Neurobiology of brain disorders : biological basis of neurological & psychiatric disorders

793 Pages·2015·66.63 MB·English

by  Michael J. Zigmond

NEUROBIOLOGY
OF BRAIN
DISORDERS
BIOLOGICAL BASIS OF
NEUROLOGICAL AND PSYCHIATRIC
DISORDERS
Edited by
M J. Z
ichael igMond
Departments of Neurology, Neurobiology, and Psychiatry, University of Pittsburgh,
Pittsburgh, Pennsylvania, USA
l P. R
ewis owland
Neurological Institute, Columbia University Medical Center,
New York, USA
J T. c
osePh oyle
Harvard Medical School, McLean Hospital, Belmont,
Massachusetts, USA
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Dedication
To our students and patients who, over the years, have
motivated us to produce this book
and
To Nancy Wexler, whose commitment to research and
education about brain disorders has been an inspiration to
each of us.
Preface
Interest in understanding the basis of neurological and with PD, and that the behavior of reserpinized ani-
psychiatric disorders is thousands of years old. People mals and patients with PD could both be improved by
of China and India, as well as the Egyptians and Greeks, L-dopa, resulted in the use of drugs that activate dopa-
all had ideas about how the brain worked and what mine receptors in the treatment of PD. This sequence of
caused the occasional functional abnormalities that they events, conducted over a period of less than 10 years, is
observed. Moreover, they often developed interventions a landmark in the use of behavioral and neurochemical
to relieve symptoms, if not treat the disease. Indeed, the approaches for studying the nervous system, and was
origins of neuroscience probably go back even farther. largely responsible for initiating the twin fields of neuro-
For example, trephination of the skull is thought to have pharmacology and biological psychiatry.
been practiced as long as 7000 years ago and may have There have been many other such moments in the
been designed to release evil spirits believed to be the emergence of biological approaches to neurological and
cause of brain disorders. Since then, some of the ancient psychiatric disorders. For example, Ernst Wilhelm von
treatments have been found to be quite effective and Brücke and colleagues, as well as their students (e.g.
have even served as the basis for much more recent Sigmund Freud), working in Austria during the latter
interventions. However, the modern era of inquiry into half of the nineteenth century, were among the first to
the neurobiological basis of brain disorders did not apply laboratory methods to the study of the nervous
begin until the nineteenth century. Several milestones system and to suggest that behavior could be under-
along the path of that inquiry can be identified; here we stood through an understanding of biological events.
mention just a few. The introduction of electrophysiology into neuroscience
Rauwolfia serpentina is a shrub from which the people can be traced as far back as the seventeenth century to
of India have been making a medicinal tea for thousands the work of Jan Swammerdam in Holland, although it is
of years.1,2 Among the many conditions for which it was Luigi Galvani, working in Italy in the nineteenth century
used was “moon disease”, which we now recognize as using nerve–muscle preparations, who is usually cred-
psychosis. In the early 1950s it was determined that most ited with initiating electrophysiology as an approach
of the tranquilizing effects of the plant extracts resulted for understanding how the nervous system functions.6
from a compound that was named reserpine. Over the Neuropathology was introduced by Paul Oscar Blocq
next decade, Arvid Carlsson and colleagues, work- and Georges Marinesco in the late nineteenth century in
ing first at the US National Institutes of Health, then at Paris. During a postmortem examination, they found a
the University of Lund, and finally at the University of tumor in the contralateral substantia nigra of a patient
Göteborg, Sweden, demonstrated that the effects of this who had exhibited the symptoms of PD, as reviewed by
natural product were due to its depletion of the neu- Catala and Poirier.7 In short, many of the principal tools
rotransmitter dopamine from the striatum, as described for understanding the neurobiology of brain disorders –
in the Nobel Lecture by Arvid Carlsson.3 This led to sev- neuropathology, histochemistry, electrophysiology,
eral key observations, including the discovery by Oleh biochemistry, and behavior – gradually emerged over
Hornykiewicz in Vienna that Parkinson disease (PD) the past 250 years as a result of investigators working
was associated with a loss of striatal dopamine and that in many different areas of the world. In the 1970s, two
many of the motor symptoms of PD could be reversed more approaches were added, molecular neurobiology
by administration of the dopamine precursor, L-dopa and brain imaging. (For an excellent treatise on the
(see Chapter 19).3,4 history of neuroscience, see Origins of Neuroscience: A
The use of reserpine as a treatment for psychosis, History of Explorations into Brain Function, by Stanley
together with the discovery of chlorpromazine for the Finger,8 and excellent articles in The Journal of the History
treatment of schizophrenia and the realization in 1963 of Neuroscience. For a timeline and an extensive bibliog-
that it, too, acted by reducing dopaminergic transmis- raphy of the history of neuroscience, see also the website
sion,5 led to the focus on reducing dopaminergic trans- of Eric Chudler at the University of Washington.9 Addi-
mission to treat schizophrenia (see Chapter 39). Likewise, tional material can be found on the website of the Society
the observation that a loss of dopamine was associated for Neuroscience.10)
xiii
xiv PREFACE
Our decision to assist in the teaching of the neu- But this raises the question: Why this abiding interest
roscience of brain disorders by preparing this text- in helping to stimulate training in the neurobiology of
book began to take shape over three decades ago. The disease? It is not because we believe that basic research in
Marine Biological Laboratory (MBL) in Woods Hole, this field is less important than research that more directly
Massachusetts (USA) twice played a role in the origins confronts disease. On the contrary, virtually all of our
of the project, as it has in the development of neuro- current understanding of the biological basis of brain dis-
science more generally.11,12 The first event occurred orders stems from discoveries made in basic science labo-
on a rainy weekend afternoon in 1979, when Edward ratories, as the examples given at the beginning of this
Kravitz invited two individuals to speak on the neu- Preface indicate (see also the excellent series of pamphlets
robiology course that he was co-teaching there. They produced by the Society for Neuroscience, “Research and
were Nancy Wexler, then a program officer at the Discoveries”13). However, knowing more about disor-
US National Institute of Neurological Diseases and ders of the nervous system can motivate researchers to
Stroke, and Marjorie Guthrie, the widow of Woody work even harder, and who among us does not want their
Guthrie. Marjorie spoke movingly about how Woody’s work to eventually make a difference in the lives of oth-
Huntington disease affected him and their entire fam- ers? Moreover, we firmly believe in the aphorism of Louis
ily; Nancy also commented on the disease. After the Pasteur that “chance favors the prepared mind”. We hope
presentations, Marjorie, Nancy (who was to become this textbook will aid in that preparation.
the president of the Huntington’s Disease Foundation
and whose family has also suffered from that condi- Michael J. Zigmond, PhD
tion), Ed, Michael Zigmond, and several others on the Lewis P. Rowland, MD
course went to “The Captain Kidd”, a popular hang- Joseph T. Coyle, MD
out in Woods Hole, to continue the discussion. The
group immediately began to talk about how moving
References
the presentations by Marjorie and Nancy had been and
how valuable it would be to expose others in the field 1. S en G, Bose K. Rauwolfia serpentina, a new Indian drug for insanity
to such experiences. Ed took this idea and ran with and hypertension. Indian Med World. 1931;21:194–201.
2. L ele RD. Beyond reverse pharmacology: mechanism-based
it, obtaining funding from the National Institutes of
screening of Ayurvedic drugs. Ayurveda Integr Med. 2010;1:
Health to underwrite the “Neurobiology of Disease”
257–65.
workshop now held each year just before the annual 3. Carlsson A. A half-century of neurotransmitter research: impact
meeting of the Society for Neuroscience. on neurology and psychiatry (Nobel Lecture). Chembiochem. 2001;
The second event was a six-day workshop for faculty 2:484–93. For a video of this lecture, see http://www.nobelprize.org/
nobel_prizes/medicine/laureates/2000/carlsson-lecture.html.
on teaching about the neurobiology of disease in which
4. H ornykiewicz O. The discovery of dopamine deficiency in the par-
the three editors of the present textbook (and many oth-
kinsonian brain. J Neural Transm Suppl. 2006;70:9–15.
ers) taught during August 2011. The objective was to 5. B aumeister AA. The chlorpromazine enigma. J Hist Neurosci.
provide the participants with information and instruc- 2013;22:14–29.
tional methods that would allow them to go back to their 6. V erkhratsky A, Krishtal OA, Petersen OH. From Galvani to patch
clamp: the development of electrophysiology. Pflugers Arch.
home institutions and mount, or substantially improve,
2006;453:233–47.
a course on the neurobiology of disorders. Much of the
7. C atala M, Poirier J. Georges Marinesco (1863–1938): neurologist,
impetus for moving from courses to a textbook – and a neurohistologist and neuropathologist. Rom J Morphol Embryol.
few of the book’s authors (Ann McKee, Robert Brown) 2012;53:869–77.
and consultants (Gerald Fischbach, Donald Price) – arose 8. F inger S. Origins of Neuroscience: A History of Explorations into Brain
Function. Oxford: Oxford University Press; 2001.
from that workshop. The hope was – and remains – that
9. Chudler E. Milestones in neuroscience research. http://faculty.wa
through this book still others will be able to develop
shington.edu/chudler/hist.html
courses on the neurobiology of disease. This textbook 10. Society for Neuroscience. History of neuroscience. http://www.
is not complete; there are separate chapters on the role sfn.org/About/History-of-Neuroscience/History-Resources.
of inflammation but not mitochondrial dysfunction, on 11. Z ottoli SJ. How the early voltage clamp studies of José del Castillo
inform “modern” neuroscience. Neuroscientist. 2012;18:415–21.
PD but not Tourette syndrome, on depression but not
12. M aienschein J. Neurobiology a century ago at the Marine Biologi-
anxiety, on traumatic brain injury, but not brain tumors.
cal Laboratory, Woods Hole. Trends Neurosci. 1990;13:399–403.
These and several other topics must await a second 13. Society for Neuroscience. The research and discoveries series.
edition. www.brainfacts.org.
Acknowledgments
This textbook has been a long time in gestation. Some Working with Michael at the University of Pittsburgh,
time around 2005, Michael Zigmond was approached by Susan Giegel and later Beth Fischer provided essential
Johannes Menzel, then at the Academic Press division of administrative assistance. Finally, we greatly appreciate
Elsevier, with a proposal to organize a textbook such as the help of all those involved in the production of this
this one. Donald Price was soon brought into the conver- textbook, including our copy editor, Charlotte Pover and
sations and over the next few years played a major role project manager Chris Wortley.
in shaping the project, providing suggestions for both The royalties generated from this book will be used
topics and authors. Gerald Fischbach was also a source primarily to support the purchase and distribution of
of excellent advice. In the end, we three agreed to carry this textbook to trainees in developing countries.
the project through to its conclusion. No grant support was specifically obtained for this
Although our initial editor at Elsevier, Susan Lee, project. However, our institutions, the University of
helped to get the project started, it was Mica Haley Pittsburgh, Harvard Medical School/McLean Hospital,
and editorial project manager April Farr who made it and Columbia University provided us with the facilities
happen – being amazingly patient with us and the within which to carry out the work and, in some cases,
authors as one deadline after another came and went. support for our salaries.
And, in addition to being patient, Mica provided invalu-
able suggestions at virtually every step along the way.
xv
List of Contributors
Stanley H. Appel Department of Neurology, Methodist Samuele Cortese Child Neuropsychiatry Unit, Life and
Neurological Institute, Houston, Texas, USA Reproduction Sciences Department, Verona University,
Miroslav “Misha” Backonja Departments of Neurology, Verona, Italy; NYU Child Study Center, NYU Langone
Medical Center, New York, USA
Anesthesiology, and Rehabilitation Medicine, University of
Wisconsin School of Medicine and Public Health, Madison, Chiara Cossetti Department of Clinical Neurosciences, John
Wisconsin, USA; CRILifetree, Salt Lake City, Utah, USA van Geest Centre for Brain Repair, Wellcome Trust–MRC
Zinzi D. Bailey Department of Social and Behavioral Sciences, Stem Cell Institute and NIHR Biomedical Research Centre,
University of Cambridge, Cambridge, UK
Harvard School of Public Health, Boston, Massachusetts, USA
David R. Beers Department of Neurology, Methodist Joseph T. Coyle Harvard Medical School, McLean Hospital,
Neurological Institute, Houston, Texas, USA Belmont, Massachusetts, USA
Tommy K. Begay Norton School of Family and Consumer Daniel H. Daneshvar Center for the Study of Traumatic
Sciences, College of Agriculture and Life Sciences, Encephalopathy, Alzheimer’s Disease Center, Department
University of Arizona, Tucson, Arizona, USA of Neurology
Anna Berti Psychology Department, University of Turin, Mahlon R. DeLong Department of Neurology, School of
Turin, Italy; Neuroscience Institute of Turin (NIT), Medicine, Emory University, Atlanta, Georgia, USA; Udall
University of Turin, Turin, Italy Center of Excellence in Parkinson’s Disease Research,
Emory University, Atlanta, Georgia, USA
Marina Boido Department of Neuroscience, Neuroscience
Institute Cavalieri Ottolenghi, Turin, Italy Eva L. Feldman Department of Neurology, University of
Michigan, Ann Arbor, Michigan, USA
Maura Boldrini Columbia University, New York State
Psychiatric Institute, New York, USA Francesca Garbarini Psychology Department, University of
Turin, Turin, Italy
David Borsook PAIN Group, Department of Anesthesia,
Boston Children’s Hospital and Harvard Medical School, Thomas Gasser Department for Neurodegenerative
Boston, Massachusetts, USA Diseases, Hertie Institute for Clinical Brain Research,
German Center for Neurodegenerative Diseases, University
R.H. Brown Jr. Department of Neurology, University of
of Tübingen, Tübingen, Germany
Massachusetts Medical School, Worcester, Massachusetts, USA
Charles F. Gillespie Department of Psychiatry and
Rami Burstein Department of Anesthesia, Beth Israel
Behavioral Sciences, Emory University School of Medicine,
Deaconess Hospital, Harvard Medical School, Boston,
Atlanta, Georgia, USA
Massachusetts, USA
Michael S. Gold Pittsburgh Center for Pain Research,
Vera Joanna Burton The Johns Hopkins University/
Department of Anesthesiology; Center of Neuroscience;
Kennedy Krieger Institute Residency in Neurodevelopmental
Departments of Neurobiology and Medicine; Division of
Disabilities, Baltimore, Maryland, USA
Gastroenterology Hepatology and Nutrition, University of
Eduardo R. Butelman Laboratory on the Biology of
Pittsburgh
Addictive Diseases, The Rockefeller University, New York,
Mary Lee Gregory The Johns Hopkins University/Kennedy
USA
Krieger Institute Residency in Neurodevelopmental
Louis R. Caplan Beth Israel Deaconess Medical Center,
Disabilities, Baltimore, Maryland, USA
Boston, Massachusetts, USA
Heinz Grunze Institute of Neuroscience, Newcastle
F. Xavier Castellanos NYU Child Study Center, NYU
University, Newcastle upon Tyne, UK
Langone Medical Center, New York, USA; Nathan Kline
Institute for Psychiatric Research, Orangeburg, New York, Randi Hagerman Medical Investigation of
USA Neurodevelopmental Disorders (MIND) Institute,
Department of Pediatrics, University of California –
Elena Cattaneo Department of Biosciences, University of
Davis, Sacramento, California, USA
Milan, Italy
James C. Harris Psychiatry and Behavioral Sciences,
Paula R. Clemens Neurology Service, Department of
Pediatrics, Mental Health, and History of Medicine, The
Veterans Affairs, University of Pittsburgh, Pennsylvania,
Johns Hopkins University School of Medicine, Baltimore,
USA, and Department of Neurology, University of Pittsburgh
Maryland, USA
School of Medicine, Pittsburgh, Pennsylvania, USA
xvii
xviii LIST OF CONTRIBUTORS
Norman J. Haughey Department of Neurology, Division Giulia Mallucci Department of Clinical Neurosciences, John
of Neuroimmunology and Neurological Infections, The van Geest Centre for Brain Repair, Wellcome Trust–MRC
Johns Hopkins University School of Medicine, Baltimore, Stem Cell Institute and NIHR Biomedical Research Centre,
Maryland, USA University of Cambridge, Cambridge, UK
Judy Illes National Core for Neuroethics, Division of J. John Mann Columbia University, New York State
Neurology, Department of Medicine, The University of Psychiatric Institute, New York, USA
British Columbia, Vancouver, British Columbia, Canada Justin C. McArthur Department of Neurology, Division
Raffaele Iorio Department of Laboratory Medicine and of Neuroimmunology and Neurological Infections, The
Pathology, Mayo Clinic, College of Medicine, Rochester, Johns Hopkins University School of Medicine, Baltimore,
Minnesota, USA Maryland, USA
James W. Ironside National CJD Research & Surveillance Bruce S. McEwen Laboratory of Neuroendocrinology, The
Unit, Western General Hospital, Edinburgh, UK Rockefeller University, New York, USA
Henry J. Kaminski Department of Neurology, George Ann C. McKee Center for the Study of Traumatic
Washington University, Washington, DC, USA Encephalopathy, Alzheimer’s Disease Center, Department
of Neurology, Department of Pathology, Boston University
Charlotte Kilstrup-Nielsen Laboratory of Genetic and
School of Medicine, Boston, Massachusetts, USA, VA
Epigenetic Control of Gene Expression, Department of
Boston HealthCare System, Boston, Massachusetts, USA
Theoretical and Applied Sciences, Division of Biomedical
Research, University of Insubria, Busto Arsizio, Italy Guy McKhann Mind/Brain Institute, Johns Hopkins
University, Baltimore, Maryland, USA
Bhumsoo Kim Department of Neurology, University of
Michigan, Ann Arbor, Michigan, USA Tatiana Melnikova Department of Pathology, The Johns
Hopkins University School of Medicine, Baltimore,
Nastassja Koen Department of Psychiatry, University of Cape
Maryland, USA
Town, Groote Schuur Hospital, Cape Town, South Africa
Emmanuel Mignot Stanford Center for Sleep Sciences,
Glenn T. Konopaske Harvard Medical School, McLean
Stanford University School of Medicine, Palo Alto,
Hospital, Belmont, Massachusetts, USA
California, USA
Birgitte Rahbek Kornum Molecular Sleep Laboratory,
Andrew H. Miller Department of Psychiatry and Behavioral
Department of Diagnostics and Danish Center for Sleep
Sciences, Emory University School of Medicine, Atlanta,
Medicine, Copenhagen University Hospital Glostrup,
Georgia, USA
Glostrup, Denmark
Mary Jeanne Kreek Laboratory on the Biology of Addictive William C. Mobley Department of Neurosciences, University
Diseases, The Rockefeller University, New York, USA of California – San Diego, La Jolla, California, USA
Krister Kristensson Department of Neuroscience, Marco Neppi-Modona Psychology Department, University
Karolinska Institutet, Stockholm, Sweden of Turin, Turin, Italy; Neuroscience Institute of Turin (NIT),
University of Turin, Turin, Italy
John F. Kurtzke VA Multiple Sclerosis Center of Excellence–
East, Georgetown University School of Medicine, Orna O’Toole Department of Laboratory Medicine and
Department of Veterans Affairs Medical Center Neurology Pathology, Mayo Clinic, College of Medicine, Rochester,
Service, Washington, DC, USA Minnesota, USA; Department of Neurology, Mayo Clinic,
College of Medicine, Rochester, Minnesota, USA
Linda L. Kusner Department of Pharmacology and
Physiology, George Washington University, Washington, Matthew P. Parsons Department of Psychiatry, Brain
DC, USA Research Centre, University of British Columbia,
Canada
Nicoletta Landsberger Laboratory of Genetic and
Epigenetic Control of Gene Expression, Department of O.M. Peters Department of Neurology, University of
Theoretical and Applied Sciences, Division of Biomedical Massachusetts Medical School, Worcester, Massachusetts,
Research, University of Insubria, Busto Arsizio, Italy; San USA
Raffaele Rett Research Center, Division of Neuroscience, Roberto Picetti Laboratory on the Biology of Addictive
San Raffaele Scientific Institute, Milan, Italy
Diseases, The Rockefeller University, New York, USA
Tong Li Department of Pathology, The Johns Hopkins
Sean J. Pittock Department of Laboratory Medicine and
University School of Medicine, Baltimore, Maryland, USA
Pathology, Mayo Clinic, College of Medicine, Rochester,
Paweł P. Liberski Department of Molecular Pathology and Minnesota, USA; Department of Neurology, Mayo Clinic,
Neuropathology, Medical University of Lodz, Lodz, Poland College of Medicine, Rochester, Minnesota, USA
Jennifer L. Lyons Department of Neurology, Division of Stefano Pluchino Department of Clinical Neurosciences,
Neurological Infections, Brigham and Women’s Hospital John van Geest Centre for Brain Repair, Wellcome Trust–
and Harvard Medical School, Boston, Massachusetts, USA MRC Stem Cell Institute and NIHR Biomedical Research
Centre, University of Cambridge, Cambridge, UK
Nasim Maleki PAIN Group, Department of Anesthesia,
Boston Children’s Hospital and Harvard Medical School, Peter Pressman Memory and Aging Center, University of
Boston, Massachusetts, USA California, San Francisco, California, USA
LIST OF CONTRIBUTORS xix
Donald L. Price Department of Pathology, The Johns Hopkins Roger P. Simon The Neuroscience Institute, Morehouse
University School of Medicine, Baltimore, Maryland, USA; School of Medicine, Atlanta, Georgia, USA
Department of Neurology, The Johns Hopkins University Catrina Sims-Robinson Department of Neurology,
School of Medicine, Baltimore, Maryland, USA; Department
University of Michigan, Ann Arbor, Michigan, USA
of Neuroscience, The Johns Hopkins University School of
Dan J. Stein Department of Psychiatry, University of Cape
Medicine, Baltimore, Maryland, USA
Town, Groote Schuur Hospital, Cape Town, South Africa
Charles L. Raison Department of Psychiatry, College of
Scott M. Summers Medical Investigation of
Medicine, University of Arizona, Tucson, Arizona, USA;
Neurodevelopmental Disorders (MIND) Institute,
Norton School of Family and Consumer Sciences, College
Department of Psychiatry and Behavioral Sciences,
of Agriculture and Life Sciences, University of Arizona,
University of California-Davis, Sacramento, California, USA
Tucson, Arizona, USA
Kiran T. Thakur Department of Neurology, Division of
Lynn A. Raymond Department of Psychiatry, Brain
Neuroimmunology and Neurological Infections, The
Research Centre, University of British Columbia, Canada
Johns Hopkins University School of Medicine, Baltimore,
Brian Reed Laboratory on the Biology of Addictive
Maryland, USA
Diseases, The Rockefeller University, New York, USA
Luis B. Tovar-y-Romo Instituto de Fisiología Celular,
Peter B. Reiner National Core for Neuroethics, Department
Universidad Nacional Autónoma de Mexico, Mexico
of Psychiatry, The University of British Columbia,
Arshya Vahabzadeh Department of Psychiatry and
Vancouver, British Columbia, Canada
Behavioral Sciences, Emory University School of Medicine,
Kerry J. Ressler Department of Psychiatry and Behavioral
Atlanta, Georgia, USA
Sciences, Emory University School of Medicine, Atlanta,
Alessandro Vercelli Department of Neuroscience,
Georgia, USA; Yerkes National Primate Research Center,
Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy
Atlanta, Georgia, USA; Howard Hughes Medical Institute,
Chevy Chase, Maryland, USA Mitchell T. Wallin VA Multiple Sclerosis Center of
Excellence–East, Georgetown University School of
Graham W. Rook Centre for Clinical Microbiology,
Medicine, Department of Veterans Affairs Medical Center
Department of Infection, University College London,
Neurology Service, Washington, DC, USA
London, UK
Thomas Wichmann Department of Neurology, School of
Howard J. Rosen Memory and Aging Center, University of
Medicine, Emory University, Atlanta, Georgia, USA; Udall
California, San Francisco, California, USA
Center of Excellence in Parkinson’s Disease Research,
Lewis P. Rowland Neurological Institute, Columbia
Emory University, Atlanta, Georgia, USA; Yerkes National
University Medical Center, New York, USA
Primate Research Center, Emory University, Atlanta,
Aarti Ruparelia Department of Neurosciences, University of Georgia, USA
California – San Diego, La Jolla, California, USA
Clayton A. Wiley Division of Neuropathology, UPMC
Mario A. Saporta Department of Neurology, Universidade Presbyterian Hospital, Pittsburgh, Pennsylvania, USA
Federal Fluminense, Rio de Janeiro, Brazil
David R. Williams Department of Social and Behavioral
Alena V. Savonenko Department of Pathology, The Johns Sciences, Harvard School of Public Health, Boston,
Hopkins University School of Medicine, Baltimore, Maryland, Massachusetts, USA
USA; Department of Neurology, The Johns Hopkins
Philip C. Wong Department of Pathology, The Johns
University School of Medicine, Baltimore, Maryland, USA
Hopkins University School of Medicine, Baltimore,
Julia Schaeffer Department of Clinical Neurosciences, John Maryland, USA; Department of Neuroscience, The Johns
van Geest Centre for Brain Repair, Wellcome Trust–MRC Hopkins University School of Medicine, Baltimore,
Stem Cell Institute and NIHR Biomedical Research Centre, Maryland, USA
University of Cambridge, Cambridge, UK
Vadim Yuferov Laboratory on the Biology of Addictive
Helen E. Scharfman Departments of Child & Adolescent Diseases, The Rockefeller University, New York, USA
Psychiatry, Physiology & Neuroscience, and Psychiatry,
Weihua Zhao Department of Neurology, Methodist
New York University Langone Medical Center, New York,
Neurological Institute, Houston, Texas, USA
USA; The Nathan Kline Institute, Dementia Research,
Michael J. Zigmond Departments of Neurology,
Orangeburg, New York, USA
Neurobiology, and Psychiatry, University of Pittsburgh,
Bruce K. Shapiro The Johns Hopkins University/Kennedy
Pittsburgh, Pennsylvania, USA
Krieger Institute Residency in Neurodevelopmental
Saša A. Živković Neurology Service, Department of Veterans
Disabilities, Baltimore, Maryland, USA
Affairs, University of Pittsburgh, Pennsylvania, USA, and
Michael E. Shy Department of Neurology, University of Department of Neurology, University of Pittsburgh School of
Iowa, Iowa City, Iowa, USA Medicine, Pittsburgh, Pennsylvania, USA
C H A P T E R
1
An Introduction: A Clinical Neuroscientist and
Disorders of the Brain
Guy McKhann
Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, USA
O U T L I N E
Introduction 1 Development of New Drugs 6
Localization of Lesions 2 Clinical Trials 7
Imaging 2 Trials in Alzheimer Disease 7
Selective Vulnerability of Neuronal Populations 2 Biomarkers of Disease 8
Recovery After Injury 3 Psychiatric Disease 9
Stem Cells in Recovery 4 Genetics of Neurological and Psychiatric Disorders 9
Brain Transplants 5 Temperament and Disease 10
Neurology as a Therapeutic Field 5 Conclusion 10
Animal Models of Human Disease 6 References 11
INTRODUCTION clinician. This is not an extensive review of many topics;
rather, I have focused on a few of the areas with which I
I will start by saying what this article is not about. This am familiar. I am a neurologist, so much of my emphasis
is not a commentary about how to perform and interpret is on disorders that fall under the province of neurology.
an examination of the nervous system. Thus, I will not However, I have also included some comments about
comment on the importance of obtaining a proper his- psychiatry.
tory, or the nuances of eliciting clinical responses as part As a clinician, I am interested in disease: What can go
of the examination. In other words, I will downplay the wrong with the nervous system? The word “disease” or
clinical aspects of my title. Those seeking such informa- “disorder”, the somewhat softer term we have chosen
tion might consider referring to one of many excellent to use in this textbook, implies a change from a person’s
textbooks on the subject.1–3 Rather, I will focus on the normal state. That change can vary markedly from per-
application of neuroscience to current questions about son to person. For example, I once was asked to evaluate
diseases of the nervous system. I will emphasize those a 70-year-old patient who had been one of the youngest
areas in which my background as a neuroscientist has graduates from the Massachusetts Institute of Technol-
helped me. Further, I will try to highlight areas where ogy (MIT), at age 14. His family and business associates
those in neuroscience can, and I hope will, help me as a reported that he was starting to have cognitive problems,
1
Neurobiology of Brain Disorders
http://dx.doi.org/10.1016/B978-0-12-398270-4.00001-X © 2015 Elsevier Inc. All rights reserved.