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Koen Van Laere

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YNICL Journal 2023 Journal Article

Longitudinal changes in 18F-Flutemetamol amyloid load in cognitively intact APOE4 carriers versus noncarriers: Methodological considerations

  • Emma S. Luckett
  • Jolien Schaeverbeke
  • Steffi De Meyer
  • Katarzyna Adamczuk
  • Koen Van Laere
  • Patrick Dupont
  • Rik Vandenberghe

PURPOSE: Measuring longitudinal changes in amyloid load in the asymptomatic stage of Alzheimer's disease is of high relevance for clinical research and progress towards more efficacious, timely treatments. Apolipoprotein E ε4 (APOE4) has a well-established effect on the rate of amyloid accumulation. Here we investigated which region of interest and which reference region perform best at detecting the effect of APOE4 on longitudinal amyloid load in individuals participating in the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK). METHODS: ), and amyloid rate of change derived: (follow-up amyloid load - baseline amyloid load) / time interval (years). Four reference regions were used to derive amyloid load: whole cerebellum, cerebellar grey matter, eroded subcortical white matter, and pons. RESULTS: ). CONCLUSION: In this cognitively intact cohort, a composite neocortical volume of interest together with whole cerebellum or cerebellar grey matter as reference region are the methods of choice for detecting APOE4-dependent differences in amyloid rate of change.

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YNICL Journal 2022 Journal Article

Simplified Edinburgh and modified Boston criteria in relation to amyloid PET for lobar intracerebral hemorrhage

  • Laura Michiels
  • Laurens Dobbels
  • Jelle Demeestere
  • Philippe Demaerel
  • Koen Van Laere
  • Robin Lemmens

BACKGROUND: Histopathological evidence of cerebral vascular amyloid β accumulation is the gold standard to diagnose cerebral amyloid angiopathy (CAA). Neuroimaging findings obtained with CT and MRI can suggest the presence of CAA when histopathology is lacking. We explored the role of amyloid PET in patients with lobar intracerebral hemorrhage (ICH) as this may provide molecular evidence for CAA as well. METHODS: In this retrospective, monocenter analysis, we included consecutive patients with non-traumatic lobar ICH who had undergone amyloid PET. We categorized patients according to amyloid PET status and compared demographics and neuroimaging findings. We calculated sensitivity and specificity of the simplified Edinburgh criteria and amyloid PET with probable modified Boston criteria as reference standard, as well as sensitivity and specificity of the simplified Edinburgh and modified Boston criteria with amyloid PET status as molecular marker for presence or absence of CAA. RESULTS: We included 38 patients of whom 24 (63%) were amyloid PET positive. Amyloid PET positive patients were older at presentation (p = 0.004). We observed no difference in prevalence of subarachnoid hemorrhages, fingerlike projections or microbleeds between both groups, but cortical superficial siderosis (p = 0.003) was more frequent in the amyloid PET positive group. In 5 out of 38 patients (13%), the modified Boston criteria were not fulfilled due to young age or concomitant vitamin K antagonist use with INR > 3.0. With the modified Boston criteria as reference standard, there was no difference in sensitivity nor specificity between the simplified Edinburgh criteria and amyloid PET status. With amyloid PET status as reference standard, there was also no difference in sensitivity nor specificity between the simplified Edinburgh and modified Boston criteria. CONCLUSIONS: Amyloid PET was positive in 63% of lobar ICH patients. Under certain circumstances, patients might not be diagnosed with probable CAA according to the modified Boston criteria and in these cases, amyloid PET may be useful. Accuracy to predict CAA based on amyloid PET status did not differ between the simplified Edinburgh and modified Boston criteria.

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YNIMG Journal 2021 Journal Article

Age-related GABAergic differences in the primary sensorimotor cortex: A multimodal approach combining PET, MRS and TMS

  • Koen Cuypers
  • Melina Hehl
  • June van Aalst
  • Sima Chalavi
  • Mark Mikkelsen
  • Koen Van Laere
  • Patrick Dupont
  • Dante Mantini

Healthy aging is associated with mechanistic changes in gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter in the human brain. While previous work mainly focused on magnetic resonance spectroscopy (MRS)-based GABA+ levels and transcranial magnetic stimulation (TMS)-based GABAA receptor (GABAAR) activity in the primary sensorimotor (SM1) cortex, the aim of the current study was to identify age-related differences in positron emission tomography (PET)-based GABAAR availability and its relationship with GABA+ levels (i. e. GABA with the contribution of macromolecules) and GABAAR activity. For this purpose, fifteen young (aged 20–28 years) and fifteen older (aged 65–80 years) participants were recruited. PET and MRS images were acquired using simultaneous time-of-flight PET/MR to evaluate age-related differences in GABAAR availability (distribution volume ratio with pons as reference region) and GABA+ levels. TMS was applied to identify age-related differences in GABAAR activity by measuring short-interval intracortical inhibition (SICI). Whereas GABAAR availability was significantly higher in the SM cortex of older as compared to young adults (18. 5%), there were neither age-related differences in GABA+ levels nor SICI. A correlation analysis revealed no significant associations between GABAAR availability, GABAAR activity and GABA+ levels. Although the exact mechanisms need to be further elucidated, it is possible that a higher GABAAR availability in older adults is a compensatory mechanism to ensure optimal inhibitory functionality during the aging process.

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YNIMG Journal 2021 Journal Article

Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study

  • Laura Michiels
  • Aline Delva
  • June van Aalst
  • Jenny Ceccarini
  • Wim Vandenberghe
  • Mathieu Vandenbulcke
  • Michel Koole
  • Robin Lemmens

RATIONALE: C-UCB-J binding were investigated in healthy volunteers over 7 adult decades, assuming that the number of SV2A vesicles per synapse is not influenced by age or sex. METHODS: C-UCB-J binding with age and with sex were investigated by a voxel-based and volume-of-interest (VOI)-based approach, and with and without PVC to assess the contribution of underlying morphology changes upon aging. RESULTS: C-UCB-J SUVR, nor an interaction between aging and sex for this parameter. CONCLUSION: C-UCB-J does not support a cortical decrease of synaptic density with aging, whereas subcortically a small effect with aging in the caudate nucleus was observed. In addition, no association between synaptic density and sex was detected, which allows pooling of datasets of both sexes.

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YNICL Journal 2017 Journal Article

Cholinergic depletion and basal forebrain volume in primary progressive aphasia

  • Jolien Schaeverbeke
  • Charlotte Evenepoel
  • Rose Bruffaerts
  • Koen Van Laere
  • Guy Bormans
  • Eva Dries
  • Thomas Tousseyn
  • Natalie Nelissen

C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. Whole brain and BF volumes were quantified using voxel-based morphometry on high-resolution magnetic resonance imaging (MRI) scans. In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion.

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YNIMG Journal 2017 Journal Article

Differential brain responses to gradual intragastric nutrient infusion and gastric balloon distension: A role for gut peptides?

  • Huynh Giao Ly
  • Patrick Dupont
  • Koen Van Laere
  • Inge Depoortere
  • Jan Tack
  • Lukas Van Oudenhove

Background Rapid gastric balloon distension to discomfort threshold activates the “pain neuromatrix” and deactivates exteroceptive sensory and “default mode network” regions. However, little is known about brain mechanisms underlying tolerance of meal-induced gastric distension. We aimed to directly compare brain responses to gradual balloon distension and intragastric nutrient infusion and to explore the role of differential gut peptide release in these responses. Materials and methods Brain responses to balloon- and nutrient-induced distension (to individually titrated pain or maximal satiation threshold) were measured in 15 healthy volunteers using H2 15O-PET on 2 separate days in counterbalanced order. The effects of increasing gastric distension and plasma levels of ghrelin and peptide YY3-36 (PYY3-36) on neural activity were assessed. Results Balloon distension progressively activated pain-responsive regions and deactivated exteroceptive sensory and “default mode network” areas. During nutrient infusion, “pain neuromatrix” regions and the orbitofrontal cortex were progressively deactivated, while the midbrain was activated. Plasma levels of PYY3-36 and ghrelin increased and decreased, respectively, during nutrient infusion only; decreasing ghrelin levels correlated with increasing midbrain activity. Conclusion Different brain responses to gastric balloon distension and intragastric nutrient infusion are associated with nutrient-induced gut-brain signals, particularly to the midbrain, where these signals may interfere with both descending pain modulatory and mesolimbic reward processes. Deactivation of the “pain neuromatrix” during nutrient infusion may constitute the neurophysiological mechanism underlying the tolerance of normal meal volumes in health without induction of (painful) symptoms. Nutrient-induced deactivation of the orbitofrontal cortex may represent a key interoceptive meal termination signal.

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YNICL Journal 2016 Journal Article

Face shape and face identity processing in behavioral variant fronto-temporal dementia: A specific deficit for familiarity and name recognition of famous faces

  • François-Laurent De Winter
  • Dorien Timmers
  • Beatrice de Gelder
  • Marc Van Orshoven
  • Marleen Vieren
  • Miriam Bouckaert
  • Gert Cypers
  • Jo Caekebeke

Deficits in face processing have been described in the behavioral variant of fronto-temporal dementia (bvFTD), primarily regarding the recognition of facial expressions. Less is known about face shape and face identity processing. Here we used a hierarchical strategy targeting face shape and face identity recognition in bvFTD and matched healthy controls. Participants performed 3 psychophysical experiments targeting face shape detection (Experiment 1), unfamiliar face identity matching (Experiment 2), familiarity categorization and famous face-name matching (Experiment 3). The results revealed group differences only in Experiment 3, with a deficit in the bvFTD group for both familiarity categorization and famous face-name matching. Voxel-based morphometry regression analyses in the bvFTD group revealed an association between grey matter volume of the left ventral anterior temporal lobe and familiarity recognition, while face-name matching correlated with grey matter volume of the bilateral ventral anterior temporal lobes. Subsequently, we quantified familiarity-specific and name-specific recognition deficits as the sum of the celebrities of which respectively only the name or only the familiarity was accurately recognized. Both indices were associated with grey matter volume of the bilateral anterior temporal cortices. These findings extent previous results by documenting the involvement of the left anterior temporal lobe (ATL) in familiarity detection and the right ATL in name recognition deficits in fronto-temporal lobar degeneration.

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YNIMG Journal 2015 Journal Article

Parametric imaging and quantitative analysis of the PET amyloid ligand [ 18 F]flutemetamol

  • Kerstin Heurling
  • Chris Buckley
  • Koen Van Laere
  • Rik Vandenberghe
  • Mark Lubberink

Objectives The amyloid imaging PET tracer [18F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling. Methods The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time–activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels. Results The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2′ (R2 =0. 98), or using a cohort mean k2′ (R2 =0. 97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70–90min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R2 =0. 97, RPM R2 =0. 96 and SUVR R2 =0. 95) Poorest agreement was seen with MRTM without pre-filtering (R2 =0. 68). Conclusions Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

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YNICL Journal 2013 Journal Article

Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer's disease

  • Rik Vandenberghe
  • Katarzyna Adamczuk
  • Patrick Dupont
  • Koen Van Laere
  • Gaël Chételat

Amyloid imaging is currently introduced to the market for clinical use. We will review the evidence demonstrating that the different amyloid PET ligands that are currently available are valid biomarkers for Alzheimer-related β amyloidosis. Based on recent findings from cross-sectional and longitudinal imaging studies using different modalities, we will incorporate amyloid imaging into a multidimensional model of Alzheimer's disease. Aside from the critical role in improving clinical trial design for amyloid-lowering drugs, we will also propose a tentative algorithm for when it may be useful in a memory clinic environment. Gaps in our evidence-based knowledge of the added value of amyloid imaging in a clinical context will be identified and will need to be addressed by dedicated studies of clinical utility.

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YNIMG Journal 2013 Journal Article

Binary classification of 18F-flutemetamol PET using machine learning: Comparison with visual reads and structural MRI

  • Rik Vandenberghe
  • Natalie Nelissen
  • Eric Salmon
  • Adrian Ivanoiu
  • Steen Hasselbalch
  • Allan Andersen
  • Alex Korner
  • Lennart Minthon

18F-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as ‘normal’ versus ‘Alzheimer-like’, is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how 18F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed 18F-flutemetamol scans and volumetric MRI scans from 72 cases from the 18F-flutemetamol phase 2 study (27 clinically probable Alzheimer's disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the 18F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The 18F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the 18F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the 18F-flutemetamol- and the gray matter volume-based classifiers were identical (85. 2%), albeit with discordant classification in three cases. Specificity of the 18F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the 18F-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of 18F-flutemetamol scans can be replicated using SVM. In this sample the specificity of 18F-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM.

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YNIMG Journal 2013 Journal Article

Evaluation of [18F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human

  • Eric D. Hostetler
  • Sandra Sanabria-Bohórquez
  • Waisi Eng
  • Aniket D. Joshi
  • Shailendra Patel
  • Raymond E. Gibson
  • Stacey O'Malley
  • Stephen M. Krause

Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity 18F for positron emission tomography (PET) studies. Evaluation of [18F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [18F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [18F]MK-0911 in all gray matter regions. Baseline PET studies with [18F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [18F]MK-0911 uptake in repeat human baseline PET studies showed a test–retest variability in volume of distribution (V T) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [18F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [18F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [18F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states.

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YNIMG Journal 2013 Journal Article

Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia

  • Jenny Ceccarini
  • Marc De Hert
  • Ruud Van Winkel
  • Joseph Peuskens
  • Guy Bormans
  • Laura Kranaster
  • Frank Enning
  • Dagmar Koethe

Increasing animal genetic, post-mortem and pharmacological evidence supports a role for the cerebral type 1 cannabinoid (CB1) receptor in the pathogenesis of schizophrenia (SCZ) and/or neural circuit dysfunctions responsible for its symptomatology. Moreover, since important interspecies differences are present in CB1 receptor expression, in vivo human data are of direct interest. We investigated an in vivo CB1 receptor expression in SCZ patients compared to healthy controls (CON), and in relation with psychopathological symptom severity using positron emission tomography (PET) and the selective high-affinity radioligand [18F]MK-9470. A total of sixty-seven patients with SCZ, with (SCZ-T, n=51) and without (SCZ-F, n=16) antipsychotic treatment, and 12 age and gender-matched CON were investigated with [18F]MK-9470 PET. Parametric modified standardized uptake value (mSUV) images, reflecting CB1 receptor binding, were compared and related to psychopathological symptoms. Compared to CON, there was a significant increase of CB1 receptor binding in SCZ patients in the nucleus accumbens, insula, cingulate cortex, inferior frontal cortex, parietal and mediotemporal lobe. Furthermore, in the SCZ-F group only, CB1 receptor binding was negatively correlated to negative symptoms and to depression scores, especially in the nucleus accumbens. Present findings strongly support that CB1 receptor binding is altered in the mesocorticolimbic circuitry of both SCZ-T and SCZ-F patients, especially in the nucleus accumbens. In SCZ-F patients, it is associated with negative symptoms and depression scores.

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YNIMG Journal 2013 Journal Article

No association between striatal dopamine transporter binding and body mass index: A multi-center European study in healthy volunteers

  • Elsmarieke van de Giessen
  • Swen Hesse
  • Matthan W.A. Caan
  • Franziska Zientek
  • John C. Dickson
  • Livia Tossici-Bolt
  • Terez Sera
  • Susanne Asenbaum

Introduction Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D2 receptor availability is lower in obesity and there are indications that striatal dopamine transporter (DAT) availability is also decreased. In this study, we tested whether BMI and striatal DAT availability are associated. Methods The study included 123 healthy individuals from a large European multi-center database. They had a BMI range of 18. 2–41. 1kg/m2 and were scanned using [123I]FP-CIT SPECT imaging. Scans were analyzed with both region-of-interest and voxel-based analysis to determine the binding potential for DAT availability in the caudate nucleus and putamen. A direct relation between BMI and DAT availability was assessed and groups with high and low BMI were compared for DAT availability. Results No association between BMI and striatal DAT availability was found. Conclusion The lack of an association between BMI and striatal DAT availability suggests that the regulation of striatal synaptic dopamine levels by DAT plays no or a limited role in the pathophysiology of overweight and obesity.

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YNICL Journal 2013 Journal Article

Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers

  • Katarzyna Adamczuk
  • An-Sofie De Weer
  • Natalie Nelissen
  • Kewei Chen
  • Kristel Sleegers
  • Karolien Bettens
  • Christine Van Broeckhoven
  • Mathieu Vandenbulcke

Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of (18)F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.

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YNIMG Journal 2011 Journal Article

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

  • Johan Lataster
  • Dina Collip
  • Jenny Ceccarini
  • David Haas
  • Linda Booij
  • Jim van Os
  • Jens Pruessner
  • Koen Van Laere

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 100min 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.

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