Neurovascular coupling of D2/D3 dopamine receptors using simultaneous PET/MR in humans
Poster No:
2623
Submission Type:
Abstract Submission
Authors:
Christian Schmitz1, Xenia Hart1, Moritz Spangemacher1, Jana Roth1, Karen Büsing2, Robert Becker1, Gabriele Ende1, Gerhard Gründer1
Institutions:
1Central Institute of Mental Health, Mannheim, Baden-Wurttemberg, 2University Hospital Mannheim, University of Heidelberg, Mannheim, Baden-Wurttemberg
First Author:
Co-Author(s):
Introduction:
The dopamine (DA) system is a major therapeutic target in multiple psychiatric disorders such as schizophrenia or substance use disorder. Even though pharmaceutical substances that modulate DA transmission are frequently used, e.g. antipsychotic drugs, (NICE, 2014; SIGN, 2013), the scope of the functional effects as well as the long-term side effects induced by substances acting on the dopamine system is widely unknown.
The neurovascular coupling of the dopamine system can be used to evaluate the functional domain of the DA system by investigating the functional effects of drugs that modify or intervene with the dopamine transmission. For example, translational studies have shown neurovascular coupling of the DA system using functional magnetic resonance imaging (fMRI) in combination with different DA agonistic interventions (Sander, 2013).
Even though there is clear evidence for the neurovascular coupling of D2/3 receptors in animal models, major knowledge gaps remain regarding the dynamic relationship between DA neurochemistry and hemodynamic dopaminergic activity in humans. With this study, we want to evaluate the hemodynamic changes induced by the DA agonist apomorphine as a pharmacological challenge first time in humans and correlate the functional changes with the D2/3R non-displaceable binding potential (BP).
The neurovascular coupling of the dopamine system can be used to evaluate the functional domain of the DA system by investigating the functional effects of drugs that modify or intervene with the dopamine transmission. For example, translational studies have shown neurovascular coupling of the DA system using functional magnetic resonance imaging (fMRI) in combination with different DA agonistic interventions (Sander, 2013).
Even though there is clear evidence for the neurovascular coupling of D2/3 receptors in animal models, major knowledge gaps remain regarding the dynamic relationship between DA neurochemistry and hemodynamic dopaminergic activity in humans. With this study, we want to evaluate the hemodynamic changes induced by the DA agonist apomorphine as a pharmacological challenge first time in humans and correlate the functional changes with the D2/3R non-displaceable binding potential (BP).
Methods:
We are piloting the use of combined PET/fMRI imaging on a high resolution Siemens Biograph mMR (Siemens AG, Germany) with a pharmacological intervention in 9 healthy humans (four males and five females of mean age 35.1 years (SD 9.3; range 24–46 years). Using [18F]fallypride, a selective dopamine D2/3 receptor-tracer, we are determining the average dopamine non-displaceable binding potential (BPND) ) based on a simplified reference tissue model (Vernaleken, 2011). In addition, we are using the dopamine receptor D2 agonist apomorphine as pharmacological challenge in order to evaluate the hemodynamic changes and correlate the activity changes with the D2/3R BP. Simultaneously, the cerebrovascular blood flow (CBF) in the striatum is measured with a multi-delay pseudo-continuous arterial spin labelling sequence (Wang, 2013).
Results:
The preliminary data of 9 healthy subjects shows an average dopamine BPND of 19.3 in the striatal areas. We can show a median increase of CBF upon the injection of apomorphine of 1.75±2.6 ml/100g/min in this region. The BPND and the increase of CBF show a significant pearson correlation of r=.362 (p =.0019).
Conclusions:
With our study approach, we are able to show that the simultaneous investigation of dopamine BPND and CBF is feasible. We demonstrate that the DA agonist apomorphine induces an increased blood flow in striatal areas that is correlated with the D2/3R BPND. Thus, with the use of simultaneous PET/fMR-imaging this study introduces a new methodology for investigating neurovascular coupling of the DA system first time in humans and delineates a possible mechanistic and diagnostic entry-point of pathologies of the dopamine system like dopamine supersensitivity or tardive dyskinesia.
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI) 2
PET Modeling and Analysis
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Systems
Novel Imaging Acquisition Methods:
Non-BOLD fMRI
Physiology, Metabolism and Neurotransmission :
Pharmacology and Neurotransmission 1
Keywords:
Cerebral Blood Flow
Dopamine
MRI
Neurotransmitter
Positron Emission Tomography (PET)
Psychiatric
1|2Indicates the priority used for review
Provide references using author date format
SIGN, Scottish Intercollegiate Guidelines Network (2013), Management of schizophrenia. A national clinical guideline. Guideline 131
Sander CY, Hooker JM, Catana C, Normandin MD, Alpert NM, Knudsen GM, Vanduffel W, Rosen BR, Mandeville JB (2013). Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI. Proc Natl Acad Sci USA :11169-74
Vernaleken I, Peters L, Raptis M, Lin R, Buchholz HG, Zhou Y, Winz O, Rösch F, Bartenstein P, Wong DF, Schäfer WM, Gründer G (2011), The applicability of SRTM in [(18)F]fallypride PET investigations: impact of scan durations. J Cereb Blood Flow Metab. 2011 Sep;31(9):1958-66.
Wang DJ, Alger JR, Qiao JX, Gunther M, Pope WB, Saver JL, Salamon N, Liebeskind DS; UCLA Stroke Investigators (2013), Multi-delay multi-parametric arterial spin-labeled perfusion MRI in acute ischemic stroke - Comparison with dynamic susceptibility contrast enhanced perfusion imaging. Neuroimage Clin. 6;3:1-7