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1. Background and achievements of our research groupThe endocannabinoid system (ECS) is strongly involved in various physiological central nervous system (CNS) functions including motor activity, cognition, behaviour and immune response 1. CB1 receptors (CB1R) are the most widely expressed G-coupled receptors in the brain and directly or indirectly modulate major neurotransmitters such as glutamate, GABA and dopamine. CB2 receptors (CB2R) are present in only small quantities in the healthy human brain but are overexpressed on activated microglia and therefore in neuroinflammation 2. There is accumulating evidence that the endocannabinoid system (ECS) is involved in the pathogenesis and clinical expression of neurodegenerative disorders 3,4. In vitro and preclinical studies have demonstrated a potential neuroprotective role of the ECS in neurodegenerative disease, which involves pathways through both receptors 4,5.^ Depending on the clinical question, selective cannabinoid agonists and antagonists without psychoactive side-profile may be useful in counteracting the neurodegenerative process or in providing symptomatic improvement of cognitive and/or behavioural disturbances 6. Until recently, positron emission tomography (PET) of the ECS was hampered by poor performance or unavailability of radioligands for in vivo quantitative assessment of the CB1R and CB2R. Our research team has successfully imaged and quantified the CB1R in the human brain using [18F]MK-9470 PET, a potent CB1R inverse agonist with 0.7 nM binding affinity for the human CB1R and a 60-fold selectivity for CB1R over CB2R 7-10. The group has related its expression to fundamental human behavioral traits 11 and used it in drug development for CB1R inverse agonists 12.^ Pilot studies in movement disorders have been carried out and it was found that in early and advanced Parkinson’s disease (PD) regional decreases in CB1R binding are present in the substantia nigra (SN), and that by contrast increased binding occurs in the basal ganglia (BG) and primary motor cortex that correlates with clinical motor impairment 11. In Huntington’s disease (HD), a pilot study was carried out where we have shown substantial cortical and subcortical decreases in CB1R binding in vivo. In the frontal cortex this decrease correlates with disease burden, as quantified by number of CAG repeat [(CAGn) – 35.5] x age 13. For AD we recently demonstrated that a lower [18F]MK-9470 availability is associated with cognitive impairment (manuscript under preparation).1.^ Aim of the studyIn the present project, we want to build on the previous work by studying the contribution of the CB1R and CB2R as key effectors of the ECS in the pathophysiology and clinical expression of neurodegeneration in human PD, HD and AD. These three diseases are characterized by deficits in cerebral functions in which the CB1R is known to play a crucial modulatory role: cognitive deficits, behavioural impairment, as well as motor impairment in HD and PD. Also, (regional) neuroinflammation is an essential component of the disease burden 5. The relative importance of CB1 and CB2 in neurodegeneration is currently unknown, but needs to be identified in order to provide proof-of-mechanism for possible ECS-based therapies based on modulation of endogenous agonists or selective exogenous agonists or antagonists 16.^ We will investigate quantitatively the regional distribution of activated microglia using CB2 overexpression by [11C]-NE40 PET in PD, HD and AD, compare this to historical and post-mortem literature data to assess the utility of the CB2 target for quantifying the extent of neuroinflammation. The signal derived from TSPO ligands (which bind to the mitochondrial located protein) as in previous PET imaging studies of neuroinflammation may be weaker than CB2 receptor upregulation (membrane expression), hence allowing a potentially stronger biomarker for regional neuroinflammation. We will also study this CB2R signal in relation to regional CB1 receptor availability and neurocognitive performance in patients. Next to behaviour and imaging,we also want to link these data to genetic single nucleotide polymorphisms (SNPs) which may be involved in the response of the ECS in the face of chronic neurotoxic protein deposition as seen in these three disorders.^ In an ongoing study in healthy volunteers, the SNPs for CB1R are being related to functional (regional) CNS expression. The following general hypotheses will be tested:1. Do regional changes of CB1R availability relate to behavioral abnormalities in AD, PD andHD ? Aside from cognitive, executive and motor domains, also psychiatric domains (depression, psychosis and impulse control loss) will be included.2. Is increased CB2R availability present in AD, PDand HD and does the (regional) intensity of this CB2R expression dependon disease burden ? For AD, regional disease load will be measured by simultaneous 11C-PIB amyloid imaging 17,18, for PD by 123I-FPCIT dopamine transporter imaging 19, for HD using 18F-FDG PET 20. 3. Do genetic polymorphisms of the CB1R and CB2R affect differential receptor expression in ageing and do these modulate the ECS response to neurodegeneration?PD is a progressive neurodegenerative disease with motor and non-motor symptoms.^ Altered CB1R-coupled neurotransmission in the basal ganglia may be responsible, at least partially, for motor symptomatology in PD 21. mRNA expression of the CB1R is altered in PD and an increased binding capacity has been described inpost-mortem tissue 22, in correspondence with our group’s recent in vivo data (Van Laere et al, Neurobiol Aging, under 2nd revision). Furthermore, there is a strong functional interaction between the CB1R and dopaminergic dysfunction 23. Recently, more attention has also been given to non-motor pathology in PD, such as mood and behavioural disturbances, also cognitive and executive function disturbances 24. Our previous [18F]MK-9470 PET experiments in PD patients suggest that cognitive dysfunction and loss of initiative in PD correlate with regional CB1R binding in the limbic and prefrontal cortex.The current study will dissect these possible relationships in more detail.^ Early microglial activation has also been observed in PD 25 and is more widespread than the substantia nigra, where dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack.HD is an autosomal dominant, progressive neurodegenerative disorder characterized by widespread neuronal dysfunction especially in the basal ganglia and prefrontal cortex, as well as neuroinflammation 26. The clinical picture of HD encompasses motor features related to basal ganglia dysfunction,but also various non-motor features including cognitive and psychiatricdeficits and subtle changes in personality and cognition are already present in the presymptomatic stage. One of the earliest neurochemical alterations observed in HD patients is the loss of CB1R binding in the basal ganglia 27 which precedes the development of any identifiable structural pathology.^ Using [18F]MK-9470 PET, we demonstrated in vivo that this dysregulation extends to the neocortex and relates to disease burden in the prefrontal cortex in symptomatic patients 13. Microglial activation has been observed in HD in vivo, andis related to disease severity in the striatum in symptomatic patients 28, and even before the onset of symptoms 29. Upregulation of the CB2R is also present in animal models of HD 30 and is thought to be part of an endogenous mechanism of defense that limits the toxic influence of microglia on neuronal homeostasis 31.AD is characterized by beta-amyloid peptide (Aβ) deposition as one of its pathological hallmarks, the senile plaque. Activated microglia clusters at senile plaques contribute to the ongoing inflammatory process and to the progression of the disease 25.^ An immunohistochemical post-mortem AD study showed consistent CB1R immunoreactivity in cortical plaques along with markers of microglial activation, suggesting a direct involvement in the noxious effects of microglia, with a significant reduction of CB1R bindingin the frontal cortex 32. In animal models, stimulation of CB1R/CB2Rs has been shown useful against Aβ neurotoxicity by attenuation of the toxic effects of these fibrilogenic peptides 32,33. The ECS may play a crucial role in synaptic dysfunction of AD patients (34) and disruption of this processes may partially account for memory deficits in AD 4. Furthermore, several clinical aspects of β-amyloid deposition in vivo have been studied in patients with AD, mild cognitive impairment (MCI) and healthy controls, using the Pittsburgh Compound (11C-PIB) (17) and novel 18F-labelled tracers have been evaluated in phase I and II studies 34.^ Thus, the in vivo measurement of CB1 and CB2R expression in relation to regional amyloid deposits will be feasible for the first time.2.^ Materials and methods· Step 1: safety and dosimetry of 11C-NE40 in 6 healthy volunteers· Step 2: Kinetic modeling of 11C-NE40 in 5 control (≥55 years) and 5 patients with PD using arterial sampling and metabolite determination.· Step 3: Test-retest stability of full kinetic model parameters for CB2R availability in 5 controls subjects and 5 patients with PD, and evaluation of using simplified measures.· Step 4: Patient study (if possible using simplified parametric measures) for CB1R and CB2R imaging in:o Presymptomatic HD (15 presymptomatic carriers, 15 non-carrier siblings)o Symptomatic HD (15 symptomatic patients)o Symptomatic PD (40 patients)o AD (20 additional patients)o 20 controls (these subjects may be shareable between clinical populations)Study subjects will receive a single dose of 370 MBq [11C]-NE40 and a single dose of 185 MBq [18F]MK-9470. Scans will be performed on a HiRez Biograph 16 slice PET/CT camera (Siemens).^ Aside from in vivo multitracer imaging, subjects will also undergo MRI volumetric im

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Weinig beroepen zijn zo essentieel én nobel als die van geneesheer. Tegelijk kan de arts vele gedaanten hebben: huisarts, specialist, arts zonder grenzen, beleidsmedewerker, wetenschappelijk onderzoeker, wetsdokter, arbeidsgeneesheer, psychiater… De vijf universitaire opleidingen in Vlaanderen (U Gent, KU Leuven, U Hasselt, U Antwerpen en Vrije U Brussel) sloegen de handen in elkaar. Zij riepen tientallen artsen op om aan hun afstuderende studenten een brief te schrijven. Hoe hebben ze hun eigen loopbaan ervaren? Wat is eigen aan hun specialisatie? Hoe evalueren ze de stand van de geneeskunde in Vlaanderen? Hoe kunnen de nieuwe artsen inspelen op de uitdagingen van de toekomst?