DOCSLIB.ORG

New Insights Into Brain Structure, Function and Neurochemistry 2012

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Insights Into Brain Structure, Function and Neurochemistry 2012 Inês Ribeiro Violante The neurobiological basis of Neurofibromatosis type I: new insights into brain structure, function and neurochemistry 2012 The neurobiological basis of Neurofibromatosis type 1: new insights into brain structure, function and neurochemistry Contributions to understand impaired cognitive function Inês Ribeiro Violante 2012 The studies presented in this thesis were carried out at the Visual Neurosciences Laboratory at IBILI (Instituto Biomédico de Investigação da luz e Imagem), Faculty of Medicine, University of Coimbra, Portugal, and were supported in part by a fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD/41348/2007) and by grants from the University of Coimbra [Grant number III/14/2008] and the Portuguese Foundation for Science and Technology [Grant numbers PIC/IC/83155/2007, PIC/ IC/82986/2007]. Cover design: Inês Violante ISBN: 978-989-20-3250-4 Copyright © 2012 Inês Violante Universidade de Coimbra Faculdade de Medicina The neurobiological basis of Neurofibromatosis type 1: new insights into brain structure, function and neurochemistry Dissertation presented to obtain a Ph.D. degree in Biomedical Sciences at the Faculty of Medicine of the University of Coimbra Dissertação de Doutoramento apresentada à Faculdade de Medicina da Universidade de Coimbra, para prestação de provas de Doutoramento em Ciências Biomédicas Inês Ribeiro Violante 2012 Supervised by: Miguel Castelo-Branco, M.D., Ph.D. Co-Superviser by: Carlos F.G.C. Geraldes, D.Phil. Para a Natália e o António “Why, sometimes I’ve believed as many as six impossible things before breakfast.” The White Queen in Lewis Carroll, Alice Through the Looking Glass CONTENTS Abbreviations VIII Summary XI Sumário XIII Introduction Chapter 1 - Introduction 19 Aims and outline of the Thesis 41 Materials and Methods Chapter 2 - Fundamentals of magnetic resonance for the study of brain 57 structure, function and neurochemistry Chapter 3 - Research methodology: patient and control groups 75 Results Chapter 4 - Abnormal brain activation in Neurofibromatosis type 1: 85 a link between visual processing and the default mode network Chapter 5 - GABA is reduced in the visual cortex of patients with 115 Neurofibromatosis type 1: a new perspective on the disease mechanism Chapter 6 - Gyrification, cortical and subcortical morphometry 139 in Neurofibromatosis type 1: an uneven profile of developmental abnormalities Concluding Remarks Chapter 7 - Discussion and Conclusions 171 List of Publications 187 Agradecimentos 189 Curriculum Vitae 191 VIII ABBREVI A TIONS AC Adenylate cyclise / Adenylyl cyclase AC-PC Anterior comissure - posterior commissure ADC Apparent diffusion coefficient ADHD Attention deficit hyperactive disorder AKT Serine/threonine protein kinase ANCOVA Analysis of covariance ANOVA Analysis of variance BA Brodmann area BOLD Blood-oxygen-level-dependent CC Corpus callosum cDNA Complementary DNA Cho Choline cpd Cycles per degree Cr Creatine CSF Cerebrospinal fluid d Dorsal DMN Default-mode-network DNA Deoxyribonucleic acid DSM-IV Diagnostic and statistical manual of mental disorders - fourth edition DTI Diffusion tensor imaging EPI Echo planar imaging ERK Extracellular signal-regulated kinase FA Fractional anisotropy FA Flip angle FID Free induction decay FDA Food and drug administration FDR False discovery rate FLAIR Fluid attenuated inversion recovery fMRI Functional magnetic resonance imaging FOV Field of view FRT Facial recognition test FSIQ Full-scale intelligent quotient FWHM Full width at half maximum GABA γ-Aminobutyric acid IX GABA-T GABA transaminase GAD Glutamic acid decarboxylase GAP GTPase activating protein GATs GABA transporters GC Ganglion cell GEFs Guanine-necleotide exchange factors GLM General linear model Gln Glutamine Glu Glutamate Glx Glutamate + Glutamine GM Grey matter GPCR G protein-coupled receptor Hb Deoxyhaemoglobin HbO2 Oxyhaemoglobin Ins Inositol IPSP Inhibitory postsynaptic potentials IQ Intelligent quotient JLO Judgment of line orientation lGI Local gyrification index LGN Lateral geniculate nucleus LTP Long-term potentiation M Magnocellular MAPK Mitogen-activated protein kinase mEPSCs Miniature excitatory postsynaptic currents mIPSCs Miniature inhibitory postsynaptic currents MLPA Multiplex ligation-dependent probe amplification MPNST Malignant peripheral nerve sheath tumours MPRAGE Magnetization prepared rapid gradient echo MR Magnetic resonance MRI Magnetic resonance imaging MRS Magnetic resonance spectroscopy mTOR Mammalian target of rapamycin NAA N-acetylaspartate NF1 Neurofibromatosis type 1 X NMDAR N-methyl-D-aspartate receptor NS Non significant P Parvocellular PCr Phosphocreatine PD Proton density PET Positron emission tomography PI3K Phosphatidylinositol 3-kinase PIQ Performance intelligent quotient PK Protein kinase RF Radiofrequency RFX Random effects RNA Ribonucleic acid ROI Region-of-interest RTK receptor tyrosine kinase rut Rutabaga SD Standard deviation SE Standard error SEM Standard error of the mean SHP2 Src homology-2 containing tyrosine phosphatase sIPSCs Spontaneous inhibitory postsynaptic currents T1w T1-weighted T2w T2-weighted tCr Total creatine TD Typically Developing TE Echo time TI Inversion Time TIV Total intracranial volume TR Repetition time UBOs Unidentified bright objects v Ventral VGAT Vesicular neurotransmitter transporter VIQ Verbal intelligent quotient WISC-III Wechsler intelligence scale for children - third edition WM White matter WT Wild type XI SUMM A RY Neurofibromatosis type 1 (NF1) is a single-gene disorder associated with complex cognitive dysfunction including learning disabilities, attention deficit hyperactive disorder, executive function, visuospatial and motor coordination deficits. Neuroimaging techniques can contribute to identify the neurobiological basis underlying these impairments. Here, I used spectroscopy, functional and structural brain imaging to identify the neural and neurotransmitter systems involved in the aetiology of the cognitive deficits in NF1. Particularly, I focused on basic physiological features that have the potential to unravel downstream alterations that can cause higher order cognitive deficits. This approach was chosen to scrutinise the contributions of visual sensory processing, neurotransmitter regulation and neuroanatomical characteristics to the NF1 phenotype. Visual sensory processing was investigated by probing the neural activation of the two main pathways conduction information from the retina to the cortex, the magnocellular and parvocellular streams. This study examined for the first time the function of the early visual cortex in patients with NF1 and identified a pattern ofdeficient activation to both stimulus types. This analysis was performed in children, adolescents and adults with NF1 to investigate whether deficits in visual sensory processing ameliorated with age. It is shown that this is not the case and that the pattern observed in children persists into adulthood. Furthermore, we investigated the activation pattern of high-level visual and non-visual regions modulated by the different stimuli to examine possible functional consequences of low-level visual impairments. This led to the observation that during M-biased stimulation, patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network, while controls deactivated these regions. By definition, the default mode network is composed by a set of brain regions that are active during task-irrelevant thoughts and deactivate during performance of cognitively demanding or engaging tasks. The observation that the early visual magnocellular processing is impaired in NF1 and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly attentional. NF1 belongs to a cluster of neurodevelopmental disorders for which alterations in the main inhibitory neurotransmitter, γ-aminobutyric acid (GABA), were proposed as the underlying cause of the cognitive deficits. This theory is the result of cellular and molecular studies on a mouse model of the disorder (Nf1+/-), which indicated an imbalance in XII excitatory/inhibitory push-pull systems as a consequence of increased GABA-mediated inhibitory neurotransmission. To test whether a similar mechanism translates to the human disorder, magnetic resonance spectroscopy was applied to measure GABA levels in the visual cortex of children and adolescents with NF1 and matched controls. Measurements were performed in the visual cortex to provide further insight into the neural mechanisms causing the deficient visual sensory processing previously observed. We found that patients with NF1 have significantly lower GABA levels than controls and that NF1 mutation type significantly predicted cortical GABA. Our results provide the first evidence of GABAergic dysfunction in patients with NF1. This constitutes a relevant finding to understand the physiological profile of the disorder with implications for the identification of targets for therapeutic strategies. I finalize the set of studies presented in this thesis by providing novel data on NF1 neuroanatomy. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with this condition. Here we investigated the volumes of subcortical structures and for the first time the composite dimensions of the
Load more

Recommended publications
  • Description Treatment
    Description Megalencephaly, also called macrencephaly, is a condition in which an infant or child has an abnormally large, heavy, and usually malfunctioning brain. By definition, the brain weight is greater than average for the age and gender of the child. Head enlargement may be evident at birth or the head may become abnormally large in the early years of life. Megalencephaly is thought to be related to a disturbance in the regulation of cell production in the brain. In normal development, neuron proliferation - the process in which nerve cells divide to form new generations of cells - is regulated so that the correct number of cells is produced in the proper place at the appropriate time. In a megalencephalic brain, too many cells are produced either during development or progressively as part of another disorder, such as one of the neurofibromatoses or leukodystrophies. Symptoms of megalencephaly include delayed development, seizures, and corticospinal (brain cortex and spinal cord) dysfunction. Megalencephaly affects males more often than females. Unilateral megalencephaly or hemimegalencephaly is a rare condition that is characterized by the enlargement of one side of the brain. Children with this disorder may have a large, asymmetrical head accompanied by seizures, partial paralysis, and impaired cognitive development. Megalencephaly is different from macrocephaly (also called megacephaly or megalocephaly), which describes a big head, and which doesn’t necessarily indicate abnormality. Large head size is passed down through the generations in some families. Treatment There is no standard treatment for megalencephaly. Treatment will depend upon the disorder with which the megalencephaly is associated and will address individual symptoms and disabilities.
    [Show full text]
  • Megalencephaly and Macrocephaly
    277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ►
    [Show full text]
  • Polymicrogyria (PMG) ‘Many–Small–Folds’
    Polymicrogyria Dr Andrew Fry Clinical Senior Lecturer in Medical Genetics Institute of Medical Genetics, Cardiff [email protected] Polymicrogyria (PMG) ‘Many–small–folds’ • PMG is heterogeneous – in aetiology and phenotype • A disorder of post-migrational cortical organisation. PMG often appears thick on MRI with blurring of the grey-white matter boundary Normal PMG On MRI PMG looks thick but the cortex is actually thin – with folded, fused gyri Courtesy of Dr Jeff Golden, Pen State Unv, Philadelphia PMG is often confused with pachygyria (lissencephaly) Thick cortex (10 – 20mm) Axial MRI 4 cortical layers Lissencephaly Polymicrogyria Cerebrum Classical lissencephaly is due Many small gyri – often to under-migration. fused together. Axial MRI image at 7T showing morphological aspects of PMG. Guerrini & Dobyns Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014 Jul; 13(7): 710–726. PMG - aetiology Pregnancy history • Intrauterine hypoxic/ischemic brain injury (e.g. death of twin) • Intrauterine infection (e.g. CMV, Zika virus) TORCH, CMV PCR, [+deafness & cerebral calcification] CT scan • Metabolic (e.g. Zellweger syndrome, glycine encephalopathy) VLCFA, metabolic Ix • Genetic: Family history Familial recurrence (XL, AD, AR) Chromosomal abnormalities (e.g. 1p36 del, 22q11.2 del) Syndromic (e.g. Aicardi syndrome, Kabuki syndrome) Examin - Monogenic (e.g. TUBB2B, TUBA1A, GPR56) Array ation CGH Gene test/Panel/WES/WGS A cohort of 121 PMG patients Aim: To explore the natural history of PMG and identify new genes. Recruited: • 99 unrelated patients • 22 patients from 10 families 87% White British, 53% male ~92% sporadic cases (NB. ascertainment bias) Sporadic PMG • Array CGH, single gene and gene panel testing - then a subset (n=57) had trio-WES.
    [Show full text]
  • CONGENITAL ABNORMALITIES of the CENTRAL NERVOUS SYSTEM Christopher Verity, Helen Firth, Charles Ffrench-Constant *I3
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.suppl_1.i3 on 1 March 2003. Downloaded from CONGENITAL ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM Christopher Verity, Helen Firth, Charles ffrench-Constant *i3 J Neurol Neurosurg Psychiatry 2003;74(Suppl I):i3–i8 dvances in genetics and molecular biology have led to a better understanding of the control of central nervous system (CNS) development. It is possible to classify CNS abnormalities Aaccording to the developmental stages at which they occur, as is shown below. The careful assessment of patients with these abnormalities is important in order to provide an accurate prog- nosis and genetic counselling. c NORMAL DEVELOPMENT OF THE CNS Before we review the various abnormalities that can affect the CNS, a brief overview of the normal development of the CNS is appropriate. c Induction—After development of the three cell layers of the early embryo (ectoderm, mesoderm, and endoderm), the underlying mesoderm (the “inducer”) sends signals to a region of the ecto- derm (the “induced tissue”), instructing it to develop into neural tissue. c Neural tube formation—The neural ectoderm folds to form a tube, which runs for most of the length of the embryo. c Regionalisation and specification—Specification of different regions and individual cells within the neural tube occurs in both the rostral/caudal and dorsal/ventral axis. The three basic regions of copyright. the CNS (forebrain, midbrain, and hindbrain) develop at the rostral end of the tube, with the spinal cord more caudally. Within the developing spinal cord specification of the different popu- lations of neural precursors (neural crest, sensory neurones, interneurones, glial cells, and motor neurones) is observed in progressively more ventral locations.
    [Show full text]
  • Classification of Congenital Abnormalities of the CNS
    315 Classification of Congenital Abnormalities of the CNS M. S. van der Knaap1 A classification of congenital cerebral, cerebellar, and spinal malformations is pre­ J . Valk2 sented with a view to its practical application in neuroradiology. The classification is based on the MR appearance of the morphologic abnormalities, arranged according to the embryologic time the derangement occurred. The normal embryology of the brain is briefly reviewed, and comments are made to explain the classification. MR images illustrating each subset of abnormalities are presented. During the last few years, MR imaging has proved to be a diagnostic tool of major importance in children with congenital malformations of the eNS [1]. The excellent gray fwhite-matter differentiation and multi planar imaging capabilities of MR allow a systematic analysis of the condition of the brain in infants and children. This is of interest for estimating prognosis and for genetic counseling. A classification is needed to serve as a guide to the great diversity of morphologic abnormalities and to make the acquired data useful. Such a system facilitates encoding, storage, and computer processing of data. We present a practical classification of congenital cerebral , cerebellar, and spinal malformations. Our classification is based on the morphologic abnormalities shown by MR and on the time at which the derangement of neural development occurred. A classification based on etiology is not as valuable because the various presumed causes rarely lead to a specific pattern of malformations. The abnor­ malities reflect the time the noxious agent interfered with neural development, rather than the nature of the noxious agent. The vulnerability of the various structures to adverse agents is greatest during the period of most active growth and development.
    [Show full text]
  • Unilateral Megalencephaly. Correlates
    523 Unilateral Megalencephaly: Correlation of MR Imaging and Pathologic Characteristics A. James Barkovich 1 Unilateral megalencephaly is a rare and poorly understood malformation resulting in Sylvester H. Chuang2 the enlargement of all or part of a cerebral hemisphere. The clinical and radiologic features of 12 patients with unilateral megalencephaly are presented; pathologic cor­ relation was available in four. All patients had seizures and developmental delay. Two were in congestive heart failure as a result of arteriovenous shunting through the abnormal hemisphere. The affected hemispheres showed a wide spectrum of involve­ ment. Anomalies of neuronal migration were present, and there was a roughly inverse correlation between the severity of hemispheric involvement and the magnitude of enlargement. This correlation is explained via a proposed mechanism of a mild hemi­ spheric insult in the middle-to-late second trimester. One patient had an extremely anomalous hemisphere that did not have characteristics of a neuronal migration anomaly and may have been a hamartomatous malformation. Our correlation of the clinical, radiologic, and pathologic features of unilateral mega­ lencephaly, together with a theory of pathogenesis, should help elucidate this rare malformation. AJNR 11:523-531, May{June 1990 Unilateral megalencephaly is a rare anomaly of the brain in which all or part of one hemisphere is enlarged in the absence of somatic hemihypertrophy [1- 8). We recently reviewed the imaging studies of 12 patients with this anomaly; histologic material was available in four of these. In this report, we describe the clinical , radiologic, and pathologic features of this anomaly and relate the pathologic anatomy to a proposed theory of pathogenesis.
    [Show full text]
  • Supratentorial Brain Malformations
    Supratentorial Brain Malformations Edward Yang, MD PhD Department of Radiology Boston Children’s Hospital 1 May 2015/ SPR 2015 Disclosures: Consultant, Corticometrics LLC Objectives 1) Review major steps in the morphogenesis of the supratentorial brain. 2) Categorize patterns of malformation that result from failure in these steps. 3) Discuss particular imaging features that assist in recognition of these malformations. 4) Reference some of the genetic bases for these malformations to be discussed in greater detail later in the session. Overview I. Schematic overview of brain development II. Abnormalities of hemispheric cleavage III. Commissural (Callosal) abnormalities IV. Migrational abnormalities - Gray matter heterotopia - Pachygyria/Lissencephaly - Focal cortical dysplasia - Transpial migration - Polymicrogyria V. Global abnormalities in size (proliferation) VI. Fetal Life and Myelination Considerations I. Schematic Overview of Brain Development Embryology Top Mid-sagittal Top Mid-sagittal Closed Neural Tube (4 weeks) Corpus Callosum Callosum Formation Genu ! Splenium Cerebral Hemisphere (11-20 weeks) Hemispheric Cleavage (4-6 weeks) Neuronal Migration Ventricular/Subventricular Zones Ventricle ! Cortex (8-24 weeks) Neuronal Precursor Generation (Proliferation) (6-16 weeks) Embryology From ten Donkelaar Clinical Neuroembryology 2010 4mo 6mo 8mo term II. Abnormalities of Hemispheric Cleavage Holoprosencephaly (HPE) Top Mid-sagittal Imaging features: Incomplete hemispheric separation + 1)1) No septum pellucidum in any HPEs Closed Neural
    [Show full text]
  • MR Imaging of N Euronal Migration Anomaly
    대 한 방 사 선 의 학 회 지 1991; 27(3) : 323~328 Journal of Korean Radiological Society. May. 1991 MR Imaging of N euronal Migration Anomaly Hyun Sook Hong, M.D., Eun Wan Choi, M.D., Dae Ho Kim, M.D., Moo Chan Chung, M.D., Kuy Hyang Kwon, M.D., Ki Jung Kim, M.D. Department o[ RadíoJogy. Col1ege o[ Medícine. Soonchunhyang University patients ranged in age from 5 months to 42 years with Introduction a mean of 16 years. The mean age was skewed by 2 patients with schizencephaly who were 35 and 42 Abnormalities of neuronal migration Sl re years old. characterized by anectopic location of neurons in the MR was performed with a 0:2T permanent type cerebral cortex (1-9). This broad group of anomalies (Hidachi PRP 20). Slice thickness was 5mm with a includes agyria. pachygyria. schizencephaly. 2.5mm interslice gap or 7.5mm thickness. Spin echo unilateral megalencephaly. and gray matter axial images were obtained. including Tl weighted hcterotopia. Patients with this anomaly present images (TIWI) with a repetition time (TR) of clinically with a variety of symptoms which are pro­ 400-500ms and echo time (TE) of 25-40ms. in­ portional to the extent of the brain involved. These termediate images of TR/TE 2000/38. and T2 abnormalities have been characterized pathologically weighted images (T2Wl) with a TR/TE of 2000/110. in vivo by sonography and CT scan (2. 3. 10-14. Occasionally. sagittal and coronal images were ob­ 15-21). tained. Gd-DTPA enhanced Tl WI were 려 so obtain­ MR appears to be an imaging technique of choice ed in 6 patients.
    [Show full text]
  • Brain Morphometric Analysis in Neurofibromatosis 1
    ORIGINAL CONTRIBUTION Brain Morphometric Analysis in Neurofibromatosis 1 Francis J. DiMario, Jr, MD; Gale R. Ramsby, MD; Joseph A. Burleson, PhD Rationale and Objectives: To investigate the rela- Results: Therewere27patients(20boys,aged1.0-17.7years; tionships between brain and skull base growth in pa- mean age, 8.8 years) and 43 controls (22 boys, aged 0.1-17.7 tients with neurofibromatosis 1 (NF1) compared with years; mean age, 5.9 years). The mean ages between groups healthy control subjects using brain magnetic reso- (boys, girls, and totals) were not statistically different. Sig- nance imaging (MRI) for morphometric analysis. nificant differences were appreciated for 6 of 24 measures. Patients with NF1 had a significantly larger bicaudate width Methods: Evaluated patients included children who (P = .002), biatrial width (P,.001), and biparietal diameter underwent T1- and T2-weighted or dual-echo proton (P = .003), but not hemispheric length. They also had sig- density axial and T1-weighted sagittal brain MRI from nificantly increased iter measures (P = .004), descending sig- January 1, 1988, to December 31, 1995. Study subjects moid sinus (P,.001), and an age-specific increase in brain- (n = 27) received a diagnosis of NF1 by accepted stem height (P = .03) not seen in controls. National Institutes of Health clinical criteria and were compared with an age- and sex-matched control group Conclusions: Patients with NF1 experience dynamic (n = 43). Twenty-four predetermined ventricular and changes in brain morphometry, resulting in a predomi- brain parenchymal dimensions and area calculations nant lateral volume expansion of the supratentorial com- were evaluated. Data were analyzed using 2-tailed t tests, partment and an increasing velocity of brainstem growth x2 analysis, analysis of variance, and analysis of covari- as they age.
    [Show full text]
  • The Identification and Validation of Neural Tube Defects in the General Practice Research Database
    THE IDENTIFICATION AND VALIDATION OF NEURAL TUBE DEFECTS IN THE GENERAL PRACTICE RESEARCH DATABASE Scott T. Devine A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Public Health (Epidemiology). Chapel Hill 2007 Approved by Advisor: Suzanne West Reader: Elizabeth Andrews Reader: Patricia Tennis Reader: John Thorp Reader: Andrew Olshan © 2007 Scott T Devine ALL RIGHTS RESERVED - ii- ABSTRACT Scott T. Devine The Identification And Validation Of Neural Tube Defects In The General Practice Research Database (Under the direction of Dr. Suzanne West) Background: Our objectives were to develop an algorithm for the identification of pregnancies in the General Practice Research Database (GPRD) that could be used to study birth outcomes and pregnancy and to determine if the GPRD could be used to identify cases of neural tube defects (NTDs). Methods: We constructed a pregnancy identification algorithm to identify pregnancies in 15 to 45 year old women between January 1, 1987 and September 14, 2004. The algorithm was evaluated for accuracy through a series of alternate analyses and reviews of electronic records. We then created electronic case definitions of anencephaly, encephalocele, meningocele and spina bifida and used them to identify potential NTD cases. We validated cases by querying general practitioners (GPs) via questionnaire. Results: We analyzed 98,922,326 records from 980,474 individuals and identified 255,400 women who had a total of 374,878 pregnancies. There were 271,613 full-term live births, 2,106 pre- or post-term births, 1,191 multi-fetus deliveries, 55,614 spontaneous abortions or miscarriages, 43,264 elective terminations, 7 stillbirths in combination with a live birth, and 1,083 stillbirths or fetal deaths.
    [Show full text]
  • Endosomal Trafficking Defects Alter Neural Progenitor Proliferation And
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254037; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 Endosomal trafficking defects alter neural progenitor proliferation 3 and cause microcephaly 4 5 Jacopo A. Carpentieri1, Amandine Di Cicco1, David Andreau1, Laurence Del Maestro2, Fatima 6 El Marjou1, Laure Coquand1, Jean-Baptiste Brault1, Nadia Bahi-Buisson3, Alexandre D. 7 Baffet1,4,# 8 9 1- Institut Curie, PSL Research University, CNRS UMR144, 75005 Paris, France 10 2- Centre Épigénétique et destin cellulaire, Université Paris Diderot, CNRS UMR 7216, 75013 Paris, 11 France 12 3- INSERM U1163, Institut Imagine, Necker Hospital, 75015 Paris, France 13 4- Institut national de la santé et de la recherche médicale (Inserm) 14 # Corresponding author: [email protected] 15 16 Abstract 17 Primary microcephaly and megalencephaly are severe brain malformations defined by reduced 18 and increased brain size, respectively. Whether these two pathologies arise from related alterations at 19 the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, 20 leading to cell death. Here, we investigated the consequences of WDR81 loss of function, which cause 21 severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR, 22 and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial 23 progenitor cells knocked-out for WDR81 display reduced proliferation rates, leading to reduced brain 24 size.
    [Show full text]
  • Chapter III: Case Definition
    NBDPN Guidelines for Conducting Birth Defects Surveillance rev. 06/04 Appendix 3.5 Case Inclusion Guidance for Potentially Zika-related Birth Defects Appendix 3.5 A3.5-1 Case Definition NBDPN Guidelines for Conducting Birth Defects Surveillance rev. 06/04 Appendix 3.5 Case Inclusion Guidance for Potentially Zika-related Birth Defects Contents Background ................................................................................................................................................. 1 Brain Abnormalities with and without Microcephaly ............................................................................. 2 Microcephaly ............................................................................................................................................................ 2 Intracranial Calcifications ......................................................................................................................................... 5 Cerebral / Cortical Atrophy ....................................................................................................................................... 7 Abnormal Cortical Gyral Patterns ............................................................................................................................. 9 Corpus Callosum Abnormalities ............................................................................................................................. 11 Cerebellar abnormalities ........................................................................................................................................
    [Show full text]