THE CHOROID PLEXUS AND CEREBROSPINAL FLUID ELSEVIER science & technology books Companion Web Site: http://store.elsevier.com/product.jsp?&isbn=9780128017401 The Choroid Plexus and Cerebrospinal Fluid Josh Neman and Thomas C Chen Resources: · · · · Abstracts Tables and figures (PowerPoint presentation) References Glossary ACADEMIC PRESS THE CHOROID PLEXUS AND CEREBROSPINAL FLUID Emerging Roles in CNS Development, Maintenance, and Disease Progression Edited by Josh Neman Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Thomas C Chen Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA AMSTERDAM • BOSTON • HEIDELBERG LONDON • NEW YORK • OXFORD • PARIS SAN DIEGO • SAN FRANCISCO • SINGAPORE SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125, London Wall, EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-801740-1 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by Thomson Digital Publisher: Mica Haley Acquisition Editor: Natalie Farra Editorial Project Manager: Kristi Anderson Production Project Manager: Lucía Pérez Designer: Matthew Limbert Dedication To my wife, Marjan, the one true constant and enduring supporter of my scientific journey – Josh Neman To my mother, Li Hua Chen, who always believed in me – Thomas C Chen   List of Contributors Jérôme Badaut  UMR 5287-Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Université de Bordeaux, Bordeaux, France Thomas Brinker  Department of Neurosurgery, Warren Alpert Medical School, Brown University, Rhode Island Hospital, Providence, RI, USA Ellen M Carpenter  Department of Psychiatry and Biobehavioral Sciences and Interdepartmental Program in Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, CA, USA Marc C Chamberlain  Department of Neurology and Neurological Surgery, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA Thomas C Chen  Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Cecilia Choy  Division of Neurosurgery, City of Hope and Beckman Research Institute, Duarte, CA, USA Tatsuhiro Fujii  Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Jean-Franỗois Ghersi-Egea BloodBrain Interface Group, Oncoflam Team, and BIP Platform, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Faculté de Médecine RTH Laennec, Lyon, France Sean A Grimm  Cadence Health Brain and Spine Tumor Center, Warrenville, IL, USA Florence M Hofman  Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Alex Julian  Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Vahan Martirosian  Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA   xi xii LIST OF CONTRIBUTORS John Morrison  Department of Neurosurgery, Warren Alpert Medical School, Brown University, Rhode Island Hospital, Providence, RI, USA Josh Neman  Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Michael Novel  Department of History, University of California at Los Angeles, Los Angeles, CA, USA Joshua Youssefzadeh  Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Health Promotion and Disease Prevention, Keck School of Medicine of USC, Los Angeles, CA, USA About the Editors JOSH NEMAN University of Southern California, CA, USA Dr Neman is a research Assistant Professor of Neurosurgery and member of the Norris Comprehensive Cancer Center at the Keck School of Medicine of the University of Southern California Dr Neman received his PhD in Neurobiology at the UCLA David Geffen School of Medicine He then went on to complete his postdoctoral fellowship in Cancer Biology at the City of Hope’s Beckman Research Institute Dr Neman’s current research investigates the biology of primary and metastatic brain tumors His expertise and strengths in neuroscience, cancer, and stem biology have allowed for the development of novel approaches to study the brain and tumor microenvironment, a vantage point that is currently lacking in the field of primary and metastatic brain tumors Dr Neman has published in PNAS, Cancer Research, PLoS One, Spine, Neurosurgery, and Developmental Neurobiology, and has numerous reviews, abstracts, and book chapters to his name He is coeditor of the second edition of “Case Files Neuroscience” in McGraw Hill Medical’s LANGE Case Files series, which was published in October 2014 Dr Neman has been the recipient of multiple research awards including those from National Institutes of Health/National Cancer Institute, California Institute for Regenerative Medicine (CIRM), American Cancer Society, and Susan G Komen Breast Cancer Foundation   xiii xiv ABOUT THE EDITORS THOMAS C CHEN University of Southern California, CA, USA Dr Chen is currently Professor of Neurosurgery and Pathology at the Keck School of Medicine of the University of Southern California Dr Chen is a physician, a board certified neurosurgeon, and the Director of Surgical Neuro-oncology, recognized for his skills as a neurosurgeon and his cutting edge research examining glioma biology Dr Chen is the head of the Glioma Research Group at USC where he focuses on the area of translational research aimed at the development of clinical trials and novel therapeutics for malignant brain tumors He received his MD from the University of California, San Francisco before completing his neurological surgery residency and PhD in pathobiology at the University of Southern California He subsequently completed his fellowship training in spinal surgery from the Medical College of Wisconsin Preface Cerebrospinal fluid (CSF) functions to bathe the brain and spinal cord It is vital for the maintenance of fluid homeostasis within the central nervous system (CNS) The production of CSF by the choroid plexus is tightly regulated providing the necessary nutrients and removing waste that may compromise the normal homeostasis of the CNS Yet the choroid plexus and CSF have been one of the most understudied tissues in neuroscience However, recent work has begun to elucidate how the choroid plexus and CSF regulate development and disease in ways that extend far beyond traditional neurobiology roles As editors, it is our hope to combine new and established work to allow crossdisciplinary discussion from neurosciences (clinical and basic sciences), immunology, and cancer biology to showcase newfound excitement surrounding the choroid plexus and CSF Josh Neman Thomas C Chen   xv 174 GLOSSARY Leptomeningeal metastases  Refers to the spread of malignant cells through the CSF space These cells originated in primary CNS tumors as well as from distant tumors that have metastasized Li–Fraumeni Syndrome  A rare cancer-predisposed hereditary disorder characterized as autosomal dominant Lipopolysaccharide (LPS)  Also called endotoxins, they are large molecules consisting of a lipid and a polysaccharide composed of O-antigen, outer core, and inner core joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals Low-density lipoprotein (LDL)  A lipoprotein sometimes referred to as bad cholesterol because they can transport their content of fat molecules into artery walls, attract macrophages, and thus drive atherosclerosis Low-grade papillomas  Human papillomavirus test result that shows early changes to the cells of the cervix, possibly indicating an HPV infection Lumbar puncture  A diagnostic and at times therapeutic medical procedure Diagnostically it is used to collect cerebrospinal fluid (CSF) to confirm or exclude conditions such as meningitis and subarachnoid hemorrhage and it may be used in the diagnosis of other conditions Lymphocytes  A white blood cell formed in bone marrow and distributed throughout the body in lymphatic tissue (lymph nodes, spleen, thymus, tonsils, and Peyer patches), where it undergoes proliferation M2 monocyte-derived macrophages  Macrophages that function in constructive processes like wound healing and tissue repair, and those that turn off damaging immune system activation by producing anti-inflammatory cytokines Macrometastases  Defined as a relatively large metastasis (see metastasis definition) Macrophages  A type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific to the surface of healthy body cells on its surface in a process called phagocytosis MadCAM-1  Addressins (other name) are proteins that are the ligands to the homing receptors of lymphocytes The task of these ligands and their receptors is to determine which tissue the lymphocyte will enter next Magnetic resonance imaging (MRI)  A medical imaging technique used in radiology to investigate the anatomy and physiology of the body in both health and disease MRI scanners use magnetic fields and radio waves to form images of the body Mannitol  A drug that treats early kidney failure by increasing urination This helps the body get rid of extra fluids Treats brain swelling and increased pressure in the eye Matrix metalloproteinases (MMP)  Enzymes that are capable of degrading all kinds of extracellular matrix proteins Meningioma (papillary variant)  A diverse set of tumors arising from the meninges, the membranous layers surrounding the central nervous system (CNS) The papillary variants are malignant, frequently show bone and parenchymatous invasion and have the potential for extracranial metastasis Mesencephalon  See Midbrain Metencephalon  A developmental categorization of portions of the central nervous system (CNS) that is composed of the cerebellum and the pons GLOSSARY 175 Metrizamide  A nonionic, water-soluble, iodinated radiographic contrast medium used in myelography and cisternography MHC class II receptor  A family of molecules normally found only on antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells Microcolonization  Achievement of more or less stable association of a microorganism with a given environment or microenvironment Midbrain  A portion of the central nervous system (CNS) associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation Middle cerebral artery  One of the two large terminal branches (with anterior cerebral artery) of the internal carotid artery; it passes laterally around the pole of the temporal lobe, then posteriorly in the depth of the lateral cerebral fissure miRNA  A small noncoding RNA molecule (containing about 22 nucleotides) found in plants, animals, and some viruses, which functions in RNA silencing and post-transcriptional regulation of gene expression Multidrug resistance proteins (MDR)  A subfamily of ABC-binding cassette that contribute to drug resistance in cancer cells Multiple sclerosis  Common demyelinating disorder of the central nervous system (CNS), causing patches of sclerosis (plaques) in the brain and spinal cord Myelencephalon  Most posterior region of the embryonic hindbrain, from which the medulla oblongata develops N-acetylaspartate (NAA)  The second-most concentrated molecule in the brain that performs many different functions, including being involved in fluid balance in the brain N-cadherin  Calcium-dependent cell–cell adhesion glycoprotein that functions during gastrulation and is required for establishment of left–right asymmetry Nerve growth factor (NGF)  A growth factor that can be used to prevent or reverse peripheral neuropathy It is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells) Neural plate  The neuroectodermal region of the early embryo’s dorsal surface that in later development is transformed into the neural tube and neural crest Neural tube  The epithelial tube formed from the neuroectoderm of the early embryo by the closure of the neural groove; by complex processes of cell proliferation and organization, the neural tube develops into the spinal cord and brain Neuroinflammation  Inflammation of the nervous tissue that may be initiated in response to a variety of cues, including infection, traumatic brain injury, or autoimmunity Neuroprotection  The relative preservation of neuronal structure and/or function Neurotrophins  A family of proteins that induce the survival, development, and function of neurons Neurulation  The folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube The embryo at this stage is termed the neurula Nocardiosis  An infectious disease affecting either the lungs (pulmonary nocardiosis) or the whole body It is due to infection by bacterium of the genus Nocardia, most commonly Nocardia asteroides or Nocardia brasiliensis 176 GLOSSARY Organic anion transporters (Oats)  A membrane transport protein or “transporter” that mediates the transport of mainly organic anions across the cell membrane Organic anion transporting polypeptides 1, Oatp2  An uptake transporter that plays an important role in drug disposition and is responsible for the hepatic uptake of drugs and endogenous compounds Organic anion transporting polypeptides 2, Oatp1  Similar to OATP2 Organotropism  The special affinity of chemical compounds or pathogenic agents for particular tissues or organs of the body Otx2 transcription factor  A transcription factor that may play a role in brain and sensory organ development P-glycoprotein (P-gp)  An important protein of the cell membrane that pumps many foreign substances out of cells It is an ABC transporter P-selectin glycoprotein ligand (PSGL-1)  A high affinity counter-receptor for P-selectin on myeloid cells and stimulated T lymphocytes that plays a critical role in the tethering of these cells to activated platelets or endothelia expressing P-selectin P-selectins  A cell adhesion molecule (CAM) on the surface of activated endothelial cells, which line the inner surface of blood vessels and activated platelets They play an essential role in the initial recruitment of leukocytes (white blood cells) to the site of injury during inflammation Paget’s “seed and soil” hypothesis  A hypothesis by Stephen Paget about the nature of tumor metastasis The outcome of cancer metastasis depends on multiple interactions between selected metastatic cells and homeostatic mechanisms unique to some organ microenvironments Paracellular diapedisis  Transendothelial migration of leukocytes between endothelial cells Paravascular route  A route of solute exchange between the interstitial fluid of the brain parenchyma and the CSF via paravascular spaces Pericytes  One of the slender, mesenchymal-like cells found in close association with the outside wall of postcapillary venules; it is relatively undifferentiated and may become a fibroblast, endothelial cell, or smooth muscle cell Phospho-tau181 (p-tau)  Phosphorylated tau proteins can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer’s disease, fronto-temporal dementia, and other tauopathies PICA – posterior inferior cerebellar artery  The largest branch of the vertebral artery, is one of the three main arterial blood supplies for the cerebellum, part of the brain Pinocytotic vesicles  A vesicle, a fraction of a micrometer in diameter, containing fluid or solute being ingested into a cell by endocytosis Positron emission tomography (PET)  A nuclear medicine, functional imaging technique that produces a three-dimensional image of functional processes in the body by using a form of radioactive glucose as a tracer Posterior choroidal arteries (PChA)  One of a pair of blood vessels that supply oxygenated blood to the posterior aspect of the brain (occipital lobe) in human anatomy Posterior choroidal artery  Usually seen as two branches of the P2 segment of the posterior cerebral artery that supply the choroid plexus of the third ventricle GLOSSARY 177 (posterior medial choroidal artery) and parts of the choroid plexus of the lateral ventricle (posterior lateral choroidal artery) Posterior communicating arteries (PCoA)  Arteries at the base of the brain that form part of the circle of Willis and connect the ICA and PChA Posterior inferior cerebellar artery (PICA)  The largest branch of the vertebral artery, is one of the three main arterial blood supplies for the cerebellum, part of the brain Prosencephalon  The rostral-most (forward-most) portion of the brain that controls body temperature, reproductive functions, eating, sleeping, and any display of emotions Proteoglycans  Heavily glycosylated proteins that are a major component of the animal extracellular matrix, the “filler” substance existing between cells in an organism Radiotherapy  Therapy using ionizing radiation, generally as part of cancer treatment to control or kill malignant cells Receptor for advanced glycation end products (RAGE)  A transmembrane receptor of the immunoglobulin super family hypothesized to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer’s disease, and even some tumors Receptor-related proteins (LRPs)  Lipoprotein receptor proteins that mediate endocytosis of cholesterol-rich LDL Rho-associated kinases (ROCKs)  Kinase involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton Rhodamine 123  A tracer dye within water to determine the rate and direction of flow and transport Roof plate  A neural structure in the embryonic nervous system, part of the dorsal side of the neural tube, that involves the communication of general somatic and general visceral sensory impulses The caudal part later becomes the sensory axon part of the spinal cord Sjögrens syndrome  A chronic autoimmune disease in which the body’s white blood cells destroy the exocrine glands, specifically the salivary and lacrimal glands, that produce saliva and tears, respectively Sonic hedgehog signaling  A signaling pathway that transmits information to embryonic cells required for proper development Spemann and Mangold organizer  A cluster of cells in the developing embryo of an amphibian that induces development of the central nervous system (CNS) ST6GALNAC5  An enzyme that belongs to a family of sialyltransferases that modify proteins and ceramides on the cell surface to alter cell–cell or cell–extracellular matrix interactions It is a mediator of cancer cell passage through the blood– brain barrier Stereotactic radiosurgery  A minimally invasive form of surgical intervention that makes use of a three-dimensional coordinate system to locate small targets inside the body to then perform destruction of precisely selected areas of tissue using ionizing radiation Sturge–Weber syndrome  A rare congenital neurological and skin disorder It is characterized by abnormal blood vessels on the brain surface Normally, only one side of the brain is affected 178 GLOSSARY Subarchnoidal space  The anatomic space between the arachnoid membrane and pia mater Subtotal resection (STR)  A portion of the tumor can still be seen on a postoperative brain scan Subventricular zone  A paired brain structure situated throughout the lateral walls of the lateral ventricles thought to be one of the two places where neurogenesis has been found to occur in the adult brain Superior cerebellar artery (SCA)  An artery in the brain that arises near the termination of the basilar artery and supplies half of the cerebellum and parts of the midbrain T cells  A type of lymphocyte (in turn, a type of white blood cell) that plays a central role in cell-mediated immunity T1- and T2-weighted images  MRI images used to differentiate anatomical structures mainly on the basis of T1 or T2 values Tanycytes  Special ependymal cells found in the third ventricle of the brain, and on the floor of the fourth ventricle and have processes extending deep into the hypothalamus It is possible that their function is to transfer chemical signals from the cerebrospinal fluid to the central nervous system (CNS) Tela choroidea  A structure found in the ventricles of the brain (third and fourth) TGF-b2  Transforming growth factor-beta (TGF-b2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development It is known to suppress the effects of interleukindependent T-cell tumors Th1 cells  The host immunity effectors against intracellular bacteria and protozoa Th17  A subset of T helper cells producing interleukin 17 (IL-17) whose role is to provide antimicrobial immunity at epithelial/mucosal barriers Th2 cells  The host immunity effectors against extracellular parasites including helminths The metastatic cascade  The multistep process of a tumor leaving its original location and spreading to another part of the body, or metastasizing Third ventricle  One of four connected fluid-filled cavities comprising the ventricular system within the human brain It is a median cleft in the diencephalon between the two thalami, and is filled with cerebrospinal fluid (CSF) Thyroid hormone (T4)  Tyrosine-based hormone produced by the thyroid gland that are primarily responsible for regulation of metabolism TNF-a  Cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction Total-tau (T-tau)  All tau protein isoforms, a measure of which can be used as a marker for neuro-degeneration Tau is a microtubule-associated protein Toxoplasmosis  A parasitic disease caused by the protozoan Toxoplasma gondii The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid (cat) family TP53 tumor suppressor  A protein that conserves stability by preventing genome mutation and thus prevents, or suppresses cancer Transcellular diapedisis  Transendothelial migration of leukocytes through individual endothelial cells Transendothelial migration  The movement of leukocytes from different endothelial cells as needed, mainly during inflammation GLOSSARY 179 Transporters  Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations Transthyretin (TTR)  A serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol Trastuzumab (Herceptin)  A monoclonal antibody that interferes with the HER2/neu receptor Its main use is to treat certain breast cancers Tuberculosis  A widespread, and in many cases fatal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis Tumor necrosis factor (TNF)  A group of cytokines that can cause cell death and have been implicated in cancer regression TWIST1  A basic helix–loop–helix transcription factor that has been implicated in cell lineage determination and differentiation VCAM-1  Vascular cell adhesion protein also known as vascular cell adhesion molecule (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the VCAM1 gene VCAM-1 functions as a cell adhesion molecule VEGF  A signal protein produced by cells that stimulates vasculogenesis and angiogenesis It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate Ventricular system  A set of four interconnected cavities (ventricles) in the brain, where the cerebrospinal fluid is produced Ventriculo-cisternal perfusion (“Pappenheimer”)  Method for measuring cerebrospinal fluid formation rate Ventriculo-peritoneal shunt  Surgery to treat excess cerebrospinal fluid in the brain Villous hypertrophy  A condition characterized by overproduction of cerebrospinal fluid by bilaterally symmetric and enlarged, yet histologically normal, choroid plexis Vimentin positivity  Vimentin is a type of protein whose presence, or positivity, turns out to be an indicator for sarcomas and other mesenchymal neoplasm Virchow–Robin spaces  The immunological spaces between the arteries and veins (not capillaries) and pia mater that can be expanded by leukocytes Whole brain radiation therapy (WBRT)  A mainstay of treatment in patients with both identifiable brain metastases and prophylaxis for microscopic disease Wnt signaling  A group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell YKL-40  A secreted glycoprotein whose exact physiological role is not known, but it has been implicated in the development of inflammatory diseases YKL-40 is secreted by various cell types including macrophages, chondrocytes, and some types of cancer cells Zonula occludens  Tight junctions (other name) are closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid Subject Index A Ab plaque formations, 144 Absorption rates, 43, 44 Acetazolomide inhibits carbonic anhydrase in choroid epithelial cells, 162 weight loss, 162 N- Acetylaspartate (NAA), 94 AD See Alzheimer’s disease (AD) Adenosine, 33 Adhesion proteins, AICA See Anterior inferior cerebellar artery (AICA) Alzheimer’s disease (AD), 54, 130, 162 AQP4 expression, 144 CSF levels of AB, 162 etiology, 162 Amino acids, 10 transport, 84 Amyloid-B (AB) deposition, 162 Amyloid plaques, 162 Anencephaly, 18 Aneurysms, 11 Angiogenesis, 33, 82 Anterior choroidal arteries (AChA), 11 Anterior circulation, 157 Anterior inferior cerebellar artery (AICA), 11, 157 Antigen presenting cell (APC), 34, 116, 122, 124 Antigens, 116 Anti-HIV protease azidothymidine (AZT), 158 Anti-inflammatory cells, 33 Antioxidant enzymes, 134 APC See Antigen presenting cell (APC) Apicobasal extension, 19 Apoptosis, 82, 90, 96 Aquaporin, 23 aquaporin-1, 10, 11 transport, 10 aquaporin-4, 140 distribution, 135 channels, 10 Arachnoid granulations, 22 Arginine vasopressin (AVP), 162 Artificial choroid plexus, 52 Astrocytes, 43, 82, 85, 90, 113 Astrocytic end-feet, 32 ATP-binding cassette (ABC) protein, 134 Atrial natriuretic peptide (ANP) in choroid plexus epithelial cells, 162 Atypical choroid plexus papilloma (ACPP), 66 Auto-antigens, 119 Autoimmune disease, 106, 110, 118 B BBB See Blood-brain barrier (BBB) BCSFB See Blood-cerebrospinal fluid barrier (BCSFB) Benzamil, Bicarbonate, intracellular, Biomarkers, 144, 146 BLMB See Blood-leptomeningeal barrier (BLMB) Blood-brain barrier (BBB), 10, 24, 30, 41, 104, 122, 156 barbiturates, intravenous dose, 159 and brain metastases, 89–90 brain regions that lack, 84 common problems traversing, 92–94 dysfunction in cancer, 87–88 efflux mechanisms, 158 in extravasation and brain colonization, 90 maintain ionic and molecular homeostasis, 84 mediators for cancer cells penetrating, 92 181 182 Subject Index Blood-brain barrier (BBB) (cont.) requirements for a successful BBB-traversing drug, 95–97 successful drug delivery through, 91–92 vs blood–CSF barrier, 83–87 Blood–cerebrospinal fluid barrier (BCSFB), 10, 42, 86, 115 fulfills, 136 histological features of, 132 neuroprotective mechanisms, 136 role of pore-forming claudins at, 134 in vivo experiments, 133 Blood–choroid plexus barrier (BCPB), 30 Blood–CSF barrier See Blood-cerebrospinal fluid barrier (BCSFB) Blood-leptomeningeal barrier (BLMB), 30, 32, 33 Bone morphogenetic proteins (BMPs), 17 antagonists, 17 bone morphogenetic protein (BMP4) in induction of choroid plexus, 161 receptor expression, 24 signaling, 24 loss of, 24 Brain adult mammalian, 21 cortisol travel and binds to receptors on neurons, 110 extracellular fluid, 137 extracellular space (ECS) of, 47 infiltration of leukocytes into, 110 inflammation, 85 injury, 88–89 interstitial fluid composition, 162 metastases, 78 in the US population, 78–79 neurogenesis, 110 parenchyma, 29, 32, 43 lipid-insoluble molecules, 138 plasticity, 110 and function deteriorated, 106 tumor patients, 44 Brain-derived neurotrophic factor (BDNF), 110 5-Bromo-2-deoxyuridine (Brdu), C Calcarine, 11 Calcium, 90 CAM See Cell adhesion molecules (CAM) Cancer BBB dysfunction in, 87 cells, 79, 80, 82 esophageal-cancer-related gene-4 (ECGR-4), 160 herceptin delivery to breast cancer brain metastasis lesions, 94 leptomeningeal, 158 Carbachol, 118 Carbonic anhydrase, 9, 133, 162 acetazolamide inhibit, 162 choroid epithelial cell, 162 Carcinomas, 66 Caudal brain vesicles, 21 Caudal neuropores, CCR6+ T helper (Th)17 cells, 115 CD68, glycoprotein, 114 CD4+ T lymphocytes, 141 Cell adhesion molecules (CAM), 19, 81, 117 Cell death, Cell encapsulation technology, 52 Cell polarity, 19, 133 Cell proliferation, 22 Central nervous system (CNS), 1, 15, 30, 104, 130 AQP1 and distributions, 135 barriers, principal of, 30 blood–brain interfaces, 130 homeostasis, main barriers in, 84 specific macrophages, 104, 111 tumors, 66 Cerberus, 17 Cerebellum, 21 Cerebral artery, 157 Cerebral hemispheres, 2, 20 Cerebrospinal fluid (CSF), 8–10, 21, 35–37, 130, 139 barrier, 156 biomarkers, 146 YKL-40, 146 Subject Index choroidal production, 45 choroid-plexus-epithelial cells secretion, 21, 23 circulation, 137 containing key growth factors, 37 CP–CSF system rich source of, 36 CP major site for formation, 42 delivers thyroid hormone, 36 delivery and choroid plexus targeting, 160 methods, 160–161 embryonic, 26 exosomes and miRNA, 146 flow, 159 through ventricular system, fluxes, 32, 133 functional aquaporin channels and, 10 glucose, 36 mechanical buffer to protect brain, 35 microtubule-associated protein, 146 organic substances, 10 pressure, 44 production, rates of flow, 43 regulates amino acid entry into, 36 reservoir for growth factors and, 22 within ventricles into cisterna magna, 21 Cervical flexure, 20 Chemokine CC ligand (CCL)20, 115 Chemokines, 89, 104, 110, 115, 117, 142 Chemotherapeutic agents, 90 Choline acetyltransferase (ChAT), 48 Chordin, 17 Choroidectomy, 45 Choroid fissures, 5, development, Choroid plexus (CP), 15, 107, 130 anatomical considerations, 31, 157–158 as an immune modulator, 33 bacteriophage synthesized ligandmediated targeting, 160 CNS trauma, 143 183 complete absence of, 24 composed of, 24 CP–CSF system, 141 development, 23–26 Otx2 in regulating, embryonic origin, 131 epithelial cells, 130 exhibiting abnormal formations, facilitates CNS immunosurveillance, 34 formation, functions of, 26 hindbrain, 23 immune cells, 144 inducible Tregs (regulatory T cells), 33 inflammatory cells in, 32 mammalian, 23 polypeptides synthesis, 137 produce bioactive peptides and growth factors, 36 progenitors, 23 regulates metal ions in CSF, 37 secreted peptides, 41 Shh expression required for biogenesis of, 25 significant portal for macrophage entry into, 32 site for secretion of biologically active compounds, 46 stromal cells, 30 transcriptional changes in, 120 treatment with BMP4, 25 develop epithelial polarity and to express genes, 25 vascular supply of, 11 zebrafish to analyze genetic elements for development of, Choroid plexus carcinoma (CPC), 66, 163 pathology, 68 macroscopic appearance, 68 microscopic appearance, 69 prognosis, 72 radiologic appearance, 68 radiotherapy/chemotherapy, 70–71 184 Subject Index Choroid plexus epithelial cell (CPE), 23, 157, 160 synthesis of CSF, 21, 23, 157 Choroid plexus papilloma (CPP), 66, 163 pathology, 68 macroscopic appearance, 68 microscopic appearance, 69 prognosis, 71–72 radiologic appearance, 68 radiotherapy/chemotherapy, 70 Cilia, 22, 30 malfunctions, 22 Cingulin protein, 87 Circulating tumor cells (CTCs), 79 Claudins, 7, 32, 86 CNS See Central nervous system (CNS) Colonization, 82 Computed tomography (CT) scan, 45, 78 to assess ventricular washout of metrizamide, 45 utilized to delineate brain lesions for, 78 Cortisol, 120, 122 inflammation in periphery, 121 neurogenesis inhibited by, 121 overstimulation of neurons, 121 CP See Choroid plexus (CP) CPC See Choroid plexus carcinoma (CPC) CPP See Choroid plexus papilloma (CPP) Crizotinib, 93 CSF See Cerebrospinal fluid (CSF) Cuboidal-ectodermic cells, 23 Cuboidal ependymal cells line, Cuboidal epithelial cells, 30 cyclic AMP (cAMP), 85 Cyclooxygenase (COX2), 79 Cytokines, 33, 36, 104, 108, 110, 117 inhibit adult neurogenesis and, 110 Cytoskeleton, 19 Cytotoxicity, 90 D Dendritic cells (DC), 34, 119 Depocyt (liposomal Ara-C) methotrexate of, 163 Desmosomes, 22, 24 Diencephalic–telencephalic sulcus, Diencephalon, 20, 21 Drug delivery, 158–160 challenges in treatment, 92 to choroid plexus, clinical implications, 162–163 leptomeningeal, 158 through BBB, 91 use of immune cells, 161 via choroid plexus–CSF barrier pros and cons, 158–159 Drug transport, 10 E Ectoderm, 15 Efflux transporters, 84 Abcc1, Abcc4, Slco1a5, and Slc22a8, 134 Elacridar, 93 Embryogenesis, 2, 19 Embryonic brain ventricular system, Embryonic cerebrospinal fluid (eCSF), Encapsulated choroid plexus cells, 53 Encapsulated mesenchymal stem cells, 54–55 Endoderm, 15 Endoplasmic reticulum, 118 Endosome, 119 Endothelial cell, 24, 30, 85, 157 barrier, 30 Ependymal cells, 22 Ependymal cells line, 30 Epidermal growth factor (EGF), 160 Epidermal growth factor receptor (EGFR) bacteriophage targeting, 159 Epidermal growth factor receptor ligand (HBEGF), 79 Epidermal growth factor (EGF) targeting for gene delivery, 160 Epilepsy, 110 Epiplexus cells, 34, 117, 131 Epithelial membrane antigen (EMA), 69 E-selectins, 81 Esophageal-cancer-related gene-4 (ECGR-4), 160 Exchangers, Subject Index Extracellular matrix (ECM), 32, 133 Extracellular space (ECS), 30, 47, 93, 130 Extravasation in cancer cells, 81–82 “docking” stage of, 81 F F-actin, 19 Fc neonatal receptor, 134 Fenestrated endothelial cells, 31, 156 Ferroportin, 37 Follistatin, 17 G Genetic lineage analysis, 24 Glial cells, 104 Glioma, 94 Gliosis, 52 Glomus choroideum, GLUT transports, 36 Glycoproteins, 81 Glymphatic system, 139–141 Granulocytemacrophage colony-stimulating factor (GM-CSF), 34 Green fluorescent protein, Growth factors, 33 H Hematocrit, 43 Hemianesthesia, 11 Hemianopsia, 11 Hepcidin, 37 Hindbrain Shh as instructive signal for choroid plexus, 25 transcription factor maintain choroid plexus cells of, Hippocampus, 110 HLA-DR immunostained cells, 114 Homeostasis, 6, 8, 33, 46, 83, 84, 88, 134 human neuronal growth factor (hNGF), 52 Hydrocephalus, 22, 45 Hydrolases, 119 I IDO (indoleamine-2, 3-dioxygenase), 33 Immune cell infiltration, 107 185 Immune cells, 161 in neural parenchyma, 106 Immunosuppression, 143 Immunotherapy, 123 Inflammation, 32, 110 chronic, 117 Innate immunity, in periphery and CNS, 105, 108 Insulin-like growth factor (IGF-1), 110 Insulin-like growth factor-II (IGF-2), 87 Internal carotid artery (ICA), 11 Interstitial fluid (ISF), 30, 130 filling, 130 in neurodegenerative diseases, 144 rates of flow, 43 Intracranial pressure, 11, 44 Inulin, 44 Ion channels, Ionic flux, 133 Ischemic injury, 11 J Junctional adhesion molecule (JAM), 86, 133 K K+ levels, 133 Kolmer cells, 131 L Lacrimal glands, 118 chronic stimulation of, 120, 121 epithelial cells, 118 overstimulation of, 121 L1 cell adhesion molecule (L1CAM) serpins protecting, 90 LDL receptor-related proteins (LRPs), 136 Leptomeninges carcinomatosis, 163 metastasis, 88 seeding of carcinoma cells, 163 Leukocytes, 32, 123, 141 cytoskeletal changes aid, extravasation process, 81 JAMs, involved in, 87 newly transplanted, 124 Lie–Fraumeni syndrome, 72 Lipocalin 2, 37 186 Subject Index Lipopolysaccharide (LPS), 117 Low-density lipoprotein (LDL), 136 L-proline, 10 Lumbar puncture, 44, 146 Lymphocytes, 122 M Macrophages, 33–34 enter CNS parenchyma, 33 M1 macrophages, 33 enter CNS through, 33 express CCR2-receptor for ligand CCL1, 33 leptomeninges support entrance of, 33 M2 macrophages, 33, 107 breach CP barrier, 33 proinflammatory, 116 Magnetic resonance imaging (MRI), 146 contrast-enhanced, 78 CSF flow from subarachnoid space, 140 flow measurements, 45 Mannitol, 85 Masserman technique, 44 Matrix metalloproteinases (MMP), 86 Mechanical injury, 33 Medulla oblongata, 20 Memory B-cells, 116 Mesencephalon, 2, 20, 21 Mesenechymal-like fibroblasts, 30 Mesoderm, 15 Metastases brain, 78–79 to choroid plexus, 83 eptomeningeal, 72 Metastatic cascade, 79 colonization, 82 extravasation in cancer cells, 81–82 forms of invasion, 80 steps of a circulating tumor cell, 80 theory of organotropism, 81 Metencephalon, 20, 21 Metrizamide, 45 Metronomic biofeedback pump (MBP), 160 components, 160 leptomeningeal carcinomatosis treatment, 160 MHC class II receptor, 104 Microcolonization, 82 Microglia, 85 Microperoxidase, 30 Microtubule polymerization, 19 Microvilli, 30 Midbrain–hindbrain boundaries, Molecular mimicry, 118 Monodelphis domestica model, choroid plexus epithelium, to identify cells functionally mature, maintaining correct CSF composition and, Morphogenesis, of brain tissue, cell adhesion molecules also play a role in, 19 determined by, MS See Multiple sclerosis (MS) Mucosal addressin cell adhesion molecule (MAdCAM)-1, 115 Multidrug resistance proteins (MDR) efflux drugs, 93 Multiple sclerosis (MS), 111–112 pathogenesis, 112–113 Mutation, TP53 tumor suppressor gene, 66, 72 Myelencephalon, 20, 21 Myeloid cells, 142 N N-Cadherin, 19 expression in mice, 19 mutant, Neural plate, 16–20 Neural-progenitor cells, 20 Neural tube, 1, formation, 16–20 Neuro-blastomas, 83 Neurodegenerative diseases, 144 brain diseases – biomarkers, 146 clearance of metabolites, 144 Subject Index CSF/ISF process, 144 multiple sclerosis and AD, 143 pathophysiological process, 137 pathophysiology/biomarkers, 144, 146 Neuroepithelial morphogenesis, Neuroepithelial tissue, 2, 24 Neurogenesis, 24, 110 Neuroimmune surveillance, 141 choroid plexus–CSF system in, 141–143 Neuroinflammation, 34, 106, 162 associated with multiple sclerosis and AD, 143 conditions, 161 Neuronal biomarkers, 94 Neuronal processes, 32 Neuropores, 18 Neuroprotection, 136 Neuroradiological investigations, 45 Neuroregeneration, 46 Neurotrophic factors, 110, 121 Neurulation, 2, 17 Noggin, 17 Notch3 signaling, 69 Notochord cells, 17 lengthen along apico-basal axis, 18 O Occludins, 7, 32, 33, 85, 86 tyrosine phosphorylation in, 96 Occlusions, 11 Oligodendrocytes, 121, 123, 124 Ommaya reservoir via lumbar intrathecal delivery, 158 Organic anion transporters (Oats), 93 Organic anion transporting polypeptides, 10 Organizer, 16 Organotropism, 79 Osmotic gradient, 10 Otx2 coding, Otx2 transcription factor, Ouabain, P 187 Papillomas, 66 “Pappenheimer” technique, 44 Paracellular diapedisis, 32 Paravascular flow, 139–141 Parieto–occipital branches, 11 Peptides distribution, pharmacological considerations, 47–51 Pericytes, 25, 32 Perivascular spaces (PVS), 48 fluid movements along, 51 morphology, 49 P-glycoprotein (P-gp), 93 Phagocytotic cells, 116 Phosphoinositide-3-kinase (PI3K) pathway, 96 Phosphorylation of myosin light chain, 19 tyrosine, 96 Pinocytotic vesicles, 30, 32 Pittsburgh Compound B (PiB), 146 Plasma-protein, 136 Platelet-derived growth factor receptor, 69 Platelet/endothelial cell adhesion molecule-1 (PECAM-1), 95 Pluripotent-embryonic-stem cells, 24 Positron emission tomography (PET), 146 Posterior cerebral artery (PCA), 11 Posterior choroidal arteries (PChA), 11 Posterior communicating artery (PCoA), 11 Posterior inferior cerebellar artery (PICA), 11, 157 Potassium rectifying channel 4.1 (Kir4.1), 144 Primary choroid plexus tumors, 66, 67 Primary neuroinflammatory diseases, 141 choroid plexus–CSF system in, 141–143 Primitive neural tube, Progenitor cells, 20, 21, 37 Prosencephalon, 20 Proteases, 33, 119 188 Subject Index Protein complex, to form cohesive neuroepithelium, Proteomic, 79 P-selectin glycoprotein ligand (PSGL-1), 141 P-selectins, 81, 141 Pseudotumor cerebri, 162 PVS See Perivascular spaces (PVS) Spina bifida, 19 Spinal cord (SC), 1, 15, 33 parenchyma, 33 Src signaling, 96 Stromal cells, 23, 157 -derived factor 1-alpha, 82 Sturge–Weber syndrome, 68 Subarachnoid space, 21, 30, 32 Superior cerebellar artery (SCA), 11 R T Radiotracer experiments, 43 Radiotracer studies, 45 Receptor for advanced glycation end products (RAGE), 95 Relative cerebral blood volume (rCBV), 94 Retinoblastomas, 83 Rho-associated kinases (ROCKs), 19 Rhodamine 123, Rho GTPases, 19, 85 Rhombencephalon, 20 Rho/Rac signaling pathway, 96 S SC See Spinal cord (SC) Scanning electron microscopy, Secondary choroid plexus tumors, 72 Secretion, limiting factor, 131 “Seed and soil” hypothesis, 79 Seizures, 110 Shh-expressing cells, 25 Shh signaling, 25 Shroom3 protein, 19 Sjögrens syndrome, 118, 120, 121 Slc22 families, 134 Slco families, 134 Sodium-coupled bicarbonate cotransporter, 10 transporters, Sodium–hydrogen ion exchangers, Sodium–potassium ATP pumps, 4, Somatic therapy, with engineered choroid plexus cells, 161 Sonic Hedgehog (Shh), 4, 20 role in ventricle formation, Tanycytes, 7, 22 T-cells, 35, 104 activated, 116 activity, 33 cytotoxic, 122 interactions, 106 migration, molecular mechanisms, 115 and myeloid cell infiltration, 141 neutrophils and monocytes, 144 in physiological condition, 143 Tela choroidea, Telencephalon, 20, 21, 24 Therapeutic efficacy, of neuropeptides, 52 Thyroxine transport protein, 10 Toll-like receptors, 110 TP53 suppressor gene, 66 Tracer experiments, 137 Transcellular diapedisis, 32 Transcription factor, TWIST1, 69 Transendothelial migration (TEM), 81 cytokine-activated, 81 Transferin, 37 Transmembrane protein families, 86 Transthyretin, 10, 23, 87 lack of expression, 24 Trastuzumab, 94 Tryptophan synthesis, 33 Tumor angiogenesis, 24 Tumorgenesis, 69 Tumor necrosis factor (TNF), 94 -related apoptosis-inducing ligand pathway, 69 TWIST1 gene, 90 V Subject Index Vascular cell adhesion molecule (VCAM)-1, 115 expression, 33 Vascular-endothelial cells, 24 Vascular endothelial growth factor (VEGF), 82, 89 endothelial cells, 131 Vascularity, 25, 82 Ventricular system CSF flow through, development of, 15, 21–22 Ventriculo-cisternal/ventriculo-lumbar perfusion techniques, 44 Ventriculostomy, 46 Vertebral artery, 157 Virchow–Robin spaces, 138 W Water transporters, 43 WM lesions, 113 Wnt signaling, 19 Z Zebrafish formation of eCSF depends on, mutants, Zonula occludens proteins, 85–87 189 ... OF THE CHOROID PLEXUS The choroidal arteries are the main vascular support systems for the choroid plexus There are two main choroidal arteries: the anterior choroidal arteries (AChA) and the. .. Cyclooxygenase Choroid plexus Choroid plexus carcinoma Choroid plexus epithelial cell Choroid plexus papilloma Choroid plexus tumors Cerebrospinal fluid Craniospinal axis radiotherapy Computed... branch and supplies among other structures the choroid plexus 12 1.  Introduction to the Ventricular System and Choroid Plexus of the lateral ventricles The vascular supply to the choroid plexus