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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

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Introduction

Human research

Animal research

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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)

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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)

?

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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)

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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)

?

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AN and BN

Etiology ? – Personality traits

– Neurobiological vulnerabilities

(e.g. 5-HT)

– Genetics

– Consequences of malnutrition

– Environmental pressures

Understanding possible mechanisms

New treatment options

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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

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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)

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Type 1 cannabinoid receptor (CB1R)

Predominantly presynaptic, highly expressed in brain

modulation of neurotransmitter release via retrograde

mechanism

(Wilson et al. Science 2002)

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CB1R imaging

[18F]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

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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)

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Project

Translational in vivo PET imaging

of CB1R in eating disorders

HUMAN ANIMAL

- Anorexia Nervosa

- Boulimia Nervosa

- Activity-based anorexia model

- Binge-eating model

CB1R characterization in ED

Potential target for therapy?

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Introduction

Human research

Animal research

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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 ?

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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

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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

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PET imagingProcessing :

[18F]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)

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Voxel-based morphometry

Group comparisons (AN-BN-CON)

Correlation analyses

Data analysis

Statistical Parametric Mapping (SPM2)

Predefined Volume-of-Interest analysis (VOI; Pmod)

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Results

Clinical characteristics

AN : lower BMI ANOVA : p = 3.10-6

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Results

ED related questionnaires

AN BN p-value

EDES ED symptoms < < p<1.10-6

EDI ED symptoms > > p<1.10-6

BDI Depression > > p<1.10-6

FMPS Perfectionism > > p=9.10-6

SCL-90 Discomfort > > p<1.10-6

DII Impulsivity - - p=0.2

Versus controls :

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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

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Results

Relative CB1R availability

AN > CON : bilateral insular increase (BA 47 and 48)

pheight < 0.001 uncorrectedpcluster = 0.002 left corrected 0.011 right

+ 5.9%

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Results

Relative CB1R availability

BN > CON : left insular increase (BA 47)

pheight < 0.001 uncorrectedpcluster = 2.10-5 corrected

+ 5.0%

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Results

Relative CB1R availability

BN > CON : left superior frontal cortex increase (BA 10)

pheight < 0.001 uncorrectedpcluster = 0.003 corrected

+ 3.5%

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Results

To do

correlation analyses :

BMI as a marker of disease severity

ED questionnaire scores

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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)

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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?

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Human research in progress

Longitudinal approach :

Second CB1R PET scan when the patient fulfills criteria

indicating recovery

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Introduction

Human research

Animal research

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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

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CB1R imaging in ABA

Global absolute [18F]-MK9470 binding is increased in male

ABA rats

SPM : pcluster < 0.04 (corrected)

VOI : average difference 37%

(Van Laere et al. submitted)

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CB1R imaging in ABA : ongoing

cross-sectional acquisitions in female rats

Further differentiation of behavioral components in ABA

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CB1R imaging in ABA : ongoing

longitudinal acquisitions in female rats

baseline / in ABA model / recovery

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Conclusion

[18F]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 !