Jaidevsinh Dolia, Mohamad Ezzeldin, Daniel Vela Duarte, Vinodh Doss, Sourabh Lahoti, David Hasan, Alejandro Spiotta, Khaled Asi, Vasu Saini, Tapan Mehta, Ameer Hassan, Diogo Haussen, Dileep Yavagal, Jesse Jones, Omar Tanweer, Waleed Brinjikji

Faculty, Staff and Students Publications

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) has become the standard of care for treatment of acute ischemic stroke secondary to large vessel occlusion up to 24 h from the last known normal time. With ADAPT and SOLUMBRA techniques, classically, a large bore aspiration catheter is delivered over a microcatheter and microwire crossing the clot to perform thrombectomy. Recently, a novel macrowire (Colossus 035 in.) has been introduced as a potential alternative to the use of microwire-microcatheter to allow the delivery of the aspiration catheter (ID = 0.070 in. up to 0.088 in.) over a macrowire alone.

OBJECTIVE: To test the …

Identification Of An Early Subset Of Cerebellar Nuclei Neurons In Mice, Maryam Rahimi-Balaei, Shayan Amiri, Thomas Lamonerie, Sih-Rong Wu, Huda Y Zoghbi, G Giacomo Consalez, Daniel Goldowitz, Hassan Marzban

Duncan NRI Faculty and Staff Publications

Cerebellar nuclei (CN) neurons serve as the primary output of the cerebellum and originate from the cerebellar primordium at early stages of cerebellar development. These neurons are diverse, integrating information from the cerebellar cortex and relaying it to various brain regions. Employing various methodologies, we have characterized a specific subset of CN neurons that do not originate from the rhombic lip or ventricular zone of the cerebellar primordium. Embryos were collected at early stages of development and processed for immunohistochemistry (IHC), western blotting, in situ hybridization (ISH), embryonic culture, DiI labeling, and flow cytometry analysis (FCM). Our findings indicate that …

Global Impact Of Aging On The Hemodynamic Response Function In The Gray Matter Of Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, Keisjon Mosby, Ruosha Li, Jung Hwan Kim, David Ress

Faculty, Staff and Students Publications

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI cognitive aging studies. In this study, use was made of a multisensory task to evoke the HRF in ~87% of cerebral cortex in cognitively intact adults with ages ranging from 22 to 75 years. This widespread activation enabled us to investigate age trends in the spatial distributions of HRF characteristics within the majority of cortical gray matter, which we termed as global age trends. The task evoked both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. We found significant global age trends in the distributions of HRF parameters in terms of both amplitudes (e.g., peak amplitude and contrast-to-noise ratio) and temporal dynamics (e.g., full-width-at-half-maximum). Our findings offer insight into how age-dependent changes affect neurovascular coupling and show promise for use of HRF parameters as non-invasive indicators for age-related pathology.

Simple Improvements In Vector Design Afford Substantial Gains In Aav Delivery Of Aggregation-Slowing Aβ Variants, Ella Borgenheimer, Cameron Trueblood, Bryan L Nguyen, William R Lagor, Joanna L Jankowsky

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that …

Clinical And Radiologic Findings In Children With Anomalous Pontine Cranial Nerves, Karen K Moeller, Brandon H Tran, Thierry A G M Huisman, Nilesh K Desai, Marcia K Kukreja, Rajan P Patel, Uma S Ramaswamy, Carol Liu, Stephen F Kralik

Faculty, Staff and Students Publications

We retrospectively reviewed the clinical and radiologic findings in 17 children with an aberrant cisternal cranial nerve 7 (CN7), and found that these patients had additional anomalies involving other pontine cranial nerves (CNs). The hallmark imaging feature identified in all patients was an aberrant cisternal segment of an enlarged-appearing CN7. The abnormal nerve coursed anteriorly toward the Gasserian ganglion, where it fanned out toward the internal auditory canal, Meckel cave, or both. This finding was accompanied by a small cisternal CN5, which often had a lateral bowed appearance. CN5 and CN7 were abnormally close to each other. Meckel's cave appeared …

Spino-Plastic Surgery: Addressing Spinal Tumors With New Techniques, Casey Martinez, Isra Abdulwadood, Sebastian Winocour, Alexander E Ropper, Marco Innocenti, Michael Bohl, Maziyar Kalani, Edward M Reece

Faculty, Staff and Students Publications

Background/Objectives: Spino-plastic surgery describes a specialized, multidisciplinary approach to addressing various spinal pathologies. The field is the innovative product of a multidisciplinary collaboration between plastic and reconstructive, orthopedic, and neurosurgery. Over the last few decades, this collaboration has borne promising surgical techniques and treatment plans geared toward restoring form, function, and aesthetics in patients with a variety of spinal conditions, including failed fusions, pseudoarthrosis, and the need for oncologic reconstruction. This paper explores the application of spino-plastic surgery in the context of post-sarcoma resection reconstructions, focusing on the efficacy in addressing the unique challenges posed by extensive tissue loss and …

3d Genome Topology Distinguishes Molecular Subgroups Of Medulloblastoma, John J Y Lee, Michael J Johnston, Hamza Farooq, Huey-Miin Chen, Subhi Talal Younes, Raul Suarez, Melissa Zwaig, Nikoleta Juretic, William A Weiss, Jiannis Ragoussis, Nada Jabado, Michael D Taylor, Marco Gallo

Faculty, Staff and Students Publications

Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD …

Rna Splicing As A Biomarker And Phenotypic Driver Of Meningioma Dna-Methylation Groups, Nathan K Leclair, Abrar Choudury, William C Chen, Stephen T Magill, Kathleen Mccortney, Craig M Horbinski, Zhenhong Chen, Ezequiel Goldschmidt, Charlotte D Eaton, Ketan R Bulsara, Wenya Linda Bi, Akash J Patel, Felix Sahm, David Raleigh, Olga Anczukow

Faculty, Staff and Students Publications

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA-methylation signatures have on meningioma biology.

METHODS: This study utilizes RNA-sequencing data from 486 meningioma samples corresponding to 3 meningioma DNA-methylation groups (merlin-intact, immune-enriched, and hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines.

RESULTS: …

Prenatal Assessment Of Brain Malformations On Neuroimaging: An Expert Panel Review, Ivana Pogledic, Kshitij Mankad, Mariasavina Severino, Tally Lerman-Sagie, Andras Jakab, Efrat Hadi, Anna C Jansen, Nadia Bahi-Buisson, Natalya Di Donato, Renske Oegema, Christian Mitter, Ivan Capo, Matthew T Whitehead, Parthiv Haldipur, Grazia Mancini, Thierry A G M Huisman, Andrea Righini, Bill Dobyns, James A Barkovich, Natasa Jovanov Milosevic, Gregor Kasprian, Maarten Lequin

Faculty, Staff and Students Publications

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand road map to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. For every developmental stage, the utility of each available neuroimaging modality, including prenatal multiplanar neuro sonography, anatomical MRI and advanced MRI techniques, as …

Urinary Metal Levels, Cognitive Test Performance, And Dementia In The Multi-Ethnic Study Of Atherosclerosis, Arce Domingo-Relloso, Katlyn E Mcgraw, Susan R Heckbert, Jose A Luchsinger, Kathrin Schilling, Ronald A Glabonjat, Irene Martinez-Morata, Melanie Mayer, Yongmei Liu, Alexis C Wood, Jeff Goldsmith, Kathleen M Hayden, Mohamad Habes, Ilya M Nasrallah, R Nick Bryan, Tanweer Rashid, Wendy S Post, Jerome I Rotter, Priya Palta, Linda Valeri, Timothy M Hughes, Ana Navas-Acien

Faculty, Staff and Students Publications

IMPORTANCE: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited.

OBJECTIVE: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4).

DESIGN, SETTING, AND PARTICIPANTS: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024.

EXPOSURE: Urine samples were collected at baseline …

Individualized Functional Magnetic Resonance Imaging Neuromodulation Enhances Visuospatial Perception: A Proof-Of-Concept Study, Anthony Allam, Vincent Allam, Sandy Reddy, Eric M Rohren, Sameer A Sheth, Emmanouil Froudarakis, T Dorina Papageorgiou

Duncan NRI Faculty and Staff Publications

This proof-of-concept study uses individualized functional magnetic resonance imaging neuromodulation (iNM) to explore the mechanisms that enhance BOLD signals in visuospatial perception (VP) networks that are crucial for navigation. Healthy participants (n = 8) performed a VP up- and down-direction discrimination task at full and subthreshold coherence through peripheral vision, and superimposed direction through visual imagery (VI) at central space under iNM and control conditions. iNM targets individualized anatomical and functional middle- and medial-superior temporal (MST) networks that control VP. We found that iNM engaged selective exteroceptive and interoceptive attention (SEIA) and motor planning (MP) networks. Specifically, iNM increased …

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

Faculty, Staff and Students Publications

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …