ECAT HRRT Research Articles

42.4 THE ENDOCANNABINOID SYSTEM IN FIRST-EPISODE PSYCHOSIS

BackgroundThe endocannabinoid (EC) system comprises of fatty acid neurotransmitters such as anandamide and 2-acylglycerol, at least two specific cannabinoid (CB) receptor subtypes and enzyme machinery for synthesis and degradation of ECs. The EC system regulates a wide array of functions in central nervous system and peripheral tissues such as brain development, plasticity, reward and stress sensitivity as well as metabolic functions a such as energy/lipid metabolism including liver function and insulin resistance (1). One of the aims of the METSY project (www.metsy.eu) is to study the central and peripheral EC system in FEPs and their involvement in brain mechanisms in psychosis as well as related metabolic co-morbidities. The cannabinoid CB1 receptor (CB1R) is the most abundant cannabinoid receptor subtype in the human brain and is the predominant mediator of various EC effects. In this first series of METSY experiments we report in vivo brain CB1R binding characteristics in patients with first-episode psychosis (FEP) and controls.MethodsBrain CB1R availability was measured using [18F]-FMPEP-d2 and 3D ECAT HRRT positron emission tomography (PET) using distribution volume (DVt) as a proxy for CB1R availability. Our studies in healthy volunteers revealed a marked sex difference in [18F]-FMPEP DVt with males having higher CB1R availability. The overall CB1R sex difference was widespread but also regionally different with most significant effects in the occipital cortex. Therefore, subsequent studies focused first on male patients with FEP and controls (n=18).ResultsThe results indicate a significant and relatively widespread decrease in CB1R DVt in patients with FEP in fronto-temporal regions, putamen, posterior cingulate as well as parietal regions with large effect sizes. Largely similar results were seen in an independent sample of medication-free male patients with FEP (n=17, the other METSY PET site, King’s College, London, UK) (2). Those studies used another validated CB1R tracer, the [11C]-MePPEP. The reduced CB1R in patients was also state-dependent as [18F]-FMPEP DVt correlated negatively with psychotic symptoms (BPRS) in a highly significant manner.DiscussionEpidemiological studies have convincingly shown that cannabis use is associated with an increased risk of both psychotic symptoms and schizophrenia-like psychoses. We now provide direct in vivo evidence for a robust and partly state-dependent dysregulation of the endocannabinoid system in first-episode psychosis. This is well in line with a recent PET study with CB1R tracer, [11C]-OMAR in patients with schizophrenia (3). Based on previous experimental data the reduced CB1R availability is indicative of an increased endocannabinoid drive in psychosis.AcknowledgementsFunding from the EU’s 7th Framework Programme; METSY - Neuroimaging platform for characterization of metabolic co-morbidities in psychotic disorders (no. 602478).References1) Eriksson O et al The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue. J Nucl Med. 2015 Dec;56(12):1937–41.2) METSY: Endocannabinoid pathways in early psychosis – brain imaging studies (Hietala J, Howes O, Laurikainen H, Borgan F and the METSY PET Imaging group).3) Ranganathan M et al Reduced Brain Cannabinoid Receptor Availability in Schizophrenia. Biol Psychiatry. 2016 Jun 15;79(12):997–1005.

Brain glucose metabolism in neuropathologically confirmed multiple system atrophy

The second consensus statement on the diagnosis of multiple system atrophy (MSA) [1] suggests clinical diagnostic criteria for the assessment of the disease with predominantly parkinsonian features (MSA-P) or cerebellar ataxia (MSA-C). Hypometabolism on [F]fluorodeoxyglucose positron emission tomography (FDG-PET) in the putamen, the brainstem or the cerebellum was listed as an additional feature supporting the diagnosis of MSA-P, whereas hypometabolism in the putamen and presynaptic nigrostriatal dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET were considered as supporting features for MSA-C [2]. The recommendations were based on clinical imaging studies involving patients with probable/possible MSA-P and MSA-C without autopsy confirmation of the diagnoses [1]. Although there are reported studies of decreased striatal dopamine transporter binding with [I]FP-CIT SPECT (CIT-SPECT) in autopsy-confirmed cases of MSA [4], there are no reported cases of ante mortem FDG-PET with post mortem confirmation of the diagnosis. Here we report a patient with neuropathologically confirmed MSA examined with both FDG-PET and CITSPECT during the course of the disease. A 50-year-old man was referred to a neurologist in 2008 due to general fatigue, weakness in the lower extremities, difficulties in turning in bed and severe urinary incontinence that had lasted for 2 years. Family history was unremarkable. Clinical examination showed mild rigidity in the right upper extremity and right-sided dysdiadochokinesia, mild general bradykinesia, mild hypomimia and hyperreflexia in the right lower extremity. Brain magnetic resonance imaging (MRI) showed a slightly decreased T2 signal bilaterally in the dorsolateral putamen, but no atrophy or other pathology of olivopontocerebellar structures was found, such as pontine hot cross bun sign. Levodopa was initiated without a clear treatment response. One year later, the clinical examination showed additional features of dysarthria, axial dystonia and severe postural instability. The levodopa dose was increased to 600 mg/day with modest subjective benefit for rigidity. Brain CIT-SPECT and FDG-PET were performed in 2009 approximately 3 years after the first symptoms appeared. CIT-SPECT showed clearly reduced binding in the striatum (region-tooccipital ratio in the left caudate nucleus, the left putamen and the right putamen = 1.1, region-to-occipital ratio in the right caudate nucleus = 1.4). FDG-PET imaging with an ECAT HRRT high-resolution scanner (Siemens Medical Solutions) (frame of 25 min) was performed 55 min after injection of FDG (injected dose 328 MBq). Visual examination showed clear bilateral reductions in putamen and V. Kaasinen (&) Division of Clinical Neurosciences, University of Turku and Turku University Hospital, POB 52, 20521 Turku, Finland e-mail: valtteri.kaasinen@tyks.fi

Development of a High-Sensitivity Radiation Detector for Chromatography

We describe a radiotracer imaging system for measuring the biochemical production rates of organic compounds from animals or plants. It uses a high performance liquid chromatography (HPLC) column to separate the compounds and a parallel-plane radiation detector to measure the disintegrations from each compound over a period of time. Because the measurement time is much longer than conventional techniques, the sensitivity is greatly improved. This high-sensitivity radiation detector can be used to image radioactivity in the HPLC flow cell or column and can be used for a variety of analytical HPLC applications. The detector is comprised of 8 Siemens ECAT EXACT HR+ PET detector modules arranged into a parallel plane and read out with modified Siemens ECAT HRRT electronics. This high-sensitivity radiation detector was placed in line after a conventional HPLC radiation detector (a small CsI:Tl scintillator crystal coupled to a PIN photodiode) to allow a direct comparison. If we inject 9.3 μCi of [ <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">18</sup> F]FDG into the system, we see consistently shaped peaks with an excellent signal-to-noise ratio from both radiation detectors. If we inject only 5.4 nCi of [ <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">18</sup> F]FDG, we measure a signal-to-noise ratio of 28:1 with the high-sensitivity radiation detector and 5:1 with the conventional radiation detector. We have therefore achieved a sensitivity gain of 32 at low radioactivity concentrations using our high-sensitivity radiation detector compared to a conventional radiation detector. We believe that a high-sensitivity radiation detector, using parallel-plane PET detector modules, could become an important tool for analytical HPLC research.

Quantification of serotonin transporter availability with [11C]MADAM — A comparison between the ECAT HRRT and HR systems

Quantification of serotonin transporter availability with [11C]MADAM — A comparison between the ECAT HRRT and HR systems

Gap-Filling for the High-Resolution PET Sinograms With a Dedicated DCT-Domain Filter

High-resolution positron emission tomography (PET) scanners have brought many improvements to the nuclear medicine imaging field. However, the mechanical limitations in the construction of the scanners introduced gaps between the detectors, and accordingly, to the acquired projection data. When the methods requiring full-sinogram dataset, e.g., filtered backprojection (FBP) are applied, the missing parts degrade the reconstructed images. In this study, we aim to compensate the sinograms for the missing parts, i.e., gaps. For the gap filling, we propose an iterative discrete-cosine transform (DCT) domain method with two versions: 1) with basic DCT domain filter and 2) with dedicated and gap-dependent DCT domain filter. For the testing of the methods, 2-D FBP reconstructions were applied to the gap-filled sinograms. The proposed DCT domain gap-filling method with two different filters was compared to the constrained Fourier space (CFS) method. For the quantitative analysis, we used numerical phantoms at eight different Poisson noise levels with 100 realizations. Mean-square error, bias, and variance evaluations were performed over the selected regions of interest. Only the dedicated gap-dependent DCT domain filter showed quantitative improvement in all regions, at each noise level. We also assessed the methods visually with a [(11) C] raclopride human brain study reconstructed by 2-D FBP after gap filling. The visual comparisons of the methods showed that the gap filling with both DCT domain filters performed better than the CFS method. The proposed technique can be used for the sinograms, not only with limited range of projections as in the high-resolution research tomograph (ECAT HRRT) PET scanner, but also with detector failure artifacts.

Counting Rates Modeling for PET Scanners With GATE

Several developments were made in the GATE simulation platform to allow accurate modeling of the count rate performances of PET scanners over a wide range of activity concentrations. A background noise module, a dead time and limited bandwidth modeling for the coincidences, and a delayed coincidence builder were added in the code. The results obtained for the modeling of the ECAT HRRT and Focus 220 scanners with the newly developed modules are discussed. They show that GATE can be used to accurately simulate the single event, prompt coincidence and delayed coincidence rates, from very low activity levels in the field of view up to levels that saturate the acquisition system. The new developments were committed into the public release of GATE, making them available for the whole community, thanks to the open source license under which GATE is published (LGPL).

Contraction‐induced [18F]‐fluoro‐deoxy‐glucose uptake can be measured in human calf muscle using high‐resolution PET

Contraction-induced glucose uptake can be imaged and quantified by the use of positron emission tomography (PET). In the human extremities, such data may reveal important information regarding the in vivo mechanical function of e.g. the force transmitting tissues such as tendons. However, to investigate structures of limited size, a PET scanner with high resolution is required. We tested the potential of the recently developed high-resolution brain PET scanner (ECAT HRRT) for imaging of human lower extremities. [18F]-fluoro-deoxy-glucose uptake following voluntary and stimulated isometric muscle contractions was studied in a 30-year-old male. The results showed that the activated muscle or muscles are clearly delineated in the high-resolution PET images. Furthermore, the load-induced gain in tendon uptake was clearly visualized. In conclusion, the HRRT scanner is an appropriate tool for investigating physiological processes within the human extremities, and the very high resolution yields a potential for more accurate conclusions when target tissues are limited in size.

Development of a daily quality check procedure for the High-Resolution Research Tomograph (HRRT) using natural LSO background radioactivity

A daily quality check plays an important role for clinical medical systems like a positron emission tomograph (PET). To guarantee image quality a constant monitoring of the scanner integrity is essential. On present PET scanners, the built-in transmission sources are being used for the measurement of a uniform blank scan and the computation of detector-block efficiencies. These efficiencies can be compared to reference data and deviations indicate changes of the scanner condition. On the High-Resolution Research Tomograph (ECAT HRRT) the design of the transmission source makes this method impractical. For that reason we investigated the use of the natural background radioactivity from the new scintillator material LSO as a uniform source. A procedure was developed to measure detector-block sensitivities and energy spectra directly. An initial quality check scan is the basis for comparison of daily scans, so that gain shifts of photomultipliers and specific hardware defects can be detected. With an improved list mode based data acquisition it was possible to reduce the acquisition time to around 3 h despite the low LSO count rate, so that this routine is as practical as previous procedures in clinical routine.

The ECAT HRRT: performance and first clinical application of the new high resolution research tomograph

The ECAT HRRT is a three-dimensional (3-D) only dedicated brain tomograph employing the new scintillator lutetium-oxy-orthosilicate (LSO) and using depth of interaction (DOI) information to achieve uniform isotropic resolution across a 20-cm diameter volume. With its unique technological innovations it represents the prototype of a new generation of high-resolution brain tomographs. The physical performance with respect to count rate, live time, scatter, sensitivity, and resolution was evaluated with phantom studies and measurements with a point source. The HRRTs imaging performance was tested with phantoms and fluorodeoxyglucose (FDG) scans performed in animal and human brains. We find that due to the significantly improved resolution and the large solid angle covered by the panel detectors, several issues that have been adequately solved for older generation scanners demand new attention for the HRRT, like acquiring and handling large amounts of data effectively, strategies for optimal reconstruction, shielding, and correction of random coincidences.

Performance results of a new DOI detector block for a high resolution PET-LSO research tomograph HRRT

To improve the spatial resolution and uniformity in modern high resolution brain PET systems over the entire field of view (FOV), it is necessary to archive the depth of interaction (DOI) information and correct for spatial resolution degradation. In this work the authors present the performance results of a high resolution LSO/GSO phoswich block detector with DOI capability. This detector design will be used in the new CTI High Resolution Research Tomograph, ECAT HRRT. The two crystal layer (19/spl times/19/spl times/7.5 mm/sup 3/) and a light guide are stacked on each other and mounted on a (2/spl times/2) PMT set, so that the corners of the phoswich are positioned over the PMT centers. The crystal phoswich is cut into a 8/spl times/8 matrix of discrete crystals. The separation of the LSO and the GSO layer by pulse shape discrimination allows discrete DOI information to be obtained. The high light output and the light guide design results in an accurate identification of the 128 single crystals per block. Flood source measurements document a very good homogeneity of events, energy centroid stability and energy resolution (14-20% FWHM) per single crystal. An intrinsic resolution of /spl sim/1.3 mm and the DOI feasibility is extracted by coincidence measurements with a single GSO crystal.