Biomarkers identification and validation (example of the Alzheimer's Disease) Marc Dhenain URA CEA CNRS 2210 – MIRCen - Fontenay aux Roses Eq. Maladie d'Alzheimer : Modélisation, Biomarqueurs, Imageries Précliniques http://mamobipet.free.fr/Teaching/Teaching.html Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Overview Concepts of Biomarkers Overview on Alzheimer's disease Biomarkers in humans
Dubois Criteria / ADNI initiative Cerebral atrophy (MRI) Brain metabolism (PET) Amyloid plaques (PET)
Biomarkers in animal models: Why/how can we use of biomarkers in animal models?
Characterization of animal models ¾ Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ?
Therapeutic evaluations ¾ "Classical view" of translational medicine ¾ Translational bridgesTherapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Diseases and therapies… Step 1: Objective in humans: Cure the disease… Clinical outcome (Phenotype)
Disease
Ex. Cognitive alterations Death, etc…
Therapy
Empiric approaches: Is my drug treating the disease ? Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarqueurs: Un concept faussement "simple" Biomarker Definition Working group (2001) CLINICAL ENDPOINT (critère ou marqueur clinique, ~symptôme?) A characteristic or variable that reflects how a patient feels or functions, or
how long a patient survives.
BIOLOGICAL MARKER (BIOMARKER) A characteristic that is objectively measured and evaluated as an indicator of
normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Replace a distal endpoint with a more proximal one, measured earlier Can be measured more easily or frequently Faster decision making
3 types of Biomarkers (Biomarker Def Working Grp, 2001) ¾ Type 0 : Reflects natural history of a disease ¾ Type I : Reflects mechanism of action of an intervention ¾ Type II : Predicts clinical benefit of a treatment (or toxicity) (SURROGATE ENDPOINT (critère ou marqueur de substitution))
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Traductions !
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Diseases and therapies… Step 2: Objective in humans: Natural history of the disease Disease
Target
Endophenotypes
Markers
Clinical outcome (Phenotype) Ex. Cognitive alterations Death, etc…
Biomarkers Diagnostic Longitudinal Functional
Understand the disease
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Type 0 Biomarker Natural history of a disease
T0 Biomarker T0 BiomarkerT0 Biomarker Clinical outcome (Phenotype)
Disease
Ex. Cognitive alterations Death, etc…
Possible applications of T0 biomarkers (Early) diagnosis Clinical study enrichment, stratification of the patients
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Diseases and therapies… Step 3: Objective in humans: Isolate a target Disease
Target
Endophenotypes
Markers
Clinical outcome (Phenotype) Ex. Cognitive alterations Death, etc…
Biomarkers
Therapy
Understand the disease Æ isolate a potential target
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Diseases and therapies… Step 4: Objective in humans: Understand how a drug works
Disease
Target
Endophenotypes
Clinical outcome (Phenotype) Ex. Cognitive alterations Death, etc…
Mechanism of Action (MOA) to modify the target
POM
Markers Biomarkers
Therapy Proof of Mechanism (POM): Is my drug really active on the supposed mechanism ?
Æ Type I biomarkers
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Basis of translational medicine Step 5: Objective in humans: If I modify the target, do I modify the disease ? Disease
Clinical outcome
Target Markers Biomarkers
Ex. Cognitive alterations Death, etc…
POC Mechanism of Action (MOA) to modify the target
Modify Clinical outcome
POM
Therapy Proof of Mechanism (POM): Is my drug really active on the supposed mechanism ? Proof of Concept (POC): If I modify the target, do I modify the disease ?
Æ Type II biomarkers
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Basis of translational medicine Type 0 - Biomarkers
Disease
Clinical outcome
Target Type II - Biomarkers
Mechanism of Action (MOA) to modify the target Type I - Biomarkers
Ex. Cognitive alterations Death, etc…
POC Modify Clinical outcome
POM
Type II - Biomarkers
Therapy
Toxicity?
Proof of Concept (POC): If I modify the target, do I modify the disease ? Is my drug really active on the supposed mechanism ? Proof of MechanismTranslational (POM): Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Many causes of Type II (surrogate) biomarker failure
Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov. 2003 Jul;2(7):566-80. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Example of validated Type II Biomarkers
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Overview Concepts of Biomarkers Overview on Alzheimer's disease Biomarkers in humans
Dubois Criteria / ADNI initiative Cerebral atrophy (MRI) Brain metabolism (PET) Amyloid plaques (PET)
Biomarkers in animal models: Why/how can we use of biomarkers in animal models?
Characterization of animal models ¾ Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ?
Therapeutic evaluations ¾ "Classical view" of translational medicine ¾ Translational bridgesTherapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Maladie d'Alzheimer
Dépôts amyloïdes
Atrophie cérébrale
Dégener. Neurofibrillaires
Altérations fonctionnelles
Altérations cognitives Démence
AD
Ctrl Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid cascade hypothesis (simplified) Beta Amyloid
CAA
NFT
Functional alterations
Atrophy Hippoc…
Dementia
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Overview Concepts of Biomarkers Overview on Alzheimer's disease Biomarkers in humans
Dubois Criteria / ADNI initiative Cerebral atrophy (MRI) Brain metabolism (PET) Amyloid plaques (PET)
Biomarkers in animal models: Why/how can we use of biomarkers in animal models?
Characterization of animal models ¾ Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ?
Therapeutic evaluations ¾ "Classical view" of translational medicine ¾ Translational bridgesTherapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Critères de diagnostique de la MA
Episodic memory impairments Supportive features Medial temporal atrophy Alteration of the CSF Alterations of the PET ¾ Reduced glucose metabolism in bilateral temporal-parietal regions ¾ Amyloid detection by PET (PIB-FDDNP…) Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
ADNI - Principle
"sample size required to detect 25% change for a given biomarker (during one year)" Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarkers for Alzheimer's disease Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cognitive alterations
Episodic memory Capacity for "abstract" thinkings Verbal fluency -12 -9 years
-7 years
0 years (beginning of dementia)
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Results from ADNI POWER OF CLINICAL/COGNITIVE TESTS 25% CHANGE 1YR STUDY (2 ARM) : AD (155 Subjects)
Test MMSE RAVLT ADAS CDR SOB
Sample Size 803 607 592 449
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarkers for Alzheimer's disease Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral atrophy in humans with Alzheimer
Starts in the hippocampus then spread all over the brain Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral atrophy in humans with Alzheimer Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Results from ADNI POWER OF EVALUATION OF BRAIN ATROPHY 25% CHANGE 1YR STUDY (2 ARM) : AD (69 Subjects) Lab
Variable
SS/arm
Alexander
L. Hippo. Formation
334
Schuff - FS
Hippocampus
201
Dale
Hippocampus
126
Schuff - FS
Ventricles
119
Studhome
CV - % change
106
Fox
VBSI % change
105
Fox
BSI % change
71
Thompson
CV - % change
54
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Atrophy level
*
A good marker for the diagnosis (T0 biomarker) can be questionable for therapeutic follow-up (T2 biomarker) Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral atrophy ? Type 0 - Biomarkers
Disease
Clinical outcome
Target Type II - Biomarkers
Mechanism of Action (MOA) to modify the target Type I - Biomarkers
Ex. Cognitive alterations Death, etc…
POC Modify Clinical outcome
POM
Type II - Biomarkers
Therapy
Toxicity?
Proof of Concept (POC): If I modify the target, do I modify the disease ? Is my drug really active on the supposed mechanism ? Proof of MechanismTranslational (POM): Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral metabolism Normal
AD
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Results from ADNI POWER OF EVALUATION OF BRAIN METABOLISM 25% CHANGE 1YR STUDY (2 ARM) : AD (36 Subjects) Lab
Variable
SS/arm
Foster
hypometabolism1
638
Foster
hypometabolism2
549
Jagust
ROI-avg
412
Reiman
CV-fROI
96
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral metabolism ? Type 0 - Biomarkers
Disease
Clinical outcome
Target Type II - Biomarkers
Mechanism of Action (MOA) to modify the target Type I - Biomarkers
Ex. Cognitive alterations Death, etc…
POC Modify Clinical outcome
POM
Type II - Biomarkers
Therapy
Toxicity?
Proof of Concept (POC): If I modify the target, do I modify the disease ? Is my drug really active on the supposed mechanism ? Proof of MechanismTranslational (POM): Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral metabolism
Reflect clinical history of the disease Disease progression biomarker (Type 0)
Can be a better marker of clinical amelioration following treatment as compared to MRI
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarkers for Alzheimer's disease Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid imaging in humans (by PET)
Amyvid
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid in the brain of healthy controls
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid load
Reflect early history of the disease ? But is not a disease progression biomarker
Related to therapy (for amyloid reducing therapies = Type II)
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
PIB versus CSF biomarkers
• PIB gives info similar to LP • But LP gives more than amyloid • Price is not the same… Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarker – Chronology in the disease
Jack CR, Jr. (2010). Lancet Neurol 9:119-128. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid plaques ? Type 0 - Biomarkers
Disease
Clinical outcome
Target Type II - Biomarkers
Mechanism of Action (MOA) to modify the target Type I - Biomarkers
Ex. Cognitive alterations Death, etc…
POC Modify Clinical outcome
POM
Type II - Biomarkers
Therapy
Toxicity?
Proof of Concept (POC): If I modify the target, do I modify the disease ? Is my drug really active on the supposed mechanism ? Proof of MechanismTranslational (POM): Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Overview Concepts of Biomarkers Overview on Alzheimer's disease Biomarkers in humans
Dubois Criteria / ADNI initiative Cerebral atrophy (MRI) Brain metabolism (PET) Amyloid plaques (PET)
Biomarkers in animal models: Why/how can we use of biomarkers in animal models?
Characterization of animal models ¾ Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ?
Therapeutic evaluations ¾ "Classical view" of translational medicine ¾ Translational bridgesTherapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Phenotyping and endophenotyping in humans Natural history of the disease Disease
Target
Endophenotypes
Markers
Clinical outcome (Phenotype) Ex. Cognitive alterations Death, etc…
Biomarkers Diagnostic Longitudinal Functional
Understand the disease
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Identification of biological mechanisms and targets Phenotyping and endophenotyping in animal studies Disease
Target
Endophenotypes
Markers
Clinical outcome (Phenotype) Ex. Cognitive alterations Death, etc…
Biomarkers Diagnostic Longitudinal Functional -Non invasive -Slightly invasive
Understand the disease
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Why/how can we use of biomarkers in animal models
Characterization of animal models Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ? ¾ Non invasive studies in animal
Therapeutic evaluations "Classical view" of translational medicine Translational bridges ¾ Evaluation of efficacy in animals ¾ Evaluation of toxicity in animals
Therapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Characterization of animal models: Ex of the detection of amyloid plaques Markers
Histology
MRI
PET
Biomarkers
Multiphoton microscopy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Characterization of animal models Ex. of the Evaluation of cerebral atrophy in mouse lemurs
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Characterization of animal models
Precious animal
Normal
Atrophié
Selection of animals to be included in therapeutic studies Stratification Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Why/how can we use of biomarkers in animal models?
Characterization of animal models Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ? ¾ Non invasive studies in animal
Therapeutic evaluations "Classical view" of translational medicine Translational bridges ¾ Evaluation of efficacy in animals ¾ Evaluation of toxicity in animals
Therapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
"Classical view" of translational medicine
Tests in animal models Markers and biomarkers
Enough argument to validate the efficacy / lack of toxicity in animal Arguments for a predictivity in humans
Go/No Go in humans
The drug should be efficient in humans… This view is simplistic. It requires Predictive animal models
Pertinent use of biomarkers
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Different signification of biomarkers in animals and humans Example of behavioral studies
Alzheimer is a dementia Let's look a behavioral alterations in animals to predict drug efficacy…
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Altérations comportementales chez les rongeurs Lesne, Nature, 2006
Ex. Piscine de Morris – Navigation Spatiale
Controls = Tg2576-/-
- Mémoire spatiale de référence - Intégrité de l’hippocampe - Couramment utilisée "Alzheimer" Tg2576+/-
Altérations mnésiques mais pas de "démence"
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Predictivité des effets chez l'homme
AN1792
Radial arm water maze Tg mice Tg mice + Vaccine Control
Morgan et al. (2000). Nature, 408(6815), 982-5.
In humans Efficiency to reduce amyloid load No effect on behavioral alterations Morgan et al. (2000). Nature, 408(6815), 982-5. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Différence majeure cpt souris / Homme Biais de raisonnement Les troubles comportementaux des rongeurs n'ont pas la même origine que ceux de l'homme Alzheimer
Troubles comportementaux modérés
Origine Troubles Comportementaux = DNF
Origine Troubles Comportementaux = Oligomères
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Validity of mouse models of amyloidosis
Construct validity
Genetic
Face validity: a truncated model ? Extracellular amyloid deposits (but no downstream lesions) Intracellular amyloid deposits Lack of cerebral atrophy Behavioral alterations not related to Tau pathology
Human
Tg amyloidosis
Amyloid
Amyloid
Tau
Tau
Neurodegenerescence
Neurodegenerescence
Clinical alterations
Clinical alterations
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
The same biomarker does not reflect the same underlying pathology in humans and animals
The mouse model is not predictive of the full Alzheimer's disease pathology
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Translational bridges Clinical outcome
Predictivity ?
Clinical outcome
Endophenotypes
Predictivity ?
Endophenotypes
POC in animals
Predictivity ?
POC in Humans
Target POM in animals
Therapy
Target Predictivity ?
POM in human
Therapy
Proof of Mechanism (POM): Is my drug really active on the supposed mechanism ? Proof of Concept (POC): If I modify the target, do I modify the disease ? Pivotal : Is the disease modification in animals predictive of results in humans ? Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Translational bridges Clinical outcome
Not predictive
Clinical outcome
Endophenotypes
Endophenotypes
POC in animals
POC in Humans
Target
Target
POM in animals
Therapy
Predictivity ?
POM in human
Therapy
Proof of Mechanism (POM): Is my drug really active on the supposed mechanism ? Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Immunotherapies in amyloid mice
Marker of amyloid load (Histology)
Control
Vaccinated (Schenk et al, 1999)
Biomarker of amyloid load (MRI) Treatment
*
Control
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Translational bridges Target POM in animals
Therapy
Target Predictivity ?
POM in human
Therapy
It is reasonable to think that the treatment will reduce amyloid load in humans
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Discovery of new therapy strategies in amyloid mice
Control
Vaccinated (Schenk et al, 1999)
No clinical improvement MMSE=0
(Holmes et al, 2008)
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid imaging in humans (by PET)
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Translational bridges Clinical outcome
Not predictive
Clinical outcome
Endophenotypes
Predictivity ?
Endophenotypes
POC in animals
Predictivity ?
POC in Humans
Target POM in animals
Therapy
Target Predictive
POM in human
Therapy
Proof of Mechanism (POM): Is my drug really active on the supposed mechanism ? Proof of Concept (POC): If I modify the target, do I modify the disease ? Pivotal : Is the disease modification in animals predictive of results in humans ? Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Use of biomarkers to add translational bridges between humans and animals ?
Clinical outcome
Not predictive
Clinical outcome
Anatomical biomarkers
Not predictive
Anatomical biomarkers
Functional biomarkers
Predictivity?
Functional biomarkers
Molecular biomarkers
Predictivity?
Target
Predictive
Molecular biomarkers
Target
POM in animals
POM in human
Therapy
Therapy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Use of biomarkers to add translational links between humans and animals ?
Clinical outcome
Not predictive
Clinical outcome
Anatomical biomarkers
Not predictive
Anatomical biomarkers
Functional biomarkers
Functional Biomarkers
Functional biomarkers
Molecular biomarkers
Cellular/Molecular Biomarkers
Molecular biomarkers
Target
Predictive
Target
POM in animals
POM in human
Therapy
Therapy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Use of biomarkers to add translational links between humans and animals ?
Clinical outcome
Not predictive
Clinical outcome
Anatomical biomarkers
Not predictive
Anatomical biomarkers
Functional biomarkers
Functional biomarkers ?
Functional biomarkers
Molecular biomarkers
Cellular/Molecular Biomarkers
Molecular biomarkers
Target
Predictive
Target
POM in animals
Therapy
POM in human
Therapy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral metabolism Glucose metabolism (PET) Edison P et al. Neurology, 2007
Normal
AD
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid is associated to an increased glucose uptake in Tg mice FDG-PET study
a
b
c
j Cx
d
e
Hpc
Th
f
1mm
k g
h
Cx
i
St
St Th Hpc
Cortex *
* *
*
G. Poisnel et al, Neurobiology of Aging, 2012 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid plaques are associated to an increased glucose uptake 2DG autoradiography
G. Poisnel et al, Neurobiology of Aging, In press Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Use of biomarkers to add translational links between humans and animals ? Clinical outcome
Not predictive
Clinical outcome
Anatomical biomarkers
Not predictive
Anatomical biomarkers
Glucose metabolism
Not predictive
Glucose metabolism
Perfusion
Predictivity?
Perfusion
Molecular biomarkers
Cellular/Molecular Biomarkers
Molecular biomarkers
Target POM in animals
Therapy
Predictive
Target POM in human
Therapy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Perfusion measurements from MRI ASL-MRI provides overlapping information with FDG-PET
ASL-MRI
FDG-PET
Chen Y et al. NeurologyTranslational 77, 1977-85; 2011. Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Dissociation between perfusion and glucose uptake in mouse models of amyloidosis
Perfusion
Glucose uptake
Poisnel G et al. Neurobiology of Aging. of Print. Translational ResearchAhead in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Application for therapeutic evaluation
Ai-Ling Lin et al. ISMRM2012. 586. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarkers of toxicity
Clinical outcome
Target
Not predictive
Predictive
Clinical outcome
Target
POM in animals
POM in human
Therapy
Therapy
Toxicity
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Imaging biomarkers of Toxicity Example of the immunotherapy
Severe side effects detected in human studies Microhemorrhages
Meningoencephalitis
Ferrer I et al. Brain Pathol, 2004
Orgogozo JM et al. Neurology, 2003
Vasogenic edema
Salloway S et al. Neurology, 2009
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Marqueurs toxicologiques chez l'animal Neuroinflammation Control
Penet, M. F.. (2005). J Neurosci 25(32): 7352-8.
Cerebral Malaria Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Marqueurs toxicologiques chez l'animal Microhémorragies cérébrales
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Detection of cerebral microhemorrhages by MRI 71 wks
75 wks
Post-mortem Translational Research in Neurological Post-mortem+Gd staining Diseases: Biomarkers, M. Dhenain - February 2013
Why/how can we use of biomarkers in animal models
Characterization of animal models Identification of biological mechanisms and targets ¾ Choice of marker versus biomarkers ? ¾ Non invasive studies in animal
Therapeutic evaluations "Classical view" of translational medicine Translational bridges ¾ Evaluation of efficacy in animals ¾ Evaluation of toxicity in animals
Therapeutic evaluations Preparation of clinical trials
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Objective for preparation of clinical trials
Define best animal models Define best endophenotype/biomarkers that will allow to predict results in humans This requires to understand the targets
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Translational bridges Validity of the animal model
Validity of the marker/biomarkers
Clinical outcome
Predictivity ?
Clinical outcome
Endophenotypes
Predictivity ?
Endophenotypes
POC in animals
Predictivity ?
POC in Humans
Target POM in animals
Therapy
Validity of the disease/target hypothesis
Target Predictivity ?
POM in human
Therapy Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
A good animal model Construct validity
Biological (aging…) Lesions: chemical, mechanical…. Mechanistic (drug, etc…) Genetic (transgenic: standard, conditional, tissue specific…)
Face validity
Lesional: Amyloid then Tau then Neurodegerescence Endophenotyping ¾ ¾
Functional Electrophysiological alterations
Phenotyping (behaviour)
Prediction validity
Mecanistic (target engagement, downstream effects) POM POC Pivotal Toxicity
Easy to use
Access (reproducibility, ability to use the model, community) Homogeneity of the model Techniques available to evaluate the model
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
A good translational biomarker
Construct validity Biological relevance Biological parameter can be measured in humans and animals ¾ With exactly the same method (pb of scale-up) ¾ Similar methods (ex. amyloid plaque imaging)
Face validity Same behavior in animals and humans ¾ Evolution with disease evolution
Prediction validity Same modulation with same treatment in humans and animals (if
validated modelization in animal).
Easy to use Access (reproducibility, price, community) Homogeneity of the results Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Validity of the disease/target hypothesis
Construct validity Biological relevance Constructed from human data
Prediction validity Predicts the effects of treatments in humans.
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Thank you…
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Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Annex other potential biomarkers in animals Cerebral atrophy Other biomarkers of beta amyloid ¾ Liquides périphériques – –
LCR Sang
¾ Le cerveau – – –
PET Imagerie optique IRM
¾ Les yeux
Synaptic activity MEMRI
Neuronal death
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral atrophy
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
CSF and brain volumes in mice
Brain and hippocampal growth even in the presence of amyloid deposits… Delatour et al. (2006). Neurobiol Aging, 27(6), 835-847. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Conclusion atrophie souris Use in animals Biomarker
Cerebral atrophy
Use in humans
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
No
No
Yes
Clinical endpoint True benefits of a drug No
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Longitudinal follow-up of temporo-parietal atrophy
CSF volume evaluation (arbitrary units)
Animals without amyloid deposits Animals with amyloid deposits
Age (years)
Quick evolution once started Dhenain et al. Neurobiol Aging. 2000;21(1):81-8. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Use of atrophy to select animals involved in therapeutic trials
25 animals scanned
Nelly Joseph-Mathurin Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Study enrichment – 2nd cohort
Animals Screening
12 animals selected
Graphe de régression 2,75 2,5 2,25 2 1,75 1,5 1,25 1 ,75 ,5 ,25 3
3,5
4
4,5
5
5,5 6 Age IRM
6,5
7
7,5
8
Y = ,291 + ,191 * X; R^2 = ,09
Nelly Joseph-Mathurin Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral atrophy in Tau mice
rTg4510 = P301L
Control
Suggests that atrophy is a marker of Tau pathology Yang D et al. Neuroimage, 2011 (rTg4510 = P301L mice) Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Biomarqueurs de l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Amyloid imaging in humans (by PET)
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
PIB Mice – Very late marker (if marker) 30-60 min
APP 23 mice (Amyloid starts at 6 months)
14 month animals
Maeda, J., B. Ji, et al. (2007). J Neurosci 27(41): 10957-68.
Klunk, W. E., B. J. Lopresti, et al. (2005). J Neurosci 25(46): 10598-606.
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Conclusion: amyloid detection - PET
Use in animals Biomarker
Amyloid (Aggregated - PET + PIB) Futur contrast agents ?
Use in humans Clinical endpoint
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes
No
Yes
No
Yes ?
Yes ?
Yes
No
True benefits of a drug
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Human studies
Animal studies
Efficacy in the animal: MOA, POM, POC Toxicity Reglementary
Mechanism specific
Toxicity Reglementary
Mechanism of action (explanation)
Effect on the target
Proof of concept Endophenotypes
Effect on the target
Mechanism of action (explanation)
Mechanism specific
Phenotypes
Proof of concept Endophenotypes
Phenotypes
Clincal studies
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique ¾ Multiphoton microscopy ¾ Near Infra red imaging
IRM
Les yeux Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Multiphoton microscopy
Fenêtre sur le cerveau
Marquage par un fluorophore Thioflavine S (par exemple)
Résolution = 1 µm Profondeur = 150 µm Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Multiphoton microscopy
Plaques séniles
Angiopathie amyloïde Christie R. H. et al., The Journal of Neuroscience, 21(3), 858-864, 2001 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Multiphoton microscopy: Longitudinal follow up of plaque turn over
+ 2 jours
+ 104 jours
Christie R. H. et al., The Journal of Neuroscience, 21(3), 858-864, 2001 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Multiphoton microscopy: Longitudinal follow up of plaque toxicity
Neuronal varicosities associated to amyloid plaques
Neurite breakage close to amyloid plaques
Tsai, J., J. Grutzendler, et al. (2004). Nat Neurosci 7(11): 1181-3. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Multiphoton microscopy: Use to evaluate experimental therapies
Détection of amyloid clearance following immunotherapy
10D5 Ab +3 Days
Bacskai, B. J., et al. (2001). Nat Med 7(3): 369-72.
Détection of effects of treatments on amyloid-associated neuronal modifications 10D5 Ab +3 Days
Brendza, R. P., (2005). J Clin Invest 115(2): 428-33. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Conclusion: amyloid detection – Multiphoton and NIR
Use in animals
Use in humans Clinical endpoint
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Amyloid (Aggregated - PET + contrast agent)
Yes
No
Yes
No
Multiphoton
Yes
Yes
No
No
NIR
Yes
Yes
No
No
Biomarker
True benefits of a drug
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Human studies
Animal studies
Efficacy in the animal: MOA, POM, POC Toxicity Reglementary
Mechanism specific
Toxicity Reglementary
Mechanism of action (explanation)
Effect on the target
Proof of concept Endophenotypes
Effect on the target
Mechanism of action (explanation)
Mechanism specific
Phenotypes
Proof of concept Endophenotypes
Phenotypes
Clincal studies
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Conclusion
Targets
Targets
Functional improvement
Functional improvement
Clinical outcome
Improvement of Clinical outcome
Toxicity
Type1 BioM. Mechanism of action of a drug
Therapy
Aal models
Therapy
Targets Functional improvement Improvement of Clinical outcome
Targets Functional improvement
Clinical outcome
Type0 BioM. Natural history of the disease
Aal models
Humans
Type2 BioM. Predict clinical benefits Predict toxicity
Type0 BioM. Natural history of the disease
Humans
Toxicity
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Optimisation of plaque imaging thanks to contrast agents 7T Clinical Scanner Siemens 23.4 x 23.4 x 90 µm3 Tacq = 13 hours 50 min Sequence: GRE
Alexandra Petiet Anne Bertrand Chris Wiggins 2
3
3
2 1 1
7
4
4 7
1:40 mixture (Dotarem®) and formalin
6
5
6
5
Dhenain M, etTranslational al. MRM. Research 55. 687-693. 2006. Diseases: Biomarkers, M. Dhenain - February 2013 in Neurological
Passive staining: 3D Reconstructions
28 weeks old
39 weeks old Dhenain M, et al. MRM. 55. 687-693. 2006. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Evaluation des plaques amyloïdes 6 mois
9 mois
14 mois
20 mois
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
In-vivo follow up of amyloid load 5 mois
3 mois
1 mm
17 mois
9 mois
1 mm 1 mm Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Conclusion: amyloid detection - MRI
Use in animals Biomarker
Amyloid (MRI + contrast agent)
Use in humans
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes
No Yes
No
Clinical endpoint True benefits of a drug No
Dhenain, MR Insights, 2008 (http://www.la-press.com/) Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Altérations fonctionnelles associées à la MA
Métabolisme cérébral Perfusion cérébrale Transport neuronal
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Alteration of glucose metabolism in AD
Fluorodeoxyglucose (FDG)-PET Edison P et al. Neurology. 68(7):501-8; Translational Research2007. in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Cerebral metabolism AD
MCI
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
Imagerie du métabolisme cérébral
µPET Focus 220 Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - February 2013
[18F]-FDG et µTEP Hypermétabolisme chez les Souris APP_PS1/TG69 p
