Table Of ContentI ntegrative Neuroscience and
Personalized Medicine
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I ntegrative Neuroscience and
Personalized Medicine
E dited by
E vian Gordon, PhD, MBBCH
T he Brain Resource Company
S ydney, Australia and San Franscisco, CA, USA
T he University of Sydney, Australia, and
BRAINnet Foundation, USA
S tephen H. Koslow, PhD
T he Brain Resource Company
S ydney, Australia and San Francisco, CA, USA
B RAINnet Foundation, USA
B iomedical Synergy
W est Palm Beach, FL, a nd
A merican Foundation for Suicide Prevention
N ew York, NY, USA
1
2011
1
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I ntegrative neuroscience and personalized medicine/edited by Evian Gordon, Stephen H. Koslow.
p .; cm.
I ncludes bibliographical references and index.
I SBN 978-0-19-539380-4
1 . Neurogenetics. 2. Genetic polymorphisms. 3. Brain—Diseases—Genetic aspects. I. Gordon,
Evian. II. Koslow, Stephen H.
[ DNLM: 1. Mental Disorders—therapy. 2. Genetic Markers. 3. Individualized Medicine—methods.
4. Nervous System Diseases—therapy. 5. Pharmacogenetics. WM 140 I59 2011]
Q P356.22.I58 2011
6 12.8—dc22 2 010017894
9 8 7 6 5 4 3 2 1
P rinted in the United States of America
o n acid-free paper
F oreword
Neurological or brain disorders represent a huge health burden worldwide. Although there
is a long history of knowledge about and study of brain and psychiatric disorders, until
approximately forty years ago, we viewed these as illnesses of interest for which therapeu-
tics were almost universally unavailable. Until recently, there were no therapeutic treat-
ment options available for patients who suffered from depression, suicidal thoughts,
anxiety, post-traumatic stress disorder (PTSD), schizophrenia, brain tumors, Alzheimer’s
disease, Parkinson’s disease, Huntington’s disease, or diseases of movement, cognition, or
sensation. Even now, therapeutics that can completely cure the patient of the illness are
nonexistent, or are effective only in some patients.
T here is increasing interest in personalized approaches in all fi elds of medicine, includ-
ing brain-related diseases. The initial goal was to discover genetic signatures in order to
individualize disease prediction, diagnosis, treatment effi cacy, treatment course, and prog-
nosis. Research has been based on the premise that clinicians could match markers to
specifi c disease outcomes. However, much about the genetic bases of psychiatric and brain
disorders remains unknown, and signifi cant research is necessary to identify the multiple
genetic and protein markers for these diseases. Furthermore, the combined use of ever
more sophisticated brain imaging technologies, along with the ability to identify genomic,
proteomic, or metabolomic markers, may vastly aid in elucidating the diagnosis, treatment
prediction, and course of brain disorders.
We know more about some neurological conditions than others. For example, it is clear
that stroke is usually secondary to either thrombotic or hemorrhagic insults. Yet, there
are few clear prognostic indicators, and treatments are still being developed. We can, for
example, stave off some damage from ischemic stroke by infusion of tissue plasminogen
activator (tPA) within the fi rst few hours after the event. But, at present, this is the only
FDA-approved drug to treat stroke, and it is not without side effects.
Huntington’s disease is always caused by a CAG (cytosine-adenine-guanine), repeat in
a gene on chromosome 4, resulting in an abnormal polyglutamine-containing sequence in
the protein huntington. This insoluble mutant protein accumulates within neurons and
results in cell death. Thus, Huntington’s is a disorder that is more therapeutically approach-
able than other neurological disorders because of the relatively unifi ed understanding of
some of the major causes of its pathology. Although the precise genetic defi cit was discov-
ered in 1993, thus far, this has led to no signifi cant advances in therapy. This clearly
indicates that we need to expand our understanding of gene regulation and control, and also
suggests that we need to include other types of biological and epigenetic information in our
studies.
v
vi FOREWORD
H untington’s disease is exceptional in that it originates in the mutation of one gene, and
so much is known about its genetic etiology. Increasing amounts of genetic information are
being uncovered about Alzheimer’s disease, yet numerous genes on different chromosomes
have been implicated in familial disease, and the available treatments are minimal. Despite
the elucidation of some mechanisms of some psychiatric and neurological disorders, in
fact, the overall group of brain-related neurological and psychiatric disorders remains in
need of substantial clarifi cation.
B rain and psychiatric illnesses are increasing in prevalence. It is diffi cult to render a spe-
cifi c diagnosis and categorization of a specifi c treatment plan of these illnesses using current,
often subjective methods. Furthermore, treatment modalities often are based on trial and
error. For one patient with a specifi c disorder, a given treatment may be therapeutic, while
the same treatment may have no effect on another individual with the same diagnosis. This
lack of clarity challenges and complicates our capacity to do research. Therefore, discovery
of specifi c biomarkers to allow better characterization of a particular disorder is now a criti-
cal, although challenging, goal of the brain and psychiatric disorders research community.
S uccessful research, however, may require much larger patient sample sizes than are
usually used in studying brain disorders, as larger sample sizes have been more successful
in studies of other medical disorders. For example, databases of samples from thousands of
patients have been used to elucidate the role of the BRCA1 and 2 gene mutations in the
etiology of hereditary breast cancer. Similar numbers should be used to study brain disor-
ders. The goal of identifying a biological genotype and/or phenotype, or biomarker, is a
high priority. The identifi cation of a biological genotype or phenotype may, indeed, super-
sede current diagnostic schemes typically used in determining treatments. Such identifi ca-
tion fosters appropriate diagnosis, prediction, and therapeutic treatment and dramatically
changes the landscape of our approach to psychiatric illnesses.
T here are encouraging fi ndings in genomics and molecular genetics, giving clinicians
the ability to hone treatments to fi t specifi c characteristics of tumors or other diseases.
These tools should be available to those of us studying the function of the brain. To help us
gain access to genomics data and bring it into the brain disorders clinic, we should:
• Advocate for a lower cost for sequencing a complete human genome, bringing the
price down to $100 or less.
• Collect and integrate potentially complementary data, including brain-imaging data,
across scales and disciplines.
• Make all of these data accessible and transparent to investigators.
• Advocate for standardization of some of the investigational tools, so that data may
be combined, integrated, and compared, thus maximizing the statistical power and
comparability both within and across studies.
I n this way, scientists can gain a deeper understanding of the pathogenesis and possible
mechanisms of brain disorders. This increased understanding should, in turn, lead to
discoveries of new, targeted, therapeutic and biological genotypes and phenotypes.
Because of the complexity of neurological or brain disorders, investigators from multi-
ple disciplines should be encouraged to work together to discover genes, elucidate genetic
mechanisms of disease, and discover treatments and cures. Our goal, however, is not just to
accumulate data. It is to provide a new understanding of disease and its impact on the
individual patient, something we refer to as “integrative brain health.” This is a concept
with potentially far-reaching effects, and it will allow us to translate useful knowledge that
will enable clinicians to care for the patient and his or her distinct brain disorder in an
integrated manner, utilizing new diagnostic tools and new pharmaceutical (and other) treat-
ments which constitute the best management plan for that patient and that illness.
FOREWORD vii
W e will be able to take knowledge we already have, such as information on the matura-
tion of the cerebral cortex, and determine its relationship to the etiology of brain disorders
that become manifest in adolescence. For example, as the cortex matures, its size increases,
and it experiences a concurrent increase in myelination. We are learning, too, that the gray
matter gradually declines as pruning takes place. We need to distill newly gained informa-
tion from multiple modalities—e.g., molecular genetics, neuroimaging, blood and CSF-
related biomarkers, behavioral assessment, neuropsychological approaches, and brain
electrical activity—into applicable clinical use. Furthermore, we need to learn how to use
our emerging understanding of the brain and its evolution, and how factors from multiple
domains interact, to advance our ability to predict, diagnose systematically, and effectively
treat neurological and brain disorders.
Given the current scale and morbidity of brain disorders, “personalized medicine”
should be more than a lofty goal to be attained in the distant future. Imagine having the
ability to say to a patient at increased risk for a brain disorder, and even possibly to one
suffering from a given illness, that we, as clinicians, can take specifi c productive steps to
prevent the onset of the disorder, or to effect a cure! To be able to say, with a high probabil-
ity, that X is the disorder and that the diagnosis immediately signifi es specifi c symptoms,
function, and dysfunction, and that there is a specifi c personalized effective treatment,
would radically change the way brain disorders and psychiatric diseases are treated—and
even cured. For decades, researchers, clinicians, patients, families and all others concerned
with the mental health and brain disorder fi eld have yearned to have at their fi ngertips a
plethora of treatments that are likely to match the specifi c causes of disease. We are getting
ever closer to achieving that goal. This book serves to highlight the factors that seem likely
to help expedite personalized medicine, ushering it into mainstream clinical practice.
We should applaud those who are working valiantly to clarify the workings of the brain.
We should encourage them to pool knowledge, to break down their silos, to be as imagina-
tive as possible, but also to build systematic and pragmatic platforms that aggregate data
and information to enhance the productive capacity of scientists worldwide. These are all
noble efforts.
P ersonalized medicine is a goal we want to achieve. Personalized medicine offers one
of the greatest opportunities to improve health care, treat in a more tailored and effective
way, reduce the use of treatments of no value, and minimize the unfortunate accompanying
side effects of treatments. It holds out the possibility of contributing to the reduction
of health care costs, while simultaneously increasing quality of health care and quality
of life.
T his book assembles many leaders in the fi eld, who bring the reader up-to-date informa-
tion on the status of our knowledge. They will point to likely directions in research and also
articulate not just hopes for the future, but also what is more likely to be clinically available
for testing and iterative evidence-based refi ning n ow , and what requires more long-term
research.
H erbert Pardes, MD
P resident and CEO
N ew York-Presbyterian Hospital
N ew York, NY
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C ontents
C ontributors xi
I ntroduction xvii
S ection 1: Genesis of Personalized Medicine
C hapter 1: The History of Personalized Medicine 3
E dward Abrahams and Mike Silver
C hapter 2: An Applied Context for Personalized Medicine in Psychiatry 17
A lan F. Schatzberg
C hapter 3: Personalized Medicine and Integrative Neuroscience:
Toward Consensus Markers for Disorders of Brain Health 25
L eanne M. Williams and Evian Gordon
S ection 2: Personalized Medicine and Mental Disorders
C hapter 4: Does fMRI Have A Role in Personalized Health Care
for Psychiatric Patients? 55
A lex Fornito and Edward T. Bullmore
C hapter 5: Stress and the Impact of Personalized Medicine 73
C harles F. Gillespie, Elisabeth B. Binder,
Paul E. Holtzheimer, and Charles B. Nemeroff
C hapter 6: Personalized Medicine for Schizophrenia 93
J acob S. Ballon, Ragy R. Girgis, and Jeffrey A. Lieberman
C hapter 7: Personalized Integrative Markers for Attention
Defi cit/Hyperactivity Disorder in Children and Adolescents 117
M ichael R. Kohn, Simon D.Clarke, and Leanne M. Williams
S ection 3: Personalized Medicine and Other Brain Disorders
C hapter 8: The Role of Neuroimaging Biomarkers in Personalized
Medicine for Neurodegenerative and Psychiatric Disorders 141
E llen M. Migo, Steve C.R. Williams, William R. Crum,
Matthew J. Kempton, and Ulrich Ettinger
ix
