Imageries précliniques pour la maladie d'Alzheimer Recherche et utilisation de biomarqueurs pertinents Marc Dhenain URA CEA CNRS 2210 – MIRCen - Fontenay aux Roses Eq. Maladie d'Alzheimer : Modélisation, Biomarqueurs, Imageries Précliniques, Evaluations Thérapeutiques http://marc.dhenain.free.fr/Diaps/Presents.html Marc DHENAIN, Master MIRCen 2011
Plan
Maladie d'Alzheimer
Généralités Modèles animaux Concepts de biomarqueurs Quels biomarqueurs ? ¾ Marqueurs cognitifs ¾ Marqueurs de l'atrophie cérébrale ¾ Marqueurs de l'amyloïdose – Liquide biologiques – Imagerie
¾ Marqueurs fonctionnels ¾ Autres marqueurs ¾ Marqueurs toxicologiques
Exemples d'autres biomarqueurs pour d'autres pathologies
Marc DHENAIN, Master MIRCen 2011
Plan
Maladie d'Alzheimer
Généralités Modèles animaux Concepts de biomarqueurs Quels biomarqueurs ? ¾ Marqueurs cognitifs ¾ Marqueurs de l'atrophie cérébrale ¾ Marqueurs de l'amyloïdose – Liquide biologiques – Imagerie
¾ Marqueurs fonctionnels ¾ Autres marqueurs ¾ Marqueurs toxicologiques
Exemples d'autres biomarqueurs pour d'autres pathologies
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer
Dépôts amyloïdes
Atrophie cérébrale
Dégener. Neurofibrillaires
Altérations fonctionnelles
Altérations cognitives Démence
AD
Ctrl Marc DHENAIN, Master MIRCen 2011
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…) Dubois, B. et al.-2007 Lancet Neurol 6(8): 734-46. Marc DHENAIN, Master MIRCen 2011
Quelques rares causes génétiques
Tardives Précoces 50% des formes tardives Liée à l'ApoE (ApoE4/E4)
1% des patients
Marc DHENAIN, Master MIRCen 2011
Amyloid cascade hypothesis (simplified) Beta Amyloid Intracellular amyloid
Abeta truncated forms
Mutations: APP + PS1
CAA
NFT
Functional alterations
Atrophy Hippoc…
Dementia
Marc DHENAIN, Master MIRCen 2011
Vers de nouvelles thérapeutiques Schéma de naissance d'un médicament
Marc DHENAIN, Master MIRCen 2011
Basis of translational medicine Step 1: Objective in humans Biomarkers
Disease
Clinical outcome
Target POC
Ex. Cognitive alterations Death, etc…
Mechanism of Action (MOA) to modify the target POM
Markers Biomarkers Therapy
Proof of Concept (POC): If I modify the target, do I modify the disease ? Master MIRCen 2011 Proof of Mechanism (POM): Is my drug really active onMarc theDHENAIN, supposed mechanism ?
Basis of translational medicine Step 1: Objective in humans Biomarkers
Disease
Amyloid deposition POC
Inib. G. Sec Inib. B. Sec Immunothérapie …
Clinical outcome Ex. Cognitive alterations Death, etc…
Mechanism of Action (MOA) to modify the target POM
Markers Biomarkers Therapy
Proof of Concept (POC): If I modify the target, do I modify the disease ? Master MIRCen 2011 Proof of Mechanism (POM): Is my drug really active onMarc theDHENAIN, supposed mechanism ?
Basis of translational medicine Step 2: Use of animals – Selection of a validated animal model Disease
Target
Clinical outcome
POC
Choice of a good animal model ? ° Construct validity
Mechanism of Action (MOA) to modify the target
POM
° Face validity Markers
° Prediction validity
Biomarkers
Therapy
Proof of Concept (POC): If I modify the target, do I modify the disease ? Master MIRCen 2011 theDHENAIN, supposed mechanism ? Proof of Mechanism (POM): Is my drug really active onMarc
Basis of translational medicine
Préclinique
Clinique
Modèles animaux Biomarqueurs translationnels
Caractérisation des modèles Compréhension mécanismes pathologiques
Biomarqueurs de la pathologie Suivi de la pathologie chez le modèle animal
Evaluation de nouveaux traitements Marc DHENAIN, Master MIRCen 2011
Basis of translational medicine Step 3: Use of the validated animal model – Translational medicine Human
Animal model Disease
Target
Clinical outcome
Disease
Target
Clinical outcome
POC
POC Mechanism of Action (MOA) to modify the target
Mechanism of Action (MOA) to modify the target
POM
POM
Markers
Markers
Biomarkers
Biomarkers
Therapy
Therapy
Proof of Concept (POC): If I modify the target, do I modify the disease ? Master MIRCen 2011 Proof of Mechanism (POM): Is my drug really active onMarc theDHENAIN, supposed mechanism ?
Basis of translational medicine Step 3bis: Toxicity evaluation Human
Animal model Disease
Target
Clinical outcome
Mechanism of Action (MOA) to modify the target
Therapy
Disease
Target
Clinical outcome
POC Mechanism of Action (MOA) to modify the target
POM Markers
Toxicity evaluation
Biomarkers
Therapy
Marc DHENAIN, Master MIRCen 2011
Plan
Maladie d'Alzheimer
Généralités Modèles animaux Concepts de biomarqueurs Quels biomarqueurs ? ¾ Marqueurs de l'atrophie cérébrale ¾ Marqueurs de l'amyloïdose – Liquide biologiques – Imagerie
¾ Marqueurs fonctionnels ¾ Autres marqueurs ¾ Marqueurs toxicologiques
Exemples d'autres biomarqueurs pour d'autres pathologies
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Modèles animaux
Souris Transgeniques
APP/PS1
PS1
Primate Microcebus murinus
Esp Vie Max : 12 ans
100% à 4 mois Dépôts amyloïdes Rationnel
Altérations Tau
Marc DHENAIN, Master MIRCen 2011
Modèles Primates Simiens Chimpanzee
Rhesus
AD - Human
(Gearing et al, PNAS, 1994)
(Schultz, Neurob Aging, 2000) Marc DHENAIN, Master MIRCen 2011
Plan
Maladie d'Alzheimer
Généralités Modèles animaux Concepts de biomarqueurs Quels biomarqueurs ? ¾ Marqueurs cognitifs ¾ Marqueurs de l'atrophie cérébrale ¾ Marqueurs de l'amyloïdose – Liquide biologiques – Imagerie
¾ Marqueurs fonctionnels ¾ Marqueurs toxicologiques
Exemples d'autres biomarqueurs pour d'autres pathologies
Marc DHENAIN, Master MIRCen 2011
Biomarqueurs: Un concept faussement "simple" Biomarker Definition Working group (2001) http://ospp.od.nih.gov/biomarkers/ 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)) Marc DHENAIN, Master MIRCen 2011
Type 0 Biomarker Natural history of a disease T0 Biomarker T0 Biomarker T0 Biomarker True clinical outcome "clinically meaningful endpoint"
Disease
(Alteration cognitive)
Possible applications of T0 biomarkers (Early) diagnosis Clinical study enrichment
Marc DHENAIN, Master MIRCen 2011
Type 1 Biomarker Mechanism of action of an intervention
T1 Biomarker Intervention
Disease
Mechanism of action
True clinical outcome "clinically meaningful endpoint"
Marc DHENAIN, Master MIRCen 2011
Type 2 Biomarker (surrogate endpoints) (Critère ou marqueur de substitution) Clinical benefits of an intervention
Intervention T2 Biomarker = Surrogate endpoints Disease
True clinical outcome "clinically meaningful endpoint"
Modified clinical outcome Marc DHENAIN, Master MIRCen 2011
Many causes of surrogate biomarker failure
Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov. 2003 Jul;2(7):566-80. Marc DHENAIN, Master MIRCen 2011
Plan
Maladie d'Alzheimer
Généralités Modèles animaux Concepts de biomarqueurs Quels biomarqueurs ? ¾ Marqueurs cognitifs ¾ Marqueurs de l'atrophie cérébrale ¾ Marqueurs de l'amyloïdose – Liquide biologiques – Imagerie
¾ Marqueurs fonctionnels ¾ Autres marqueurs ¾ Marqueurs toxicologiques
Exemples d'autres biomarqueurs pour d'autres pathologies
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Marc DHENAIN, Master MIRCen 2011
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 Tg2576+/-
Altérations mnésiques mais pas de "démence"
Marc DHENAIN, Master MIRCen 2011
Origin of behavioral alterations: Oligomers Beta Amyloid Monomers
Fibrils
Oligomers Protofibrils
Correlation with spatial memory task
40kDaltons
Injection of Aβ*56 in young rats
56kDaltons
Lesne, Nature, 2006
Marc DHENAIN, Master MIRCen 2011
Différence majeure cpt souris / Homme Justification des études comportementales La maladie d'Alzheimer est une démence…
Biais de raisonnement Les troubles comportementaux des rongeurs n'ont pas la même origine que ceux de l'homme Alzheimer
Origine Troubles Comportementaux = DNF
Troubles comportementaux modérés
Origine Troubles Comportementaux = Oligomères Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
Conclusion comportement
Use in animals Biomarker
Behavioral/cognitive evaluation
Use in humans
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes
Yes
Yes
Clinical endpoint True benefits of a drug
Yes
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Marc DHENAIN, Master MIRCen 2011
Cerebral atrophy in humans with Alzheimer
Starts in the hippocampus then spread all over the brain Marc DHENAIN, Master MIRCen 2011
Cerebral atrophy in humans with Alzheimer Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Progression from MCI to AD (10 years)
Clifford Jack, ISMRM, 2008 Marc DHENAIN, Master MIRCen 2011
Cerebral (temporal) atrophy Effect of AN1792/QS-21 or placebo on exploratory volumetric MRI measures in the efficacy-evaluable population 6 % changes
5 Placebo
4 3
Antibody responder
2 1 0 Whole-brain volume Ventricular volume Observed change Observed change from baseline from baseline
A good marker for the diagnosis (T0 biomarker) can be questionable for therapeutic follow-up (T2 biomarker) Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
Atrophy of white matter
White matter alterations
Mammillo-thalamic tract diameter 0,30 0,29
mm
0,28 0,27 0,26 0,25 0,24
Y
O
Delatour et al. (2006). Neurobiol Aging, 27(6), 835-847. Marc DHENAIN, Master MIRCen 2011
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
Altération détectée : Atrophie substance blanche Biomarqueur de : ??? Différence par rapport à la pathologie humaine Mais voir : Villain, N., B. Desgranges, et al.
(2008). "Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer's disease." J Neurosci 28(24): 6174-81. Marc DHENAIN, Master MIRCen 2011
MRI evaluation of atrophy in mouse lemurs
IR-RARE ; TR=2500 msec, TE=6 msec, TEw=45 msec, TI=200 msec, Résol isotrope 234 µm Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
Lien entre altérations comportementales et atrophie chez les animaux âgés
ÆLe microcèbe est le seul primate (non-humain) chez qui une corrélation entre atrophie cérébrale macroscopique et les altérations cognitives a été mise en évidence Picq et al. Neurobiol Aging. In Press Marc DHENAIN, Master MIRCen 2011
Conclusion atrophie Lemurs Use in animals Biomarker
Cerebral atrophy
Use in humans
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes
No
Yes
Clinical endpoint True benefits of a drug No
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Marc DHENAIN, Master MIRCen 2011
Les plaques amyloïdes
Modifié de Hyman BT et al. Journal of Neuropathology and Experimental Neurology 1993;52(6):594-600. Marc DHENAIN, Master MIRCen 2011
Autres formes d'amyloïde
Craft, D. L., Wein L. M., Selkoe, D. J.. (2002). Bull Math Biol 64(5): 1011-31. Marc DHENAIN, Master MIRCen 2011
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in CSF and plasma in humans
Brain parenchyma Blood vessel + BBB
CSF
In Humans - Decreased Abeta42 level in AD patients - No change ? Marc DHENAIN, Master MIRCen 2011
Decreased amyloid42 level in Human CSF during AD
Andreasen, N., C. Hesse, et al. (1999). "Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease." Arch Neurol 56(6): 673-80. Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in CSF: Therapeutic evolution Tg2576 – 17 months
Marker of soluble amyloid
Lanz, T. A, et al. (2003). J Pharmacol Exp Ther 305(3): 864-71 (Pfizer). Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in Plasma: Therapeutic evaluation Tg2576 – 6 months
Lanz, T. A, et al. (2003). J Pharmacol Exp Ther 305(3): 864-71 (Pfizer). Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in CSF Use in animals
Use in humans Clinical endpoint
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Amyloid in CSF (comes from soluble amyloid)
Yes
Yes
Yes
No
Amyloid in Plasma (comes from soluble amyloid)
Yes
Yes
No
No
Biomarker
True benefits of a drug
Marc DHENAIN, Master MIRCen 2011
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Marc DHENAIN, Master MIRCen 2011
Amyloid imaging in humans (by PET)
Marc DHENAIN, Master MIRCen 2011
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…) Dubois, B. et al.-2007 Lancet Neurol 6(8): 734-46. Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
AV45 – a new marker for AD
Poisnel & Barre, ICAD, 2011 Marc DHENAIN, Master MIRCen 2011
Conclusion: amyloid detection - PET Use in animals Biomarker
Amyloid (Aggregated - PET + PIB) Futur contrast agents (AV45) ?
Use in humans Clinical endpoint
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes
No No
Yes
No
Yes Yes?
Yes Yes ??
Yes Yes
No
True benefits of a drug
Marc DHENAIN, Master MIRCen 2011
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 Marc DHENAIN, Master MIRCen 2011
Multiphoton microscopy
Fenêtre sur le cerveau
Marquage par un fluorophore Thioflavine S (par exemple)
Résolution = 1 µm Profondeur = 150 µm Marc DHENAIN, Master MIRCen 2011
Multiphoton microscopy
Plaques séniles
Angiopathie amyloïde Christie R. H. et al., The Journal of Neuroscience, 21(3), 858-864, 2001
Marc DHENAIN, Master MIRCen 2011
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
Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
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. Marc DHENAIN, Master MIRCen 2011
Near Infrared imaging : Longitudinal follow up of plaque toxicity Light source (laser and excitation filters)
CCD camera and emission filters
NIRF region 650-900nm
Hintersteiner, M., et al. (Novartis)(2005). " Nat Biotechnol 23(5): 577-83. Marc DHENAIN, Master MIRCen 2011
Near Infrared imaging : Longitudinal follow up of plaque toxicity Light source (laser and excitation filters)
CCD camera and emission filters
Hintersteiner, M., A. Enz, et al. (2005). " Nat Biotechnol 23(5): 577-83. Marc DHENAIN, Master MIRCen 2011
Near Infrared imaging : Longitudinal follow up of plaque toxicity
10 month APP23 10 month Wt
APP23 (17 months)
Wt=Control (17 months)
Hintersteiner, M., A. Enz, et al. (2005). " Nat Biotechnol 23(5): 577-83. Marc DHENAIN, Master MIRCen 2011
Near Infrared imaging : Longitudinal follow up of plaque toxicity
10 month APP23 10 month Wt
Hintersteiner, M., et al. (Novartis) (2005). " Nat Biotechnol 23(5): 577-83. Marc DHENAIN, Master MIRCen 2011
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
Multiphoton
Yes
Yes
No
No
NIR
Yes
Yes
No
No
Biomarker
True benefits of a drug
Marc DHENAIN, Master MIRCen 2011
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Marc DHENAIN, Master MIRCen 2011
Imagerie des plaques en IRM
Détection Directe (IRM)
Détection Indirecte
Postmortem Relaxivité In vivo
Contraste spontané
Agents de contraste
Marc DHENAIN, Master MIRCen 2011
Post-mortem detection of amyloid plaques
• Tg2576 (APP)/PS1 •17-19 months • T2-w images @ 7 Tesla • 2 hours Lee, S. P., M. F. Falangola, et al. (2004). Magnetic Resonance in Medicine 52: 538-544. Marc DHENAIN, Master MIRCen 2011
In-vivo plaques imaging without contrast agent
Abeta
Iron
Jack, J Neurosc, 2005 Braakman, JMRI, 2006 Marc DHENAIN, Master MIRCen 2011
Detection of thalamic plaques by MRI
Double Labeling PERLS – Congo red
APP/PS1 MRI
Iron staining (PERLS DAB)
Same mouse
Æ In APP/PS1 mice, thalamic spots are linked to the presence of iron/calcium agregates in the senile plaques Dhenain et al. Neurobiol Aging. 2009 January. Marc DHENAIN, Master MIRCen 2011
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
Dhenain M, et al. MRM. 55. 687-693. 2006.
6
5
Marc DHENAIN, Master MIRCen 2011
Gd-staining: Follow-up of amyloid plaques by MRI 6 months
9 months
14 months
20 months
1. Imaging-Methodo Resolution : 23 x 23 x 90 µm3 - Acquisition time: 13h49min
Marc Master MIRCen 2011 A.DHENAIN, Petiet (Transal), C Wiggins
Etat de l'art Détection - In vivo / 3D (Gd-staining (GdSt))
Marc DHENAIN, Master MIRCen 2011
Imagerie des plaques en IRM
Détection Directe (IRM)
Détection Indirecte
Postmortem Relaxivité In vivo
Contraste spontané
Agents de contraste
Marc DHENAIN, Master MIRCen 2011
T2 decrease in the subiculum Age < 23 weeks
- Caused by iron accumulation within the plaques El Tannir El Tayara N. Neurobiol Dis. 2006 Apr;22(1):199-208.
- Caused by amyloid plaques per se El Tannir El Tayara N. Magn Reson Med. 2007 Jul;58(1):179-84. Marc DHENAIN, Master MIRCen 2011
Conclusion: amyloid detection - MRI
Use in animals
Use in humans Clinical endpoint
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Amyloid (PET + contrast agent)
Yes
No
Yes
No
Amyloid (MRI without contrast agent)
Yes
Yes
No
No
Amyloid (MRI + contrast agent)
Yes
No
No
No
Amyloid load ( MRI + Relaxometry)
Yes
No
No
No
Biomarker
True benefits of a drug
Master MIRCen 2011 Dhenain, MR Insights,Marc 2008DHENAIN, (http://www.la-press.com/)
Où chercher l'Amyloïde béta
Liquides périphériques LCR Sang
Le cerveau PET Imagerie optique IRM
Les yeux Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in the eyes
Marc DHENAIN, Master MIRCen 2011
Evaluation of amyloid in the eyes Anti-Aβ immunogold electron photomicrograph of the lens Å
Alzheimer
ÆÅ Control Æ
Goldstein, L. E., et al. (2003)." Lancet 361(9365): 1258-65.
Æ AD related cataract in humans and animals Tg mice cataract
Human
Goldstein, L. E
Melov, 2005 Marc DHENAIN, Master MIRCen 2011
Infrared quasi-elastic light scattering (QLS) technology + Fluorescent Ligand Scanning (FLS) QLS technology - Low-power infrared laser light into the eye - Measure of the backscattered light. Æ Index of the amyloid pathology in transgenic animals Moncaster, J. A., (2008). Alzheimer's & Dementia -The journal of the Alzheimer's Association -4(4-Suppl2): T330.
FLS technology = Use of a specific contrast agent - QLS technology can be associated to the use of fluorescent ligands (ex. Methoxy-X04) that improve its ability to detect the amyloid load (Moncaster et al 2008).
Neuroptix Corporation (European Patent 1 913 866 A1). $1 million milestone payment in collaboration with merck & Co., inc., for early detection and monitoring of Alzheimer's disease process Marc DHENAIN, Master MIRCen 2011
Conclusion amyloid plaque imaging Use in animals Biomarker
QLS + FLS
Use in humans
Detection of AD-like pathology
Preclinical evaluation of drugs
Clinical diagnostic
Yes ?
Yes Yes??
Yes
Clinical endpoint True benefits of a drug No
Marc DHENAIN, Master MIRCen 2011
Maladie d'Alzheimer : Quels biomarqueurs ? Dépôts Amyloïdes
DNF
Altérations fonctionnelles
Atrophie
Marc DHENAIN, Master MIRCen 2011
Altérations fonctionnelles associées à la MA
Métabolisme cérébral Perfusion cérébrale Transport neuronal
Marc DHENAIN, Master MIRCen 2011
Altérations fonctionnelles associées à la MA
Métabolisme cérébral Perfusion cérébrale Transport neuronal
Marc DHENAIN, Master MIRCen 2011
Imagerie du métabolisme cérébral
µPET Focus 220 Marc DHENAIN, Master MIRCen 2011
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, In press Marc DHENAIN, Master MIRCen 2011
Amyloid plaques are associated to an increased glucose uptake 2DG autoradiography
G. Poisnel et al, Neurobiology of Aging, In press Marc DHENAIN, Master MIRCen 2011
[18F]-FDG et µTEP Hypométabolisme chez les Souris Alzheimer sous stimulation
18F]-FDG - µTEP - souris APP de 16 mois (Nicolakakis et al., 2008, J Neurosci 28(37): 9287-96.) - Zones cérébrales non stimulées=↑ rétention de [18F]-FDG - Stimulation des moustaches= ↓ rétention du [18F]-FDG dans cortex sensorimoteur Marc DHENAIN, Master MIRCen 2011
Altérations fonctionnelles associées à la MA
Métabolisme cérébral Perfusion cérébrale Transport neuronal
Marc DHENAIN, Master MIRCen 2011
Hypoperfusion in AD patients
Johnson et al., Radiology, 2005 Marc DHENAIN, Master MIRCen 2011
Stimulation pharmacologique MRI 1
Pharmacological Treatment
MRI 2 Control
Pre-treatment endorem
APP23
(GABA a antagonist)
Average CBV changes (%)
GABAa antagonist : Neuronal dis-inhibitor
Wt
APP23
Mueggler (Novartis), J. Neurosc., 2002 Marc DHENAIN, Master MIRCen 2011
Perfusion evaluation by MRI: Principle Imaging slice
Carotide
Comparaison of the contrast between « spin tagging » and « controle conditions »
Surface coil on the neck: Spin tagging
Perfusion Map
Frank Kober CRMBM Marc DHENAIN, Master MIRCen 2011
Cartes de perfusion dans un modèle d’ischémie cérébrale (MCAO)
CBF (ml/g/min)
C. Laigle, A. Viola, CRMBM Marc DHENAIN, Master MIRCen 2011
Cortical hypoperfusion in Tg mice Perfusion in the parietal cortex 4
*
3,5
ml/g.min
3 2,5
*
* PS1 APP/PS1
2 1,5 1
nPS1=10 nAPP/PS1=9 (age:54weeks)
0,5 0
Normocapnia
Hypercapnia
*:p
