Medicine and Health Sciences Commons^™

Levels Of Glycosaminoglycans In The Cerebrospinal Fluid Of Healthy Young Adults, Surrogate-Normal Children, And Hunter Syndrome Patients With And Without Cognitive Impairment., Christian J Hendriksz, Joseph Muenzer, Adeline Vanderver, Jonathan M Davis, Barbara K Burton, Nancy J Mendelsohn, Nan Wang, Luying Pan, Arian Pano, Ann J Barbier

Neurology Faculty Publications

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls.

Csf And Blood Levels Of Gfap In Alexander Disease(1,2,3)., Paige L Jany, Guillermo E Agosta, William S Benko, Jens C Eickhoff, Stephanie R Keller, Adeline Vanderver, +13 Additional Authors

Neurology Faculty Publications

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect …

Recessive Mutations In Polr1c Cause A Leukodystrophy By Impairing Biogenesis Of Rna Polymerase Iii, Isabelle Thiffault, Nicole I. Wolf, Diane Forget, Kether Guerrero, Adeline Vanderver, Cas Simons, Ryan J. Taft, +17 Additional Authors

Neurology Faculty Publications

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is …

Ubiquitous L1 Mosaicism In Hippocampal Neurons., Kyle R. Upton, Daniel J. Gerhardt, J. Samuel Jesuadian, Sandra R. Richardson, Francisco J. Sánchez-Luque, Gabriela O. Bodea, Adam D. Ewing, Carmen Salvador-Palomeque, Marjo S. Van Der Knaap, Paul M. Brennan, Adeline Vanderver, Geoffrey J. Faulkner

Neurology Faculty Publications

Somatic LINE-1 (L1) retrotransposition during neurogenesis is a potential source of genotypic variation among neurons. As a neurogenic niche, the hippocampus supports pronounced L1 activity. However, the basal parameters and biological impact of L1-driven mosaicism remain unclear. Here, we performed single-cell retrotransposon capture sequencing (RC-seq) on individual human hippocampal neurons and glia, as well as cortical neurons. An estimated 13.7 somatic L1 insertions occurred per hippocampal neuron and carried the sequence hallmarks of target-primed reverse transcription. Notably, hippocampal neuron L1 insertions were specifically enriched in transcribed neuronal stem cell enhancers and hippocampus genes, increasing their probability of functional relevance. In …

The Emerging Role Of Ng2 In Pediatric Diffuse Intrinsic Pontine Glioma., Sridevi Yadavilli, Joseph Scafidi, Oren J. Becher, Amanda M. Saratsis, Rebecca L. Hiner, Madhuri Kambhampati, Santi Mariarita, Tobey J. Macdonald, Kari-Elise Codispoti, Suresh N. Magge, Jyoti K. Jaiswal, Roger J. Packer, Javad Nazarian

Neurology Faculty Publications

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG …

Epidural Steroid Injections Compared With Gabapentin For Lumbosacral Radicular Pain: Multicenter Randomized Double Blind Comparative Efficacy Study, Steven P. Cohen, Steven Hanling, Mark C. Bicket, Ronald L. White, Elias Velzi, Connie Kurihara, Zirong Zhao, Salim Hayek, Kevin B. Guthmiller, Scott R. Griffith, Vitaly Gordin, Mirinda Anderson White, Yakov Vorobeychik, Paul F. Pasquina

Neurology Faculty Publications

Objective To evaluate whether an epidural steroid injection or gabapentin is a better treatment for lumbosacral radiculopathy.

Design A multicenter randomized study conducted between 2011 and 2014. Computer generated randomization was stratified by site. Patients and evaluating physicians were blinded to treatment outcomes.

Settings Eight military, Veterans Administration, and civilian hospitals.

Participants 145 people with lumbosacral radicular pain secondary to herniated disc or spinal stenosis for less than four years in duration and in whom leg pain is as severe or more severe than back pain.

Interventions Participants received either epidural steroid injection plus placebo pills or sham injection plus …

The Piriform, Perirhinal, And Entorhinal Cortex In Seizure Generation, Marta S. Vismer, Patrick A. Forcelli, Mark D. Skopin, Karen Gale, Mohamad Z. Koubeissi

Neurology Faculty Publications

Understanding neural network behavior is essential to shed light on epileptogenesis and seizure propagation. The interconnectivity and plasticity of the limbic and cortical regions of the mammalian brain provide the substrate for the hypersynchrony and hyperexcitability associated with epilepsy and seizure activity. Recurrent unprovoked seizures are the hallmark of epilepsy, and limbic epilepsy is the most common type of medically-intractable focal epilepsy in adolescents and adults that necessitates surgical evaluation. In this review, we describe the role and relationships among the piriform (PIRC), perirhinal (PRC), and entorhinal cortex (ERC) in seizure-generation and epilepsy. The inherent function, anatomy, and histological composition …

Proteomic Profiling Of High Risk Medulloblastoma Reveals Functional Biology, Jerome A. Staal, Ling San Lau, Huizhen Zhang, Wendy J. Ingram, Andrew R. Hallahan, Roger J. Packer, Brian R. Rood, Kristy J. Brown, +6 Additional Authors

Neurology Faculty Publications

Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in …

Adar1 Facilitates Hiv-1 Replication In Primary Cd4+ T Cells., Eloy Cuadrado, Thijs Booiman, John L Van Hamme, Machiel H Jansen, Karel A Van Dort, Adeline Vanderver, Gillian I Rice, Yanick J Crow, Neeltje A Kootstra, Taco W Kuijpers

Neurology Faculty Publications

Unlike resting CD4+ T cells, activated CD4+T cells are highly susceptible to infection of human immunodeficiency virus 1 (HIV-1). HIV-1 infects T cells and macrophages without activating the nucleic acid sensors and the anti-viral type I interferon response. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that displays antiviral activity against several RNA viruses. Mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieères syndrome (AGS). This disease is characterized by an inappropriate activation of the interferon-stimulated gene response. Here we show that HIV-1 replication, in ADAR1-deficient CD4+T lymphocytes from AGS patients, is blocked at the level of …

Mitral Subvalvular Aneurysm In A Patient With Chagas Disease And Recurrent Episodes Of Ventricular Tachycardia., Tereza Augusta Grillo, Guilherme Rafael S Athayde, Ana Flávia L Belfort, Reynaldo C Miranda, Andrea Z. Beaton, Bruno R Nascimento

Neurology Faculty Publications

Subvalvular left ventricular aneurysm is a rare disease of obscure origin suggesting unique causes such as congenital, traumatic, and inflammatory or infectious diseases. Its mortality is closely related to heart failure, mitral insufficiency, thromboembolic phenomena, and cardiac arrhythmias. Although association with coronary artery disease is not described, the compression of epicardial vessels by the aneurysm may lead to ischemic manifestations. We report here a case of mitral subvalvular left ventricular aneurysm of probable chagasic origin, in a patient with normal left ventricular function evolving with repeated episodes of monomorphic ventricular tachycardia, despite noninducible electrophysiological testing and the use of optimal …

Levetiracetam-Induced Pancytopenia., Talal Alzahrani, Dana Kay, Saeed A. Alqahtani, Yamane Makke, Linda Lesky, Mohamad Z. Koubeissi

Neurology Faculty Publications

Pancytopenia is a rare side effect of levetiracetam (LEV) that is associated with severe morbidity that requires hospitalization. Here, we report a patient with a right temporoparietal tumor who underwent a temporal craniotomy with resection of the mass and was started on LEV for seizure prophylaxis per the neurosurgery local protocol. The patient developed LEV-induced pancytopenia, which was successfully managed by discontinuation of this medication. Our report aims to increase awareness of this rare cause of pancytopenia among clinicians.

The Piriform, Perirhinal, And Entorhinal Cortex In Seizure Generation., Marta S Vismer, Patrick A Forcelli, Mark D Skopin, Karen Gale, Mohamad Z. Koubeissi

Neurology Faculty Publications

Understanding neural network behavior is essential to shed light on epileptogenesis and seizure propagation. The interconnectivity and plasticity of mammalian limbic and neocortical brain regions provide the substrate for the hypersynchrony and hyperexcitability associated with seizure activity. Recurrent unprovoked seizures are the hallmark of epilepsy, and limbic epilepsy is the most common type of medically-intractable focal epilepsy in adolescents and adults that necessitates surgical evaluation. In this review, we describe the role and relationships among the piriform (PIRC), perirhinal (PRC), and entorhinal cortex (ERC) in seizure-generation and epilepsy. The inherent function, anatomy, and histological composition of these cortical regions are …

A Dietary Intervention For Chronic Diabetic Neuropathy Pain: A Randomized Controlled Pilot Study, A. E. Bunner, C. L. Wells, J. Gonzales, U. Agarwal, Elham Bayat, Neal D. Barnard

Neurology Faculty Publications

Background:

Diabetic neuropathy is a common and often debilitating condition for which available treatments are limited. Because a low-fat plant-based diet has been shown to improve glycemic control in individuals with type 2 diabetes, we hypothesized that such a diet would reduce painful symptoms of diabetic neuropathy.

Methods:

In this 20-week pilot study, individuals with type 2 diabetes and painful diabetic neuropathy were randomly assigned to two groups. The intervention group was asked to follow a low-fat, plant-based diet, with weekly classes for support in following the prescribed diet, and to take a vitamin B12 supplement. The control group was …

Reduced Functional Connectivity Of Default Mode And Set-Maintenance Networks In Ornithine Transcarbamylase Deficiency., Ileana Pacheco-Colón, Stuart D. Washington, Courtney Sprouse, Guy Helman, Andrea L. Gropman, John W. Vanmeter

Neurology Faculty Publications

BACKGROUND AND PURPOSE: Ornithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks-default mode and set-maintenance-between OTCD patients and healthy controls.

METHODS: Sixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity.

RESULTS: Group comparisons revealed …