Koen Van Laere

Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [18F]fallypride

Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D₂/₃ PET radioligand [¹⁸F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹⁸F]fallypride displacement. Voxel-based statistical maps, representing specific D₂/₃ binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (nu200a=u200a26) were subjected to an [18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Influence of Chronic Nicotine Administration on Cerebral Type 1 Cannabinoid Receptor Binding: An In Vivo Micro-PET Study in the Rat Using [18F]MK-9470

Several lines of evidence suggest a functional interaction between central nicotinic and endocannabinoid systems. Furthermore, type 1 cannabinoid receptor (CB1R) antagonism is evaluated as antismoking therapy, and nicotine usage can be an important confound in positron emission tomography (PET) imaging studies of the CB1R. We evaluated CB1R binding in the rat brain using the PET radioligand [18F]MK-9470 after chronic administration of nicotine. Twelve female Wistar rats were scanned at baseline and after chronic administration of either nicotine (1xa0mg/kg; 2xa0weeks daily intraperitoneal (IP)) or saline as control. In vivo micro-PET images of CB1R binding were anatomically standardized and analyzed by voxel-based statistical parametric mapping and a predefined volume-of-interest approach. We did not observe changes in [18F]MK-9470 binding (pheightu2009<u20090.001 level; uncorrected) on a group basis in either condition. Only at a less stringent threshold of pheightu2009<u20090.005 (uncorrected) was a modest increase observed in tracer binding in the cerebellum for nicotine (peak voxel value + 6.8%, pclusteru2009=u20090.002 corrected). In conclusion, chronic IP administration of nicotine does not produce major cerebral changes in CB1R binding of [18F]MK-9470 in the rat. These results also suggest that chronic nicotine usage is unlikely to interfere with human PET imaging using this radioligand.

Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

OBJECTIVEnPatients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis.nnnMETHODnFourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis.nnnRESULTSnFirst-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives.nnnCONCLUSIONnAlthough previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.

Prevalence of the Apolipoprotein E ε4 allele in amyloid-β positive subjects across the spectrum of Alzheimer’s disease

Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimers disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Patient Safety Considerations for Combined PET/MR Imaging

Standalone PET systems have ceased to be commercially available and have systematically been replaced by hybrid PET/CT systems. Combining functional PET information with the CT-guided localization of tumor lesions has made PET/CT the modality of choice for a vast majority of oncological indications. In addition, the CT data can be used to correct the PET data for attenuation effects. Meanwhile, new advances in PET detector hardware have led to integrated clinical PET/MRI systems allowing simultaneous acquisition of both PET and MR data. APD-based (Avalanche Photon Diode) or SiPM-based (Silicon Photon Multipliers) PET detectors are MR compatible and minimize the interference between the PET and MR components. Hybrid PET/MRI systems are currently being introduced to the market with an install base that is constantly growing. In terms of patient safety, both the PET and MR imaging component of these hybrid systems need to be considered. This chapter gives on overview of patient safety issues related to PET imaging and the ionizing radiation of the administered PET tracer and the safety considerations for MR imaging, essentially related to the corresponding nonionizing radiation.

MRI/PET brain imaging

Multimodalbrain imaging has become an established clinical and research tool for diagnosis and disease progression of brain disorders. Among available imaging modalities, magnetic resonance imaging (MRI) and positron emission tomography (PET) can provide a wide spectrum of data for the in vivo mapping of neurobiological functions and brain morphology while demonstrating to relationships between behavioral and neurobiological factors. Since MRI mostly uses endogenous contrast mechanisms to visualize and quantify tissue characteristics, optimal sequence design is essential for the diagnostic information of MRI. On the other hand, PET imaging is always based on the exogenous contrast of an injected PET tracer. Therefore, characteristics of the PET tracer determine the quantitative and diagnostic potential of PET. This chapter will focus on both of these modalities and shortly discuss the potential of multimodal or hybrid MR/PET imaging. We will not cover MR spectroscopy nor specific applications of H2 15O PET since this will be discussed in other chapters of this book.

Clinical SPECT and PET for Management of Patients with Epilepsy

Epilepsy is a common chronic neurological disorder that is characterized by recurrent, unprovoked seizures and affects approximately 3% of the population. After the first seizure, about 80% of patients experience another seizure within the first 3 years. Some 60–70% of patients experience focal or partial seizures, and 30–40% generalized seizures. Epilepsy is controlled with medication in around 70% of cases. When seizures are medically intractable, resection of the epileptogenic cortex may be considered.