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In vivo molecular imaging of the Brain Type 1 Cannabinoid Receptor in Eating Disorders

In vivo molecular imaging of the Brain Type 1 Cannabinoid Receptor in Eating Disorders . w ork in progress seminar. Nathalie Gérard Division of Nuclear Medicine UZ Leuven – KU Leuven Promotor : Prof. Dr. Koen Van Laere. Outline. Introduction Anorexia nervosa / Bulimia nervosa

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In vivo molecular imaging of the Brain Type 1 Cannabinoid Receptor in Eating Disorders

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  1. In vivomolecularimaging of the Brain Type 1 Cannabinoid Receptor in Eating Disorders work in progress seminar Nathalie Gérard Division of Nuclear Medicine UZ Leuven – KU Leuven Promotor : Prof. Dr. Koen Van Laere Nathalie Gérard - MIRC seminar

  2. Outline • Introduction • Anorexia nervosa / Bulimia nervosa • Activity-based anorexia rat model • The endocannabinoid system • CB1 receptor imaging • Hypothesis and aims • CB1 receptor characterization in ananimal model for anorexia nervosa • Cross-sectional design • Longitudinal design • Pharmacologicalintervention • CB1 receptor characterization in anorexia nervosa and bulimia nervosa patients • Additional and futurework Nathalie Gérard - MIRC seminar

  3. Introduction • refusal to maintainnormal body weight • intense fear of gainingweight • distorted body perception • amenorrhea • excessivephysicalactivity • bingeeatingwith loss of control • inappropriatecompensatorybehaviour • excessiveemphasison body shape / • weight • twice a week for min. 3 months • restrictive / binge - purge • purging / (non-purging) • 0.7% in youngwomen • 47% full recovery • 5 to 10% mortalityrate • 2% in youngwomen • 50% full recovery over 10 years • 0 to 3% mortalityrate Fairburn, Lancet 2003 ; Keel, Am J Psychiatry 1997 Nathalie Gérard - MIRC seminar

  4. Introduction • activity-based anorexia model : well-characterized and validated model for • anorexia nervosa in the rat limited feeding period (1.5h / day) + running wheel • induction of hyperactivity and spontaneousfoodrestriction Routtenberg, J Comp PhysiolPsychol 1968 Nathalie Gérard - MIRC seminar

  5. Introduction the endocannabinoidsystem : important in brainneuromodulation Guzman Nature Reviews 2003 Nathalie Gérard - MIRC seminar

  6. Introduction the role of the endocannabinoid system in eatingbehaviour metabolic somatic wanting liking homeostatic hedonic dopamineneurotransmission opiates cannabinoid system Van den EyndeChildAdolescPsychiatricClin N Am 2008 Nathalie Gérard - MIRC seminar

  7. Introduction the role of the endocannabinoid system in eatingbehaviour • Cannabinoid agonistsstimulatefood intake • e.g. - cannabis-inducedhunger(Abel BehavBiol 1975) • - agonisttherapy in AIDS-related anorexia (Beal et al. J Pain Symptom Manage 1997) ; • howeverone trial with ∆⁹-THC in AN patientsfailed(Gross et al. J ClinPsychopharmacol 1983) • - orexigenic effect in animals(AriasHorcajadas Mol Neurobiol 2007) • Cannabinoid inverse agonists / antagonistsas anti-obesitymedication • (Rimonabant, Taranabant) (Pi-Sunyer et al. JAMA 2006, Addy et al. CellMetabolism 2008) • Different CB1R allelesassociatedwith Anorexia Nervosa-restrictive and Anorexia • Nervosa-bingeingpurging subtypes (Siegfried et al. Am J Med Genet 2004) • Endocannabinoid anandamideincreased in plasma of AN patients, not in BN • (Monteleone et al. Neuropsychopharmacology 2005) Nathalie Gérard - MIRC seminar

  8. Introduction Imaging of the type 1 cannabinoid receptor [18F]MK-9470 • High-affinity, highly selective CB1 receptor tracer • Preclinical validation / clinical application Burns et al. PNAS 2007 Nathalie Gérard - MIRC seminar

  9. Hypothesis and aims Is the endocannabinoid system hypoactive in anorecticconditions ? • PET characterization of in vivocerebral CB1R availability in activity-based anorexia rats / femalepatientswith anorexia orbulimia nervosa compared to controls • Endocannabinoidaugmentingtherapy in ABA Nathalie Gérard - MIRC seminar

  10. ANIMAL RESEARCH CB1R microPET in the activity-based anorexia model Nathalie Gérard - MIRC seminar

  11. Cross-sectional design CB1R microPET ABA, n = 14 DIET, n = 10 n = 44 WHEEL , n = 10 CONTROL , n = 10 time (days) randomisation IN ABA model arrival Nathalie Gérard - MIRC seminar

  12. Longitudinal design CB1R microPET CB1R microPET CB1R microPET c recovery time (days) randomisation IN ABA model OUT ABA model arrival body weight Nathalie Gérard - MIRC seminar

  13. Methods • microPET : 500 µCi18F-MK9470 • 20’ 1 hour post injection • image processing : • spatialnormalizationon18F-MK9470 binding templateoriented in standardizedPaxinosspace Activityconc * ((body weight + 250 g) / 2) mSUV = • parametric images basedonmSUVquantification Injecteddose Nathalie Gérard - MIRC seminar

  14. ABA DIET WHEEL CON Results CS LG relativemean body weight meanfood intake Nathalie Gérard - MIRC seminar

  15. ABA DIET WHEEL CON Results CS LG wheelrotations weightduringrecovery Nathalie Gérard - MIRC seminar

  16. Results : cross-sectional CB1R ABA DIET WHEEL CON + 53% + 51% mean CB1R binding (mSUV) *** p < 0,001 Nathalie Gérard - MIRC seminar mSUV

  17. Results : longitudinal CB1R BASELINE CHRONIC RECOVERY ABA median CB1R binding (mSUV) 2.3 CON mSUV ** p < 0,01 0.7 Nathalie Gérard - MIRC seminar

  18. Results : regional CB1R binding in ABA ABA > control • Most pronouncedregionalincrease in CB1R binding was consistentlyfound in the hippocampus stress + Hypercortisolism, Affectsespeciallyhippocampal neurons due to largeamounts of glucocorticoidreceptors HPA axis _ ECS ↓ Nathalie Gérard - MIRC seminar Hillebrandet al. Peptides 2005

  19. Conclusions • Global significant increase in CB1R binding in ABA ; • confirmed in a follow-up experiment • CB1R upregulation in ABA normalizeswithrecovery Couldendocannabinoidaugmentingtherapybebeneficial in ABA? CB1R upregulationsuggests a reversiblecompensationmechanismfor a hypoactive ECS Nathalie Gérard - MIRC seminar

  20. EC augmentingtherapy in ABA 4x 7 ABA rats, 1 week i.p. injectiontwice a daywith : • Exogenous CB1R agonist : • WIN 55,212-2 ; low dose 0.25 mg/kg orhigherdose 1 mg/kg • Fatty acid amidehydrolaseinhibitor: • URB-597 ; 0.3 mg/kg • Vehicle : • 1% Tween-80 in aqua Nathalie Gérard - MIRC seminar

  21. Preliminaryresults ∆ body weight (g) ∆ food intake (g) ∆ running activity (km) URB URB URB VEH VEH VEH WIN L WIN L WIN L WIN H WIN H WIN H mean mean ± SE min-max Nathalie Gérard - MIRC seminar

  22. Conclusions • No significant differencesbetweengroups in changes of body weight, food intake and running activityaftertherapycompared to beforetherapy • CAVE suboptimal low dosage vs. more rapidtolerancewithhigherdosage? • Effect of endogenous 2-AG increasewithmonoamine glycerol lipaseinhibitors? Nathalie Gérard - MIRC seminar

  23. HUMAN RESEARCH CB1R PET in anorexia and bulimia nervosa Nathalie Gérard - MIRC seminar

  24. Studyaim To characterize the in vivocerebral CB1R availability in femalepatientswith anorexia and bulimianervosa compared to healthywomen Is the in vivo cerebral CB1R availability correlated with eating disorder-related symptoms in AN or BN? Nathalie Gérard - MIRC seminar

  25. Subjects p < 0.05 : * AN vs. BN, # AN vs. controls, § BN vs. controls EDES : eating disorder evaluation scale (Vandereycken 1993) EDI : eating disorder inventory (Garner 2007) Nathalie Gérard - MIRC seminar

  26. Methods (1) 90 min. [18F]MK-9470 ~ 306 MBq PET scan 30 min. Modified Standard Uptake Values … Nathalie Gérard - MIRC seminar

  27. Methods(2) • quantification of [18F]MK-9470 PET • based on the macroparameter mSUV as index of CB1R availability activity concentration x (body mass +70)/2 injected dose mSUV = • mSUV is correlatedwithirreversibleuptakerate constant Ki which is a measure for VT, in healthysubjects and AN/BN patients, and is independent of blood flow • noarterial sampling -> betterclinicalfeasibility Nathalie Gérard - MIRC seminar Sanabria et al. 2009 (submitted)

  28. Methods (3) Normalizationon CB1R binding template PET – MRI coregistration Statistical analyses • Voxel-by-voxel : StatisticalParametricMapping (SPM2) • Volumes-of-interest • (Pmod) Nathalie Gérard - MIRC seminar

  29. Results (1) Global cerebral increase of CB1R binding in AN patients : compared to BN patients on average + 14.7 % ; p < 0.05 compared to controls on average + 24.5 % ; p < 0.001 Nathalie Gérard - MIRC seminar

  30. Results (2) Regional increases of CB1R binding in AN and BN patients compared to controls (mSUV normalized on global cerebral uptake) p height < 0.001 ; p cluster < 0.05 : AN > CON Insular cortex Inferior frontal cortex Inferior temporal cortex Nathalie Gérard - MIRC seminar

  31. Results (3) Regional increases of CB1R binding in AN and BN patients compared to controls (mSUV normalized on global cerebral uptake) p height < 0.001 ; p cluster < 0.05 : BN > CON Insular cortex No significant differences between AN and BN patients No significant differences between AN subtypes Nathalie Gérard - MIRC seminar

  32. Results (4) Regional CB1R binding correlates with disease parameters in AN, not in BN patients p height < 0.001 ; p cluster < 0.05 : Positivecorrelationin the superior temporal brainareawith the EDI subscale‘drive forthinness’ Nathalie Gérard - MIRC seminar

  33. Discussion (1) • Global cerebralincrease of in vivo CB1R availability in AN, • not in BN • Reducing the endocannabinoid tone in anorectic conditions could • reduce appetite and motivation to eat (Fride et al. Exp Biol Med 2005) • CB1R upregulation as a compensatory response ? BN : overeating(Klein et al. PhysiolBehav 2004) hormonaleffects : e.g. FAAH inhibitionbyestrogen absent in AN patients (due to amenorrhea), anandamide↓ (Waleh et al. Gene 2002) Nathalie Gérard - MIRC seminar

  34. Discussion (2) • Common feature in AN and in BN : increasedinsular CB1R • availability • Insula serves anintegrativefunction for brainprocesses relevant to • eating disorders : hunger and food intake, reward and emotion • processing, interoceptive awareness • Insulardysfunction in eatingdisorders : • µ-opioid receptor decrease in BN (Bencherif et al J Nucl Med 2005) • alteredactivitywithsymptomprovocationor taste stimuli (fMRI) • (e.g. Oberndorfer et al Biol Psychiatry 2008) Nathalie Gérard - MIRC seminar

  35. Conclusion ECS seems to be a relevant player in AN, to a lesserextent in BN Importance of insulardysfunction in AN / BN Trait- or state- relatedchanges? Follow-up study in subgroupfulfilling criteria indicatingrecovery Nathalie Gérard - MIRC seminar

  36. ADDITIONAL AND FUTURE WORK Nathalie Gérard - MIRC seminar

  37. Results : metabolicimaging in AN and BN Commonmetabolicsignatures in anorectics and bulimics : AN < HV BN < HV • parietal cortex • cingulatebrain • area • centralbrainarea Nathalie Gérard - MIRC seminar

  38. Results : metabolicimaging in AN and BN AN > HV BN > HV • occipital cortex • orbitofrontal • cortex • mesiotemporal • cortex Nathalie Gérard - MIRC seminar

  39. Human studies : ongoing • CB1R PET in eating disorders : repeatstudy in recoveringanorectics and bulimics • CB1R PET in obesity : whatabout the opposite site of the eating disorder spectrum? Nathalie Gérard - MIRC seminar

  40. Acknowledgements • All studyparticipants • UniversityHospitals Leuven : • LaboratoryforExperimental and FunctionalNeurosurgery • Merck & Co, Inc. for the tracer precursor • Research Council K.U. Leuven (OT/05/58) • Nuclear Medicine team • Centre for Eating Disorders • PET Radiopharmacy team Nathalie Gérard - MIRC seminar

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