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15-5-2008 1 In vivo molecular imaging of the type 1 cannabinoid receptor in eating disorders Nathalie Gérard Division of Nuclear Medicine UZ Leuven – KU.

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Presentation on theme: "15-5-2008 1 In vivo molecular imaging of the type 1 cannabinoid receptor in eating disorders Nathalie Gérard Division of Nuclear Medicine UZ Leuven – KU."— Presentation transcript:

1 15-5-2008 1 In vivo molecular imaging of the type 1 cannabinoid receptor in eating disorders Nathalie Gérard Division of Nuclear Medicine UZ Leuven – KU Leuven Promotor: Prof. Dr. K. Van Laere

2 15-5-2008 2  Introduction  Human research  Animal research

3 15-5-2008 3 Anorexia Nervosa (AN) DSM-IV-TR criteria Refusal to maintain body weight on a normal level Intense fear of gaining weight Distorted body perception Amenorrhea (Excessive physical activity) Subtypes : restrictive / binge-purge Prevalence : 0.7% in young women (Fairburn et al. Lancet 2003)

4 15-5-2008 4 Anorexia Nervosa Poor outcome : full recovery only in 47% high mortality rate : 5 to 10 % Therapeutic options :  Nutritional therapy  Psychotherapy  Pharmacotherapy (Fairburn et al. Lancet 2003) ?

5 15-5-2008 5 Bulimia Nervosa (BN) DSM-IV-TR criteria Binge eating episodes with loss of control Inappropriate compensatory behaviour 2x / week during minimum 3 months Excessive emphasis on body shape and weight Subtypes : purging / (non-purging) Prevalence : 2% in young women (Fairburn et al. Lancet 2003)

6 15-5-2008 6 Bulimia Nervosa Poor outcome : full recovery only in 50% over 10 years mortality rate : 0 to 3 % Therapeutic options :  Psychotherapy  Pharmacotherapy (Keel et al. Am J Psychiatry 1997) ?

7 15-5-2008 7 AN and BN Etiology ?– Personality traits – Neurobiological vulnerabilities (e.g. 5-HT) – Genetics – Consequences of malnutrition – Environmental pressures Understanding possible mechanisms New treatment options

8 15-5-2008 8 Endocannabinoid system (ECS) Psychotropic cannabis effects led to the discovery of cannabinoids G-coupled cannabinoid receptors CB1R : brain CB2R : immune system cells Endocannabinoids : e.g anandamide, 2-AG Degradation enzymes : e.g. FAAH

9 15-5-2008 9 ECS and eating disorders Genetic evidence: Different CB1R alleles in subtypes of AN (Siegfried et al. Am J Medic Genet 2004) Knockout mice : eat less after food deprivation and are leaner (Marsicano et al. Nature 2002) Pharmacological evidence: CB1R agonists in cancer and AIDS cachexia (Beal et al. J Pain Manag 1997) Inverse agonists (e.g. rimonabant) as anti-obesity medication (Van Gaal et al. Lancet 2005)

10 15-5-2008 10 Type 1 cannabinoid receptor (CB1R) Predominantly presynaptic, highly expressed in brain modulation of neurotransmitter release via retrograde mechanism (Wilson et al. Science 2002)

11 15-5-2008 11 CB1R imaging [ 18 F]MK-9470 PET : high-affinity and high-selectivity radioligand Preclinical validation and clinical application described (Burns, Van Laere et al. 2007) Human in vivo distribution (Van Laere et al. 2008) High concentrations in frontal cortex, cingulate cortex and striatum

12 15-5-2008 12 Functional neuroimaging in ED Perfusion SPECT FDG PET Receptor imaging : 5-HT DA Major conclusions : - involvement of limbic, frontal, parietal cortices - serotonergic and dopaminergic alterations (Kaye 2007)

13 15-5-2008 13 Project Translational in vivo PET imaging of CB1R in eating disorders HUMANANIMAL - Anorexia Nervosa - Boulimia Nervosa - Activity-based anorexia model - Binge-eating model CB1R characterization in ED Potential target for therapy?

14 15-5-2008 14  Introduction  Human research  Animal research

15 15-5-2008 15 Hypothesis and aim Imbalance of ECS in eating disorders with implications on cerebral availability of CB1R underactive status in AN ? hyperactive status in BN ? [18F]MK-9470 PET altered in vivo ligand binding in AN and BN versus controls ?

16 15-5-2008 16 Methods Population : Anorexia Nervosa (n = 10) Bulimia Nervosa (n = 17) Healthy age-matched control women (n = 19) Acquisitions : Eating disorder related questionnaires (EDES, EDI, BDI, DII, FMPS, SCL-90) T1 3D-MPRAGE MRI [18F]MK-9470 PET scan

17 15-5-2008 17 PET imaging Data acquisition : on average 315 MBq [18F]MK-9470 HR+ PET camera (Siemens) 30’ dynamic scanning 90’ post injection FBP reconstruction Processing (SPM2) : Coregistration to MR images Spatial normalization on CB1R template Segmentation of MR images into gray matter maps for voxel-based morphometry

18 15-5-2008 18 PET imaging Processing : [ 18 F]MK-9470 binding determined based on an area-under-the-curve (AUC) model between 90-120 min p.i. Standardized uptake values (SUV) SUV = activity concentration (kBq/cc) x body mass (kg) injected dose (MBq) (Burns et al. PNAS 2007)

19 15-5-2008 19 Voxel-based morphometry Group comparisons (AN-BN-CON) Correlation analyses Data analysis Statistical Parametric Mapping (SPM2) Predefined Volume-of-Interest analysis (VOI; Pmod)

20 15-5-2008 20 Results Clinical characteristics AN : lower BMI ANOVA : p = 3.10 -6

21 15-5-2008 21 Results ED related questionnaires ANBNp-value EDESED symptoms<>p<1.10 -6 BDIDepression>>p<1.10 -6 FMPSPerfectionism>>p=9.10 -6 SCL-90Discomfort>>p<1.10 -6 DIIImpulsivity--p=0.2 Versus controls :

22 15-5-2008 22 Results Voxel-based morphometry Mean gray matter map AN Mean gray matter map BN Mean gray matter map CON No structural changes detected => no partial volume correction required

23 15-5-2008 23 Results Relative CB1R availability AN > CON : bilateral insular increase (BA 47 and 48) p height < 0.001 uncorrected p cluster = 0.002 left corrected 0.011 right + 5.9%

24 15-5-2008 24 Results Relative CB1R availability BN > CON : left insular increase (BA 47) p height < 0.001 uncorrected p cluster = 2.10 -5 corrected + 5.0%

25 15-5-2008 25 Results Relative CB1R availability BN > CON : left superior frontal cortex increase (BA 10) p height < 0.001 uncorrected p cluster = 0.003 corrected + 3.5%

26 15-5-2008 26 Results To do correlation analyses : BMI as a marker of disease severity ED questionnaire scores

27 15-5-2008 27 Discussion Insular cortex implicated in several neuropsychiatric disorders within limbic system, especially contributing to the rewarding and sensory aspects of feeding behavior insula-striatal circuits : mediation of palatable food intake more general : processing of interoceptive information (Kaye 2007, Nagai 2007)

28 15-5-2008 28 Discussion (2) Insular cortex dysfunctional insula-striatal circuits in eating disorders insular dysfunction has been described in recovered AN and BN patients symptoms in ED related with interoceptive processing : distorted body image lack of insight and symptom recognition elevated pain tresholds (Kaye 2007, Nagai 2007) Insular ECS dysregulation might be implicated in altered reward and interoceptive responses Potential implication for cannabinoid therapy?

29 15-5-2008 29 Human research in progress Longitudinal approach : Second CB1R PET scan when the patient fulfills criteria indicating recovery

30 15-5-2008 30  Introduction  Human research  Animal research

31 15-5-2008 31 Activity-based anorexia (ABA) Running wheel + limited feeding period (1.5h/day) induce hyperactivity and spontaneous restriction of food intake (Routtenberg, J Comp Physiol Psychol 1968) Well-characterized and frequently used animal model

32 15-5-2008 32 CB1R imaging in ABA Global absolute [ 18 F]-MK9470 binding is increased in male ABA rats SPM : p cluster < 0.04 (corrected) VOI : average difference 37% (Van Laere et al. submitted)

33 15-5-2008 33 CB1R imaging in ABA : ongoing cross-sectional acquisitions in female rats Further differentiation of behavioral components in ABA

34 15-5-2008 34 CB1R imaging in ABA : ongoing longitudinal acquisitions in female rats baseline / in ABA model / recovery

35 15-5-2008 35 Conclusion [ 18 F]MK-9470 PET is a useful novel tool to study the CB1R in a variety of neurological / psychiatric diseases Link between ECS and eating behavior ‘hot topic’ for further study! THANK YOU FOR YOUR ATTENTION !


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