A High-Resolution In Vivo Atlas of the Human Brain’s Cyclooxygenase-2 (COX-2) System

2211 

Abstract Submission 

Martin Norgaard^1,2, Anthony Galassi², Nafiseh Ghazanfari², Adrian Lee², Jeih-San Liow², Sami Zoghbi², Paul Wighton³, Granville Matheson⁴, Cyril Pernet⁵, Gitte Knudsen⁵, Melanie Ganz^5,1, Adam Thomas², Douglas Greve³, Paolo Zanotti Fregonara², Robert Innis²

¹University of Copenhagen, Copenhagen, Denmark, ²NIMH Intramural Research Program, Bethesda, MD, ³Martinos Center for Biomedical Imaging at MGH, Boston, MA, ⁴Columbia University / Karolinska Institutet, Solna, Stockholms län, ⁵Neurobiology Research Unit, Copenhagen, Denmark

Martin Norgaard  
University of Copenhagen|NIMH Intramural Research Program
Copenhagen, Denmark|Bethesda, MD

Anthony Galassi  
NIMH Intramural Research Program
Bethesda, MD

Nafiseh Ghazanfari  
NIMH Intramural Research Program
Bethesda, MD

Adrian Lee  
NIMH Intramural Research Program
Bethesda, MD

Jeih-San Liow  
NIMH Intramural Research Program
Bethesda, MD

Sami Zoghbi  
NIMH Intramural Research Program
Bethesda, MD

Paul Wighton  
Martinos Center for Biomedical Imaging at MGH
Boston, MA

Granville Matheson  
Columbia University / Karolinska Institutet
Solna, Stockholms län

Cyril Pernet, PhD  
Neurobiology Research Unit
Copenhagen, Denmark

Gitte Knudsen, MD, DMSc  
Neurobiology Research Unit
Copenhagen, Denmark

Melanie Ganz  
Neurobiology Research Unit|University of Copenhagen
Copenhagen, Denmark|Copenhagen, Denmark

Adam Thomas  
NIMH Intramural Research Program
Bethesda, MD

Douglas Greve  
Martinos Center for Biomedical Imaging at MGH
Boston, MA

Paolo Zanotti Fregonara  
NIMH Intramural Research Program
Bethesda, MD

Robert Innis  
NIMH Intramural Research Program
Bethesda, MD

Cyclooxygenase-2 (COX-2) is one of the main enzymes activated by inflammatory stimuli and is a key target for anti-inflammatory drugs [1]. Here, we present a quantitative high-resolution in vivo atlas of the spatial distribution of COX-2 in the healthy human brain, obtained using Positron Emission Tomography (PET) data. The atlas will be made publicly available to the community as part of the OpenNeuroPET project (https://openneuropet.github.io/).

Twenty-seven healthy participants (12 males, 15 females; mean age: 36±10.36 years, range: 22-56) were scanned using a Siemens Biograph mCT PET scanner 120 min after a bolus injection of the radioligand [11C]MC1. Arterial sampling was done to determine the input function. Ten of the participants also had a blocking scan to determine levels of receptor occupancy and non-displaceable distribution volume (VND). An isotropic 3D T1-weighted MRI was acquired for all participants using a Philips Achieva 3T MRI-scanner. The PET data were head motion corrected using the BIDS application PETPrep_hmc (v.0.0.7) [2]. The MR data were processed using FreeSurfer (v.7.4.1) [3] and co-registered to the PET data using a rigid transformation and a normalized mutual information cost function. The PET data were quantified to estimate total distribution volume (V_T) for each region using Logan graphical analysis in PETSurfer [4, 5] and the radiometabolite-corrected plasma curve as input function estimated via the bloodstream BIDS application [6]. Occupancy and V_ND were estimated using the Lassen plot [7], from which the specific distribution volume (V_S) was calculated. Parametric images of distribution volumes V_T and V_S were created in the MNI152 (CVS volume space from FreeSurfer) as well as in surface space (fsaverage), smoothed with a 6 mm and 10 mm smoothing kernel in the volume and surface, respectively [8].

The main outcome of this work is the generation of a brain atlas of the COX-2 V_T and V_S (Figure 1). The regional V_T estimates ranged from 1.05 to 3.43 mL/cm³ across participants and scans (average = 2.14 ± 0.4 mL/cm³) and were mostly expressed in the cortex (Figure 2). V_S estimates (V_S = V_T - V_ND) were generally low in subcortical regions (Figure 2), whereas measures in cortical regions largely ranged between 0.25-0.75 mL/cm³. The estimated average occupancy across participants from the baseline-blocking condition was 72 ± 17% (range: 37% - 89%), and the average V_ND was 1.81 ± 0.15 mL/cm³ (range: 1.64 - 2.1 mL/cm³).

This quantitative in vivo brain atlas of the spatial organization of COX-2 distribution volumes in the healthy human brain provides a valuable tool for investigating the COX system; in particular, the atlas can be used as a reference to patient groups with alterations in their inflammatory system or to understand the effects of pharmacological interventions that act on the COX-2 system.

PET Modeling and Analysis ²

Segmentation and Parcellation

Brain Atlases ¹

PET

Pharmacology and Neurotransmission

Data analysis

Pain

Positron Emission Tomography (PET)

STRUCTURAL MRI

Other - Inflammation