Biomarkers of Neurological and Psychiatric Disease

454 Pages·2011·7.353 MB·English

by  Paul C. Guest and Sabine Bahn (Eds.)

International
R E V I E W O F
Neurobiology
Volume 101
SERIES EDITORS
R. ADRON HARRIS
Waggoner Center for Alcohol and Drug Addiction Research
The University of Texas at Austin
Austin, Texas, USA
PETER JENNER
Division of Pharmacology and Therapeutics
GKT School of Biomedical Sciences
King’s College, London, UK
EDITORIAL BOARD
ERICAAMODT HUDAAKIL
PHILIPPEASCHER MATTHEWJ.DURING
DONARDS.DWYER DAVIDFINK
MARTINGIURFA BARRYHALLIWELL
PAULGREENGARD JONKAAS
NOBUHATTORI LEAHKRUBITZER
DARCYKELLEY KEVINMCNAUGHT
BEAULOTTO JOSE´ A.OBESO
MICAELAMORELLI CATHYJ.PRICE
JUDITHPRATT SOLOMONH.SNYDER
EVANSNYDER STEPHENG.WAXMAN
JOHNWADDINGTON
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CONTRIBUTORS
Numbersinparenthesesindicatethepagesonwhichtheauthors’contributionsbegin.
MurtadaAlsaif(203),DepartmentofChemicalEngineeringandBiotechnology,
UniversityofCambridge,Cambridge,UnitedKingdom
Sabine Bahn (65, 95, 145, 203, 259, 279, 299), Department of Chemical
EngineeringandBiotechnology,UniversityofCambridge,Cambridge,United
Kingdom;DepartmentofNeuroscience,ErasmusMedicalCentre,Rotterdam,
The Netherlands
Anthony Barnes (299), Rules Based Medicine, Austin, Texas,USA
Man K. Chan (95), Department of Chemical Engineering and Biotechnology,
UniversityofCambridge, Cambridge,United Kingdom
Dan Cohen (169), Department of Epidemiology, University Medical Center,
Groningen, The Netherlands; Department of Severe Mental Illness, Mental
Health Care Organization, North-Holland North, Heerhugowaard, The
Netherlands
Hemmo A. Drexhage (169), Department of Immunology, Erasmus MC,
Rotterdam, The Netherlands
Roosmarijn C. Drexhage (169), Department of Immunology, Erasmus MC,
Rotterdam, The Netherlands
Agnes Ernst (203), Department of Chemical Engineering and Biotechnology,
UniversityofCambridge, Cambridge,United Kingdom
Michaela D. Filiou (1), Proteomics and Biomarkers, Max Planck Institute of
Psychiatry, Munich,Germany
Jayne C. Fox (329), AstraZeneca Pharmaceuticals, Personalized Health Care
and Biomarkers, AlderleyPark,Macclesfield, Cheshire, UnitedKingdom
Stephen J. Glatt (41), Departments of Psychiatry and Behavioral Sciences &
NeuroscienceandPhysiology,PsychiatricGeneticEpidemiology&Neurobiol-
ogyLaboratory(PsychGENeLab),MedicalGeneticsResearchCenter,SUNY
Upstate MedicalUniversity,Syracuse, New York,USA
Paul C. Guest (65, 95, 145, 203, 259, 279, 299), Department of Chemical
EngineeringandBiotechnology,UniversityofCambridge,Cambridge,United
Kingdom
xi
xii CONTRIBUTORS
LauraW.Harris(65,145),DepartmentofChemicalEngineeringandBiotech-
nology,UniversityofCambridge, Cambridge, UnitedKingdom
Witte J.G. Hoogendijk (351), Department of Psychiatry, Erasmus University
Medical Center,Rotterdam, The Netherlands
EvaHradetzky(203),DepartmentofChemicalEngineeringandBiotechnology,
UniversityofCambridge,Cambridge,UnitedKingdom
Rauf Izmailov (259, 279), Rules-Based Medicine, Inc.,Austin,Texas,USA
WolfgangKluge(203),DepartmentofChemicalEngineeringandBiotechnology,
UniversityofCambridge,Cambridge,UnitedKingdom
Chi-Ming Lee (329), AstraZeneca Pharmaceuticals, Discovery Enabling Cap-
abilities& Sciences,Alderley Park,Macclesfield, Cheshire, United Kingdom
Yishai Levin (95), Department of Chemical Engineering and Biotechnology,
UniversityofCambridge, Cambridge,United Kingdom
Christopher R. Lowe (375), Department of Chemical Engineering and
Biotechnology, Institute of Biotechnology, University of Cambridge,
Cambridge,UnitedKingdom
AlanMackay-Sim(239),NationalCentreforAdultStemCellResearch,Eskitis
Institute for Cell and Molecular Therapies, Griffith University, Brisbane,
Queensland, Australia
Daniel Martins-de-Souza (65, 145), Department of Chemical Engineering
and Biotechnology, University of Cambridge, Cambridge, United Kingdom;
Lab. de Neurocieˆncias (LIM-27), Inst. Psiquiatria, Fac. de Medicina da
Universidade deSao Paulo,Sao Paulo,Brazil
PaulM.Matthews(19),GSKClinicalImagingCentre,HammersmithHospital,
London,UnitedKingdom;CentreforNeuroscience,ImperialCollege,London,
UnitedKingdom
George Mellick (239), National Centre for Adult Stem Cell Research, Eskitis
Institute for Cell and Molecular Therapies, Griffith University, Brisbane,
Queensland, Australia
Mandy Y.M. Ng (329), AstraZeneca Pharmaceuticals, Personalized Health
CareandBiomarkers,AlderleyPark,Macclesfield,Cheshire,UnitedKingdom
Willem A. Nolen (169), Department of Psychiatry, University Medical Center,
UniversityofGroningen, Groningen, The Netherlands
RichardNoll (299),DeSales University, Center Valley, Pennsylvania, USA
David R.J. Owen (19), Division of Experimental Medicine, Imperial College,
Hammersmith Hospital, London, United Kingdom; GSK Clinical Imaging
Centre, HammersmithHospital, London,UnitedKingdom
Josue´ Pe´rez-Santiago(41), Departmentof Medicine, Universityof California
San Diego,La Jolla, California,USA
Hassan Rahmoune (95), Department of Chemical Engineering and Biotech-
nology,UniversityofCambridge, Cambridge, UnitedKingdom
CONTRIBUTORS xiii
Zolta´nSarnyai(203),DepartmentofPharmacology,UniversityofCambridge,
Cambridge,UnitedKingdom
Emanuel Schwarz (95, 259, 279, 299), Department of Chemical Engineering
and Biotechnology,UniversityofCambridge, Cambridge, UnitedKingdom
Akul Singhania (41), Veterans Affairs San Diego Healthcare System,
San Diego,California, USA
Viktoria Stelzhammer (203), Department of Chemical Engineering and
Biotechnology, UniversityofCambridge, Cambridge, United Kingdom
Ming T. Tsuang (41), Department of Psychiatry and Institute of Genomic
Medicine, Center for Behavioral Genomics, University of California San
Diego,La Jolla,California, USA
Christoph W.Turck(1),Proteomicsand Biomarkers,MaxPlanckInstitute of
Psychiatry, Munich,Germany
YagneshUmrania(95),DepartmentofChemicalEngineeringandBiotechnol-
ogy, UniversityofCambridge, Cambridge,UnitedKingdom
Nico J.M. van Beveren (351), Department of Psychiatry, Erasmus University
Medical Center,Rotterdam,The Netherlands
NicovanBeveren(169),DepartmentofPsychiatry,ErasmusMC,Rotterdam,
The Netherlands
Natacha Vanattou-Saifoudine (65, 145), DepartmentofChemicalEngineer-
ingandBiotechnology,UniversityofCambridge,Cambridge,UnitedKingdom
Nico J.M. VanBeveren (259), Department of Psychiatry, Erasmus University,
Medical Centre, Rotterdam,The Netherlands
Marjan A. Versnel (169), Department of Immunology, Erasmus MC, Rotter-
dam, The Netherlands
Karin Weigelt (169), Department of Immunology, Erasmus MC, Rotterdam,
The Netherlands
Hendrik Wesseling (203), Department of Chemical Engineering and Bio-
technology, UniversityofCambridge, Cambridge,UnitedKingdom
ChristopherH.Woelk(41),DepartmentofMedicine,UniversityofCalifornia
SanDiego,LaJolla,California,USA;VeteransAffairsSan DiegoHealthcare
System, San Diego,California, USA
Erik H.F. Wong (329), AstraZeneca Pharmaceuticals, External Science,
CNS-Pain InnovativeMedicineUnit, Wilmington, Delaware, USA
Stephen Wood (239), National Centre for Adult Stem Cell Research, Eskitis
Institute for Cell and Molecular Therapies, Griffith University, Brisbane,
Queensland, Australia
PREFACE
ThisvolumeoftheInternationalReviewofNeurobiologydescribes thestateofthe
art and the future of biomarkers in neurological and psychiatric diseases. Cur-
rently, the diagnosis for all neuropsychiatric disorders is carried out by psychia-
trists via interview, observation, and classification of patients who typically have
heterogeneoussymptomsandmedicalhistories.Therecentemergenceofmolec-
ular and image-based biomarkers for these conditions would therefore greatly
facilitatediseasediagnosisandstratification.Thismayrequiredeconstructionof
the existing long-standing procedures aimed at classification of broad patient
categoriesinfavorofidentifyingbiomarker-defineddiseasesubtypes.Ultimately,
this will assist in personalized medicine approaches and may be facilitated by
developmentsintheareasofbiosensors,neuroinformatics,ande-neuropsychiatry.
ThefirstchapterbyFiliouandTurckintroducesthecontentofthevolumeby
describing how biomarkers are now in demand in neuropsychiatric research for
diagnosis,treatmentresponsemonitoring,anddevelopmentofnoveltherapeutics.
However,biomarkerdiscoveryinthisfieldischallengingduetothefactthatthese
arecomplexdisorders,informationontheaffectedmolecularpathwaysisscarce,
and there is considerable interpatient heterogeneity within a given disorder and
overlapofsymptomsacrossdifferentconditions.Becauseofthisdiseasecomplexi-
ty,apanelofbiomarkersderivedfrommultipleplatformswillbeneededtodefine
these conditions at the molecular level. Ultimately, the coordinated effort of
researchers, physicians, funding organizations, and standardization initiatives
willbeneededtoovercomethesechallenges.
The second chapter by Owen and Matthews describes recent advances
in imaging technologies to study neuroinflammatory, neurodegenerative, and
neuropsychiatric conditions such as multiple sclerosis, Alzheimer’s disease,
Parkinson’s disease, stroke, and schizophrenia. The main technique described,
positron emission tomography (PET), is used to study the proliferation of
microglia in these conditions as this is a stereotyped response after a variety of
pathologicalinsults.Therehasbeensignificantinterestinquantifyingmicroglial
density in vivo in research and clinical decision making. However, this has
beenhinderedbythelackofappropriateradioligands.Withrecentdevelopment
of several new generation ligands with improved specific binding, this now
xv
xvi PREFACE
seems possible and should enable PET to become a more valuable tool for use
in the clinical studies of such neuropsychiatric disorders.
ThethirdchapterbyWoelketal.coverstheuseofgeneexpressionanalysisof
blood cells for diagnosis of neuropsychiatric disorders. The authors carry out a
reviewofstudieswhichhaveanalyzedgeneexpressioninbloodcellsfrompatients
with neuropsychiatric disorders with an emphasis on developing diagnostics for
schizophrenia.Theauthorsalsodiscussthefuturedirectionsofthefieldincluding
usingmicroRNAexpressionfordevelopingdiagnosticclassifiersandthepotential
use of blood cell gene expression patterns to tailor antipsychotic medications to
individualpatients.Theyalsodescribethelikelyfutureimpactofnext-generation
sequencing technologies.As the costs diminish and software tools for analysis of
thishigh-contentdatabecomesmoreavailable,thepossibilityofdevelopingmore
accurateclassificationtoolsforneuropsychiatricdisorderswillincrease.
ThefourthchapterbyMartins-de-Souzaetal.describesthestateoftheartand
possiblefuturedevelopmentsintheuseofproteomictechnologiesforthestudyof
neuropsychiatricconditionsandforthedevelopmentofnovelmoleculardiagnostic/
prognostictests.Suchadvanceshavealreadybeenpartlyachievedforillnessessuch
ascanceralthoughtheyhavehadalessprofoundimpactinthecaseofneuropsy-
chiatricdisorderssuchasschizophrenia.Theauthorsdiscussthepressingneedfor
more sensitiveandaccuratetechnologieswithoverallimportanceontechnologies
whichcanbeusedforvalidationandimplementationoftheresultingbiomarkersas
simpleandeffectivetestsforuseintheclinicalenvironment.Suchadvanceswillput
proteomicsclosertoclinicalapplicationsintheneuropsychiatryfield.
The fifth chapter by Chan et al. gives an update on emerging evidence
for identification of blood-based molecular biomarkers in schizophrenia. The
authorshavecombinedareviewoftheliteraturewiththeresultsofacomprehen-
sivein-house study showing the identification of candidate blood-based biomar-
kers for schizophrenia and for antipsychotic drug response. Taken together, the
findings suggest that there are effects on the immune system and inflammation
responseinschizophrenia.Thefindingsalsosuggestedthatthereisanactivation
ofthestressresponse,asshownbyincreasedlevelsofcortisolandactivationofthe
hypothalamic–pituitary–adrenal (HPA) axis in patients. It is expected that such
biomarkers will prove useful as an additional means of characterizing specific
immune, metabolic, or hormonal pathways in schizophrenia, which should
pave the way for development of future patient stratification and personalized
medicinestrategies.
The sixth chapter by Guest et al. describes the finding of abnormalities in
metabolism and hormonal function in patients with schizophrenia. The authors
describe decades of research converging on the fact that the pathogenesis of
schizophreniacaninvolveperturbationsinmetabolicandHPAaxispathwaysin
somepatients.Theobserveddifferencesinmanifestationoftheseeffectscouldbe
related to differences in symptoms between patients and in responses to
PREFACE xvii
antipsychotic treatments. The authors describe the identification of circulating
molecular biomarkers in schizophrenia patients including changes in vital hor-
mones and related molecules such as insulin, proinsulin, proinsulin conversion
intermediates, C-peptide, chromogranin A, pancreatic polypeptide, cortisol,
adrenocorticotrophic hormone, growth hormone, prolactin, and progesterone.
Stratificationofsubjectsaccordingtomolecular phenotypereflectingthedisease
state or trait could help to improve existing treatments through application of
novel personalized medicine strategies which target patients with metabolic or
hormonalabnormalities.
The seventh chapter by Drexhage et al. describes the occurrence of immune
and neuroimmune alterations in neuropsychiatric conditions such as mood dis-
ordersandschizophrenia.Theauthorsreviewtheliteratureoverthepast20years
which has implicated alterations in immune system function in such patients.
These findings indicate that there is a proinflammatory state of the cytokine
network which can induce the psychopathological symptoms and may also be
involved in the pathophysiology of these neuropsychiatric illnesses. The authors
alsopresenttheresultsoftheirrecentstudies,whichrelateimmuneactivationto
present theories on the influence of activated immune cells on brain function.
Increased understanding in this area could help in the development of novel
treatmentstrategiesandimprovedclinicalmanagementofmentaldisorders.This
isimportantasaproinflammatorystatemaynotaffectallpatientsbutmaybea
featureofasubsetofpatients.
The eighth chapter by Sarnyai et al. carries out a review and presents novel
findingsonbehavioralandmolecularbiomarkersintranslationalanimalmodels
for neuropsychiatric disorders. Modeling neuropsychiatric disorders in animals
presentssignificantchallengesduetothesubjectivenatureofclassifyingsymptoms
andthelackofempiricalbiomarkersand understandingofthepathophysiology.
Successfultranslation ofpreclinicalmodelstoclinicalresearchrequirescarefully
characterized animal models which are informative about disease mechanisms
andtherapeutictargets.Inthislight,theauthorsreviewbehavioral,neurobiologi-
cal, and molecular findings from selected animal models for schizophrenia,
bipolar disorder, and major depressive disorder. Importantly, they focus this
assessment on the use of appropriate statistical tools and newly developed Re-
searchDomainCriteria(RDoC)tolinkbiomarkersfromanimalmodelswiththe
human disease. They argue that this approach will lead to development of
‘‘validated’’ animal models for specific neuropsychiatric disorders and may ulti-
matelyleadtobetterunderstandingofthepathophysiologyandtoidentification
ofnovelbiomarkersandtherapeutictargets.
The ninth chapter by Mackay-Sim et al. presents the use of stem cell
models for biomarker discovery in neuropsychiatric disorders. Patient-derived
stemcellshavesignificantpotentialasdiseasemodels.Stemcellscanbeprolifer-
ated, stored, and then thawed for use in genomic, proteomic, and functional
xviii PREFACE
studies. Patient-derived induced pluripotent stem cells and adult stem cells from
the olfactory tissue in the nose have already been used to provide novel insights
into a number of brain diseases.This workwas originally inspired by the obser-
vation that the sense of smell is impaired in many brain diseases, including
neurodegenerativediseases,suchasAlzheimer’sdiseaseandParkinson’sdisease,
andneuropsychiatricdisorders,suchasschizophrenia.Thesefindingssuggestthat
biomarker discovery may be possible from investigating such disease-associated
cells in the form of patient-derived stem cells. Such cellular models carry the
disease phenotypes and span the variability encountered across patient popula-
tions.Theyalsoprovidepotentialexperimentaltoolstoidentifynovelmolecular
biomarkers that distinguish patients from controls and may therefore lead to
developmentofempiricaltestsfordifferentialdiagnosisorformonitoringdisease
progression.
The10thchapterbySchwarzetal.describestherecentadvancesinapplying
multiplexedimmunoassaysystemstoidentifymoleculardiagnosticsfor psychiat-
ricdisorders.Theauthorsdescribeapproachestoidentifydisease-relatedmolec-
ularabnormalitieswhenthereisuncertaintyregardingthevalidityoftheclinical
diagnosis. They also present an introduction to the multiplex immunoassay
approachthatfacilitatesidentificationandquantitationofmolecularbiomarkers
andalsoforextendingthesemolecularfindingsintotherealmsofidentifyingthe
associated functional consequences. As chronic sufferers of neuropsychiatic dis-
easesarelikelytohaveapoor prognosis,anaccuratemoleculartestmayleadto
earlyinterventionandtherebyimprovepatientoutcomes.Amoleculartestwould
alsoopenupthepossibilityofstratifyingpatientsmoreaccuratelywhichiscrucial
for personalizedmedicineapproaches.
The11thchapter byIzmailovetal.givesadescriptionofalgorithmdevelop-
ment for diagnostic biomarker assays. As a test case, they present the ground-
breaking development of a serum-based test to help confirm the diagnosis of
schizophrenia. They identified a multiplex panel of 51 immunoassays which
allowed reproducible identification of schizophrenia patients compared to con-
trols with high performance. Validation of this test involved development of a
linear support vector machine decision rule and they tested the performance of
this using cross-validation. This resulted in readjustment of the panel and algo-
rithm to a smaller set of assays, and they developed a simple procedure for
maintenance and recalibration of the assays across time. The resulting decision
ruledeliveredasensitiveandspecifictestforpresenceofschizophreniacompared
to controls. The next stage will be to carry out large-scale clinical validation
studies using samples from more diverse psychiatric patient populations and
settingsinaseriesofprospectivestudiesfortranslationtotheclinicalsetting.
The 12th chapter by Bahn et al. describes the challenges of introducing new
biomarker products for neuropsychiatric disorders into the market place. The
general opinion is that improvements over the current subjective tests are
PREFACE xix
essential.Despitethisthereisareluctancetoacceptthepossibilitythatidentifica-
tionofperipheralbiomarkerscanbeofanybenefit.Inaddition,psychiatristsfind
it difficult to accept that peripheral molecules such as blood-based proteins and
small molecules can reflect what ishappening inthe brain.However, thehealth
and regulatory authorities now consider that biomarkers are important for the
future of drug development and have called for efforts to modernize methods,
tools and techniques for this purpose. The authors describe the development of
thefirstevermolecularbloodtestforschizophreniaandthereactionsofresearch
scientists and psychiatrists to this development, as a case in point. There is now
reason foroptimism thatfurther technological advancements and interdisciplin-
aryapproachesinbiomarkerresearchwillovercomecurrentlimitationsandhelp
toadvanceourabilitytotreatpatientswithneuropsychiatricdisorders.
The 13th chapter by Wong et al. addresses the need and movement toward
personalizedmedicineintheneuropsychiatricfield.Advancesinhumangenetics
and molecular innovations in neuroscience have prompted the pharmaceutical
industry to move beyond the treatment of broad spectrum diseases to more
targeted (personalized) treatment approaches. Recurring failure in converting
scientific discoveries in neuroscience to novel efficacious drugs has precipitated
acrisisintheindustry.Atargetedandconsistentinvestmentisneededtorestore
confidenceintranslatingscienceintoclinicalsuccess.Therearenowmovements
forcross-pharmaceuticalcompanyandgloballycoordinatedeffortsfordiscovery
of better, therapy-linked patient stratification, as exemplified by the European
Union Innovative Medicine Initiatives project entitled: ‘‘New Medications in
Depression and Schizophrenia—NEWMEDS.’’ That fact that such efforts are
nowbeingmadebyindividualpharmaceuticalcompanies,suggeststhatthetime
andopportunityforafreshapproachinthisareaarenowwelcome.
The14thchapterbyvanBeverenandHoogendijkcoverstheclinicalaspects
ofmajorneuropsychiatricdisordersandtheneedforaparadigmshifttobiomark-
er-assisted diagnostic tests. Thus far, the identification and application of such
biomarker tests have been sparse. This is likely to be due to the fact that the
existing diagnostic methods are based on long-standing heterogeneous concepts
in psychiatry. In addition, a shift to using biomarkers for conditions which have
been categorized for decades based on clinical phenomenology would not be
clinically useful. However, there is a pressing need for biomarkers which can be
usedasanaidtothenormalproceduretoclassifyat-riskpatients,suchasyoung
people with prodromal symptoms for psychosis and existing patients who are
likelytoprogresstomoreseverestates.Theauthorsalsostressthatthereisaneed
for better classification of patient subtypes and to deconstruct the traditional
diagnosesinfavorofusingbiomarker-assistedstrategiestoaccomplishthis.
The 15th chapter by Lowe describes the potential future of biomarkers in
neuropsychiatric diseases which may include developments in the areas of bio-
sensors, neuroinformatics, and e-neuropsychiatry. The emergence of molecular