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Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model
Abstract
A method is presented for the generation of parametric images of radioligand–receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed.
... (Yushkevich et al., 2006), based on brain region delineations reported in Waxholm Space atlas of the Sprague Dawley rat brain (Papp, Leergaard, Calabrese, Johnson, & Bjaalie, 2014), where the MRI images were linearly co-registered to the atlas. Mean BPND of ROIs was calculated relative to the non-specific binding in cerebellum, using the simple reference tissue model (SRTM) (Gunn, Lammertsma, Hume, & Cunningham, 1997), as previously reported (Elmenhorst et al., 2010). Percent change in [ 11 C]ABP688 BPND was calculated as following: ((BPND BASELINE -BPND CHALLENGE)/ BPND BASELINE) × 100. ...
... Then, the PET images were co-registered with the subject's own MRI transformed into the Montreal Neurological Institute (MNI) template brain using transformed parameters obtained from the registration of MRI to MNI152 space. Mean BPND of ROI was estimated using SRTM (Gunn et al., 1997), with the cerebellar grey matter as reference region. Subcortical limbic regions amygdala and hippocampus were yielded by the segmentation generated by the ANIMAL image registration algorithm. ...
The excitatory neurotransmitter glutamate plays a critical role in experience-dependent neuroplasticity including addiction-related processes. To date, however, it is not possible to measure glutamate release in living human brain. Positron emission tomography (PET) with [11C]ABP688, a selective allosteric antagonist of metabotropic type 5 glutamate (mGlu5) receptors, could offer an effective strategy. To test this proposition, we conducted a series of studies in rats using microdialysis and [11C]ABP688 microPET imaging, and in humans using PET and magnetic resonance spectroscopy (MRS). Significant calcium-dependent glutamate release was identified in the ventral striatum of awake rats (190.5 ± 34.7%, p < 0.05; n = 7) following administration of a low dose of ethanol (EtOH; 20%, 0.5g/kg), a pharmacological challenge readily translatable to human research. Simultaneous microdialysis and microPET studies in anesthetized rats yielded concurrent increases in glutamate release (126.9 ± 5.3%, p < 0.001; n = 11) and decreases in striatal [11C]ABP688 binding (6.8 ± 9.6%, p < 0.05). These latter two effects, however, were not significantly correlated (r = 0.25, p = 0.46). In humans, a laboratory stressor yielded significant changes in self-reported mood (ps < 0.041), sympathetic system activations (ps < 0.042), and the MRS index of striatal glutamate reuptake following excitatory neurotransmission, Glx/Cr levels (p = 0.048). These effects, however, were not accompanied by significant changes in [11C]ABP688 BPND (ps > 0.21, n = 9) or correlated with each other (ps > 0.074). Together, these studies document EtOH-induced glutamate release from neurons, EtOH-induced decreases in [11C]ABP688 binding, and stress-induced changes in glutamate turnover, yet fail to provide evidence that the PET [11C]ABP688 method can be exploited to quantify moderate changes in glutamate release. The results underscore the need for highly controlled testing conditions during PET measures of mGlu5 receptors.
... Based on the parameter estimation by kinetic modeling implemented in the PMOD software v4.2 (PMOD Technologies Ltd., Zürich, Switzerland), the BP ND image of [ 11 C]MDL100907 was obtained using a basis function implementation of the SRTM [51,63,64] with cerebellar gray matter as the reference region, as suggested in previous PET studies on this radioligand [51,58,59]. Representative mean images of [ 11 C]MDL100907 PET and structural MRI are shown in Figure 3. ...
... Based on the parameter estimation by kinetic modeling implemented in the PMOD software v4.2 (PMOD Technologies Ltd., Zürich, Switzerland), the BPND image of [ 11 C]MDL100907 was obtained using a basis function implementation of the SRTM [51,63,64] with cerebellar gray matter as the reference region, as suggested in previous PET studies on this radioligand [51,58,59]. Representative mean images of [ 11 C]MDL100907 PET and structural MRI are shown in Figure 3. ...
Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In this study, we explored the relationship between 5-HT2A receptor availability in vivo and aggression traits in healthy participants. Thirty-three healthy participants underwent 3-Tesla magnetic resonance imaging and positron emission tomography (PET) with [11C]MDL100907, a selective radioligand for 5-HT2A receptors. To quantify 5-HT2A receptor availability, the binding potential (BPND) was derived using the basis function implementation of the simplified reference tissue model, with the cerebellum as the reference region. The participants’ aggression levels were assessed using the Buss–Perry Aggression Questionnaire. The voxel-based correlation analysis with age and sex as covariates revealed that the total aggression score was significantly positively correlated with [11C]MDL100907 BPND in the right middle temporal gyrus (MTG) pole, left fusiform gyrus (FUSI), right parahippocampal gyrus, and right hippocampus. The physical aggression subscale score had significant positive correlations with [11C]MDL100907 BPND in the left olfactory cortex, left orbital superior frontal gyrus (SFG), right anterior cingulate and paracingulate gyri, left orbitomedial SFG, left gyrus rectus, left MTG, left inferior temporal gyrus, and left angular gyrus. The verbal aggression subscale score showed significant positive correlations with [11C]MDL100907 BPND in the bilateral SFG, right medial SFG, left FUSI, and right MTG pole. Overall, our findings suggest the possibility of positive correlations between aggression traits and in vivo 5-HT2A receptor availability in healthy individuals. Future research should incorporate multimodal neuroimaging to investigate the downstream effects of 5-HT2A receptor-mediated signaling and integrate molecular and systems-level information in relation to aggression traits.
... The Hammers and Svarer templates incorporated in PVElab software were used to define cortical gray matter regions of interest (ROIs) on the co-registered MRI scans [33,34]. Receptor parametric mapping (RPM) was applied to the PET data to obtain parametric images of BP ND and R 1 , with the cerebellum gray matter as a reference region [35]. Previous research from our group has demonstrated that RPM is the best parametric method for [ 18 F]flortaucipir [36], and has an excellent test-retest repeatability [9]. ...
... Out of the 61 individuals who underwent follow-up, 35 were Aβ+ and 26 Aβ− at baseline (Table 1, Fig. 1). Baseline demographics and characteristics of the total baseline sample (including the baseline-only sample, n = 147) are shown in sTable 1. Relative to the total baseline sample, the follow-up sample consisted of younger patients, with relatively higher MMSE scores and higher levels of global tau PET BP ND . ...
Purpose
Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF.
Methods
We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [¹⁸F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [¹⁸F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [¹⁸F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ− cognitively normal (CN) individuals and Aβ+ (CN and CI) individuals separately.
Results
In Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ− individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals.
Conclusion
We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.
... In recent years, positron emission tomography (PET) has widely clinical and research applications in oncology, cardiology and neurology [1,2]. It is a unique imaging modality that enables the measurements of a diverse range of functional and biological processes (e.g., tumor metabolism [3], proliferation [4], blood flow [5] and receptor-binding [6]), depending on the administrated radiotracer. In daily clinical practice, PET imag- † These authors contributed equally. ...
... To correct this effect, the delay term is jointly estimated with other parameters in compartmental models. Take 1C model as an example, replacing the residue function in (3) by (6) gives: (10) In this setting, (V B , K 1 , k2, ∆) are estimated. Similarly for 2C model, (V B , K 1 , k2, k3, ∆) or (V B , K 1 , k2, k3, k4, ∆) are derived but the estimation procedure is more computationally expensive. ...
Positron emission tomography (PET) scanning is an important diagnostic imaging technique used in disease diagnosis, therapy planning, treatment monitoring and medical research. The standardized uptake value (SUV) obtained at a single time frame has been widely employed in clinical practice. Well beyond this simple static measure, more detailed metabolic information can be recovered from dynamic PET scans, followed by the recovery of arterial input function and application of appropriate tracer kinetic models. Many efforts have been devoted to the development of quantitative techniques over the last couple of decades.
The advent of new-generation total-body PET scanners characterized by ultra-high sensitivity and long axial field of view, i.e., uEXPLORER (United Imaging Healthcare), PennPET Explorer (University of Pennsylvania) and Biograph Vision Quadra (Siemens Healthineers), further stimulate valuable inspiration to map kinetics for multiple organs simultaneously. But some emerging issues also need to be addressed, e.g., the large-scale data size and organ-specific physiology. The direct implementation of classical methods for total-body PET imaging without proper validation may lead to less accurate results.
In this contribution, the published dynamic total-body PET datasets are outlined and several challenges/opportunities for quantitation of such types of studies are presented. An overview of the basic equation, calculation of input function (based on blood sampling, image, population or mathematical model) and kinetic analysis encompassing parametric (compartmental model, graphical plot and spectral analysis) and non-parametric (B-spline and piece-wise basis elements) approaches is provided. The discussion mainly focuses on the feasibilities, recent developments and future perspectives of these methodologies for a diverse-tissue environment.
... A relative regional cerebral blood ow (rCBF R ) measure can be estimated using reference tissue models when arterial sampling is not available [28]. Measures of both receptor binding, quanti ed as Binding Potential (BP) and R1 can be estimated at the same time, using the simpli ed reference tissue model (SRTM) [29,30]. ...
... In H 2 O, the measure of rCBF R , F, was estimated following the double-integration method presented in Koopman et al [28], but modi ed to use the cerebellum instead of the whole-brain as a x-point for the perfusion value 0.5 mL×cm 3 ×min 1 . A similar measure of rCBF R , R1, was calculated from the dynamic FE-PE2I data, using SRTM [29,30]. It is worth noting that the R1 values are expected to be two times the perfusion values (due to the 0.5 cerebellum x-point mentioned above and their 95% con dence intervals were calculated using the "Reliability analysis module" in SPSS based on a 2-way mixed-effects model, mean-rating (k = 58) using the consistency de nition. ...
Background
Dopamine transporter (DAT) imaging is used in the diagnostic work-up in suspected parkinsonian syndromes and dementia with Lewy-bodies but cannot differentiate between these syndromes, and an extra brain imaging examination of the regional cerebral blood flow (rCBF) or glucose metabolism is often needed for differential diagnosis. The requirement of two different imaging examinations is resource consuming and inconvenient for the patients. Therefore, a dual-phase imaging concept, i.e. imaging of both cortical blood flow and DAT imaging with the same radiotracer would be more convenient and cost-effective. The aim of this study was to test whether relative regional cerebral blood flow (rCBFR) can be measured with the DAT specific positron emission tomography (PET) tracer [¹⁸F]FE-PE2I (FE-PE2I), by validation with cerebral perfusion measured with [¹⁵O]H2O PET (H2O).
Methods
The linear relationship and intraclass correlation (ICC) between rCBFR measured with FE-PE2I (R1) and H2O (F) was tested in image data derived from 29 patients with recent onset parkinsonism and 29 healthy controls. The R1 was calculated using the simplified reference tissue model, and F was calculated with a modified Koopman double-integration method.
Results
There was a strong linear correlation between R1 and F in the frontal, parietal, temporal, cingulate and occipital cortex as well as in the striatum (r ≥ 0.705–0.920, p < 0.001) with a good to excellent ICC, ranging from 0.716 to 0.942 (p < 0.001).
Conclusions
Our results suggest that FE-PE2I may be used as a proxy for cerebral perfusion, thus potentially serve as a radiotracer for assessment of both DAT availability and rCBFR in one single dynamic scan. This could be valuable in the differential diagnosis of parkinsonian syndromes.
... The linearisation of SRTM with basis functions is implemented based on Gunn et al. (1997), with the operational function where B i are the number of basis functions and the basis functions are calculated as ...
... Details on solving the linearised problem and calculations of the kinetic parameters of interest R 1 , k 2 and BP ND can be found in Gunn et al. (1997) and Wu and Carson (2002). ...
Current PET datasets are becoming larger, thereby increasing the demand for fast and reproducible processing pipelines. This paper presents a freely available, open source, Python-based software package called NiftyPAD, for versatile analyses of static, full or dual-time window dynamic brain PET data. The key novelties of NiftyPAD are the analyses of dual-time window scans with reference input processing, pharmacokinetic modelling with shortened PET acquisitions through the incorporation of arterial spin labelling (ASL)-derived relative perfusion measures, as well as optional PET data-based motion correction. Results obtained with NiftyPAD were compared with the well-established software packages PPET and QModeling for a range of kinetic models. Clinical data from eight subjects scanned with four different amyloid tracers were used to validate the computational performance. NiftyPAD achieved R2>0.999 correlation with PPET, with absolute difference ∼10-2 for linearised Logan and MRTM2 methods, and R2>0.999999 correlation with QModeling, with absolute difference ∼10-4 for basis function based SRTM and SRTM2 models. For the recently published SRTM ASL method, which is unavailable in existing software packages, high correlations with negligible bias were observed with the full scan SRTM in terms of non-displaceable binding potential (R2=0.96), indicating reliable model implementation in NiftyPAD. Together, these findings illustrate that NiftyPAD is versatile, flexible, and produces comparable results with established software packages for quantification of dynamic PET data. It is freely available (https://github.com/AMYPAD/NiftyPAD), and allows for multi-platform usage. The modular setup makes adding new functionalities easy, and the package is lightweight with minimal dependencies, making it easy to use and integrate into existing processing pipelines.
... A relative regional cerebral blood flow (rCBF R ) measure can be estimated using reference tissue models when arterial sampling is not available [28]. Measures of both receptor binding, quantified as binding potential (BP) and R1, can be estimated at the same time, using the simplified reference tissue model (SRTM) [29,30]. ...
... In H 2 O, the measure of rCBF R , F, was estimated following the double-integration method presented by Koopman et al. [28], but modified to use the cerebellum instead of the whole brain as a fix-point for the perfusion value 0.5 mL × cm −3 × min −1 . A similar measure of rCBF R , R1, was calculated from the dynamic FE-PE2I data, using SRTM [29,30]. It is worth noting that the R1 values are expected to be two times the perfusion values (due to the 0.5 cerebellum fix-point mentioned above). ...
Background
Dopamine transporter (DAT) imaging is used in the diagnostic work-up in suspected parkinsonian syndromes and dementia with Lewy bodies but cannot differentiate between these syndromes, and an extra brain imaging examination of the regional cerebral blood flow (rCBF) or glucose metabolism is often needed for differential diagnosis. The requirement of two different imaging examinations is resource-consuming and inconvenient for the patients. Therefore, imaging of both cortical blood flow and DAT imaging with the same radiotracer would be more convenient and cost-effective. The aim of this study was to test whether relative regional cerebral blood flow (rCBFR) can be measured with the DAT-specific positron emission tomography (PET) tracer [¹⁸F]FE-PE2I (FE-PE2I), by validation with cerebral perfusion measured with [¹⁵O]H2O PET (H2O).
Methods
The rCBFR was quantified by kinetic modeling for FE-PE2I (R1) and H2O (F). The R1 was calculated using the simplified reference tissue model, and F was calculated with a modified Koopman double-integration method. The linear relationship and intraclass correlation (ICC) between R1 and F were tested in image data derived from 29 patients with recent onset parkinsonism and 30 healthy controls.
Results
There was a strong linear correlation across all subjects between R1 and F in the frontal, parietal, temporal, cingulate and occipital cortex as well as in the striatum (r ≥ 0.731–0.905, p < 0.001) with a good-to-excellent ICC, ranging from 0.727 to 0.943 (p < 0.001).
Conclusions
Our results suggest that FE-PE2I may be used as a proxy for cerebral perfusion, thus potentially serving as a radiotracer for assessment of both DAT availability and rCBFR in one single dynamic scan. This could be valuable in the differential diagnosis of parkinsonian syndromes.
Trial registration: EUDRA-CT 2015-003045-26. Registered 23 October 2015 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003045-26
... Time activity curves (TACs) were acquired by projecting the grey matter VOIs over the dynamic [ 11 C]PE2I PET datasets, and regional SUVs were obtained by normalization of the activity values by patient weight and injected radioactivity dose. Parametric [ 11 C]PE2I R 1 (relative delivery, reflecting cerebral blood flow relative to cerebellum) and BP ND (non-displaceable binding potential, proportional to DAT availability) images were derived using a basis function implementation of the simplified reference tissue model [36,37] with the cerebellar grey matter as a reference region. The same VOI template was projected on the parametric images to obtain regional R 1 and BP ND estimates. ...
... Physica Medica 97 (2022)[36][37][38][39][40][41][42][43] ...
In positron emission tomography (PET), ⁶⁸Ge-transmission scanning is considered the gold standard in attenuation correction (AC) though not available in current dual imaging systems. In this experimental study we evaluated a novel AC method for PET/magnetic resonance (MR) imaging which is essentially based on a composite database of multiple ⁶⁸Ge-transmission maps and T1-weighted (T1w) MR image-pairs (composite transmission, CTR-AC).
This proof-of-concept study used retrospectively a database with 125 pairs of co-registered ⁶⁸Ge-AC maps and T1w MR images from anatomical normal subjects and a validation dataset comprising dynamic [¹¹C]PE2I PET data from nine patients with Parkinsonism. CTR-AC maps were generated by non-rigid image registration of all database T1w MRI to each subject’s T1w, applying the same transformation to every ⁶⁸Ge-AC map, and averaging the resulting ⁶⁸Ge-AC maps. [¹¹C]PE2I PET images were reconstructed using CTR-AC and a patient-specific ⁶⁸Ge-AC map as the reference standard. Standardized uptake values (SUV) and quantitative parameters of kinetic analysis were compared, i.e., relative delivery (R1) and non-displaceable binding potential (BPND).
CTR-AC showed high accuracy for whole-brain SUV (mean %bias ± SD: 0.5 ± 3.5%), whole-brain R1 (−0.1 ± 3.2%), and putamen BPND (3.7 ± 8.1%). SUV and R1 precision (SD of %bias) were modest and lowest in the anterior cortex, with an R1 %bias of −1.1 ± 6.4%).
The prototype CTR-AC is capable of providing accurate MRAC-maps with continuous linear attenuation coefficients though still experimental. The method’s accuracy is comparable to the best MRAC methods published so far, both in SUV and as found for ZTE-AC in quantitative parameters of kinetic modelling.
... [ 11 C]carfentanil uptake was quantified by binding potential relative to non-displaceable binding (BPND) in 21 regions (amygdala, caudate, cerebellum, dorsal anterior cingulate cortex, hippocampus, inferior temporal cortex, insula, medulla, midbrain, middle temporal cortex, nucleus accumbens, orbitofrontal cortex, pars opercularis, posterior cingulate cortex, pons, putamen, rostral anterior cingulate cortex, superior frontal gyrus, superior temporal sulcus, temporal pole, and thalamus). BPND was estimated with the simplified reference tissue model (SRTM) in region of interest (ROI (Lammertsma & Hume, 1996) and voxel-level (Gunn et al., 1997) (SRTM) in ROI using the occipital cortex as the reference region. Due to the small sample size, we focused on (SRTM) in region-of-interest ROI analyses, whereas the voxel-level BPND images were used solely for the illustration. ...
BACKGROUND
Fear promotes rapid detection of threats and appropriate fight-or-flight responses. The endogenous opioid system modulates responses to pain and psychological stressors. Opioid agonists also have also anxiolytic effects. Fear and anxiety constitute major psychological stressors for humans, yet the contribution of the opioid system to acute human fear remains poorly characterized.
METHODS
We induced intense unconditioned fear in the subjects by gradually exposing them to a living constrictor snake (threat trials) versus an indoor plant (safety trials). Brain haemodynamic responses were recorded from 33 subjects during functional magnetic resonance imaging (fMRI). In addition, 15 subjects underwent brain positron emission tomography (PET) imaging using [ ¹¹ C]carfentanil, a high affinity agonist radioligand for μ-opioid receptors (MORs). PET studies under threat or safety exposure were performed on separate days. Pupillary arousal responses to snake and plant exposure were recorded in 36 subjects. Subjective fear ratings were measured throughout the experiments.
RESULTS
Self-reports and pupillometric responses confirmed significant experience of fear and autonomic activation during the threat trials. fMRI data revealed that proximity with the snake robustly engaged brainstem defense circuits as well as thalamus, dorsal attention network, and motor and premotor cortices. These effects were diminished during repeated exposures. PET data revealed that [ ¹¹ C]carfentanil binding to MORs was significantly higher during the fear versus safety condition, and the acute haemodynamic responses to threat were dependent on baseline MOR binding in the cingulate gyrus and thalamus. Finally, baseline MOR tone predicted dampening of the haemodynamic threat responses during the experiment.
CONCLUSIONS
Preparatory response during acute fear episodes involves a strong motor component in addition to the brainstem responses. These haemodynamic changes are coupled with a deactivation of the opioidergic circuit, highlighting the role of MORs in modulating the human fear response.
... Further to being closely associated with motor dysfunctions in PD, DAT deficits can also lead to anomalies in ENS architecture together with gastrointestinal dysmotility [10,11]. Several studies have also demonstrated the association between the striatal DAT binding and the activities of gut microbes, suggesting potential DAT modulations in both the central and peripheral regions [12,13]. ...
Purpose
Dynamic total-body imaging enables new perspectives to investigate the potential relationship between the central and peripheral regions. Employing uEXPLORER dynamic [¹¹C]CFT PET/CT imaging with voxel-wise simplified reference tissue model (SRTM) kinetic modeling and semi-quantitative measures, we explored how the correlation pattern between nigrostriatal and digestive regions differed between the healthy participants as controls (HC) and patients with Parkinson’s disease (PD).
Methods
Eleven participants (six HCs and five PDs) underwent 75-min dynamic [¹¹C]CFT scans on a total-body PET/CT scanner (uEXPLORER, United Imaging Healthcare) were retrospectively enrolled. Time activity curves for four nigrostriatal nuclei (caudate, putamen, pallidum, and substantia nigra) and three digestive organs (pancreas, stomach, and duodenum) were obtained. Total-body parametric images of relative transporter rate constant (R1) and distribution volume ratio (DVR) were generated using the SRTM with occipital lobe as the reference tissue and a linear regression with spatial-constraint algorithm. Standardized uptake value ratio (SUVR) at early (1–3 min, SUVREP) and late (60–75 min, SUVRLP) phases were calculated as the semi-quantitative substitutes for R1 and DVR, respectively.
Results
Significant differences in estimates between the HC and PD groups were identified in DVR and SUVRLP of putamen (DVR: 4.82 ± 1.58 vs. 2.58 ± 0.53; SUVRLP: 4.65 ± 1.36 vs. 2.84 ± 0.67; for HC and PD, respectively, both p < 0.05) and SUVREP of stomach (1.12 ± 0.27 vs. 2.27 ± 0.65 for HC and PD, respectively; p < 0.01). In the HC group, negative correlations were observed between stomach and substantia nigra in both the R1 and SUVREP values (r=-0.83, p < 0.05 for R1; r=-0.94, p < 0.01 for SUVREP). Positive correlations were identified between pancreas and putamen in both DVR and SUVRLP values (r = 0.94, p < 0.01 for DVR; r = 1.00, p < 0.001 for SUVRLP). By contrast, in the PD group, no correlations were found between the aforementioned target nigrostriatal and digestive areas.
Conclusions
The parametric images of R1 and DVR generated from the SRTM model, along with SUVREP and SUVRLP, were proposed to quantify dynamic total-body [¹¹C]CFT PET/CT in HC and PD groups. The distinction in correlation patterns of nigrostriatal and digestive regions between HC and PD groups identified by R1 and DVR, or SUVRs, may provide new insights into the disease mechanism.
... For every region, a time-activity curve was extracted and modeled using the simplified reference tissue model (SRTM) with the cerebellum as reference region to estimate the regional binding potential (BP ND ) and relative input parameter (R1). A voxel-level approach, still using the cerebellum curve as reference, was applied to normalized images to create parametric BP ND maps 59 . The NM data were processed using an automated voxel-wise analysis pipeline that has been shown to be reliable and reproducible 60 . ...
Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using ¹⁸ F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials.
... After coregistration of the T1-weighed MRI images to a summation over the first 5 min of the PET scan, using Statistical Parametric Mapping 8 (SPM8; Wellcome Trust Centre for Neuroimaging Institute of Neurology, University College of London, UK), the image was segmented into grey and white matter. A basis function implementation of the simplified reference tissue method was used to obtain parametric images of non-displaceable binding potential (BP ND ) [36][37][38]. For reference region, the cranial half of the subjects' white matter segmentation images, with the two outer layers of voxels removed by global erosion, was selected. ...
b> Introduction: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABA<sub>A</sub> receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. Methods: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [<sup>11</sup>C]flumazenil positron emission tomography to assess GABA<sub>A</sub> receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABA<sub>A</sub> receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABA<sub>A</sub> receptor activity, long-interval intracortical inhibition representing GABA<sub>B</sub> receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. Results: No significant differences in baseline GABA<sub>A</sub> receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABA<sub>A</sub> receptor availability and TMS outcomes. Changes in GABA<sub>A</sub> receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. Conclusion: We found that a change in GABA<sub>A</sub> receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.
... Accordingly, the BPND for the tracer should be interpreted as the density of the receptors unoccupied by endogenous ligand (i.e., receptor availability). Binding potential was calculated by applying the basis function method (Gunn et al., 1997) for each voxel using the simplified reference tissue model (Lammertsma & Hume, 1996), with occipital cortex serving as the reference region (Frost et al., 1989). The parametric images were spatially normalized to MNI-space via segmentation and normalization of T1-weighted anatomical images, and finally smoothed with an 8-mm FWHM Gaussian kernel. ...
Functional neuroimaging studies suggest that a large-scale brain network transforms others' pain into its vicarious representation in the observer, potentially modulating helping behaviour. The neuromolecular basis of individual differences in vicarious pain and helping have however remain poorly understood. Here we investigated the role of the endogenous mu-opioid receptor (MOR) system - known for its role in analgesia and sociability - in altruistic costly helping. MOR density was measured with high-affinity agonist radioligand [11C]carfentanil. In a separate fMRI experiment, participants could choose to donate money to reduce the pain of the confederate who was subjected to electric shocks of varying intensity. We found people were in general willing to engage in costly helping, and haemodynamic activity in amydala, aIns, anterior cingulate cortex, striatum, primary motor cortex, primary somatosensory cortex, and thalamus increased when participants witnessed the pain of others. These haemodynamic responses were negatively associated with MORs availability in the striatolimbic and cortical emotion circuits. In turn, haemodynamic responses during helping were positively associated with MOR availability in the anterior cingulate cortex and hippocampus. Altogether these data suggest that endogenous MOR system modulates processing of altruistic behaviour and costly helping in the human brain.
... By this, a probability map of ROIs for the MRI scan of interest is obtained. Voxel-wise parametric images of R 1 were generated using receptor parametric mapping (RPM, a basis function approach of simplified reference tissue model) with cerebellar GM as the reference region [26][27][28]. For this purpose, the entire duration of the PET scan was used. ...
Background
Dynamic PET imaging studies provide accurate estimates of specific binding, but also measure the relative tracer delivery (R 1 ), which is a proxy for relative cerebral blood flow (rCBF). Recently, studies suggested that R 1 obtained from different tracers could be used interchangeably and is irrespective of target tissue. However, the similarities or differences of R 1 obtained from different PET tracers still require validation. Therefore, the goal of the current study was to compare R 1 estimates, derived from dynamic [ ¹⁸ F]florbetapir (amyloid) and [ ¹⁸ F]flortaucipir (tau) PET, in the same subjects with subjective cognitive decline (SCD).
Results
Voxel-wise analysis presented a small cluster (1.6% of the whole brain) with higher R 1 values for [ ¹⁸ F]flortaucipir compared to [ ¹⁸ F]florbetapir in the Aβ-negative group. These voxels were part of the hippocampus and the left middle occipital gyrus. In part of the thalamus, midbrain and cerebellum, voxels (2.5% of the whole brain) with higher R 1 values for [ ¹⁸ F]florbetapir were observed. In the Aβ-positive group, a cluster (0.2% of the whole brain) of higher R 1 values was observed in part of the hippocampus, right parahippocampal gyrus and in the left sagittal stratum for [ ¹⁸ F]flortaucipir compared to [ ¹⁸ F]florbetapir. Furthermore, in part of the thalamus, left amygdala, midbrain and right parahippocampal gyrus voxels (0.4% of the whole brain) with higher R 1 values for [ ¹⁸ F]florbetapir were observed. Despite these differences, [ ¹⁸ F]florbetapir R 1 had high correspondence with [ ¹⁸ F]flortaucipir R 1 across all regions of interest (ROIs) and subjects (Aβ−: r ² = 0.79, slope = 0.85, ICC = 0.76; Aβ+: r ² = 0.87, slope = 0.93, ICC = 0.77).
Conclusion
[ ¹⁸ F]flortaucipir and [ ¹⁸ F]florbetapir showed similar R 1 estimates in cortical regions. This finding, put together with previous studies, indicates that R 1 could be considered a surrogate for relative cerebral blood flow (rCBF) in the cortex and may be used interchangeably, but with caution, regardless of the choice of these two tracers.
... To quantify specific binding of [ 11 C]DCZ, a parameter representing radioligand-receptor binding was calculated to serve as an index of neuroreceptor density. The distribution volume ratio (DVR) was estimated from the PET time series for each voxel in this parametric image, and DVR images were calculated using the SRTM2 algorithm (Gunn et al., 1997;Wu and Carson, 2002), with the cerebellar grey matter as the reference region of negligible specific ligand-receptor binding. The DVR images were spatially transformed into a common T1-weighted MRI template space made from 592 rhesus monkeys (Fox et al., 2015a) and blurred with a 2 mm FWHM smoothing kernel using Advanced Normalization Tools (ANTS; Avants et al., 2010;. ...
Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [¹¹C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.
... Briefly, averaged PET images for each animal were coregistered to their respective structural MRI, which was then non-linearly transformed into the Waxholm Sprague Dawley Space Atlas (https://www.nitrc.org/projects/whs-sd-atlas). The binding potential (BPND) maps were generated using the SRTM model, [ 18 F]NAV-4694 BPND was calculated for each voxel using cerebellar gray matter as a reference region and for [ 18 F]MK-6240 BPND was calculated for each voxel using the striatum (36). The parametric maps were blurred using a 1mm Full Width Half Maximum Gaussian kernel. ...
Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 A resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
... A Patlak plot was used to calculate the parametric 18 F-FDOPA K i images, and a simplified reference tissue model was used to calculate 11 C-MADAM and 11 C-carfentanil BP ND images. The cerebellar cortex was used as the reference region for 11 C-MADAM, and the occipital cortex for 18 F-FDOPA and 11 C-carfentanil (Gunn, Lammertsma, Hume, & Cunningham, 1997;Patlak & Blasberg, 1985). The parametric images were normalized to the Montreal Neurological Institute standard space (MNI152) using the spatial information from T1 s with DARTEL (Ashburner, 2007) and finally smoothed with a Gaussian kernel of 8 mm to improve the signal-to-noise ratio for statistical analyses. ...
Background:
The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities.
Methods:
Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (18F-FDOPA), opioid (11C-carfentanil) and serotonin (11C-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches.
Results:
Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (PFWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC 11C-MADAM binding (p = 0.03) but not in 18F-FDOPA uptake or 11C-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex 11C-MADAM binding (PFWE <0.05). Right NAcc 11C-MADAM binding potential correlated with attentional impulsivity in individuals with gambling disorder (r = -0.73, p = 0.005).
Discussion:
Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify potential treatment targets for gambling disorder.
... The epidemic SIR/SIRD models are non-linear and the identification of the parameters is challenging, compared to the linear models where analytical approaches exist (Godfrey and DiStefano, [15]). For the case of non-linear models there are methods for identifying the parameters, that are assumed to be constant, by using Taylor series (Gun et al, [16]; Pohjanpalo [17]) or differential algebra (Audoly et al, [18]; Eisenberg [19]). Differential algebra can also be an useful tool in the case of time dependent parameters (Hadeler,[20], Mummert,[21]). ...
In this paper, we propose a parameter identification methodology of the SIRD model, an extension of the classical SIR model, that considers the deceased as a separate category. In addition, our model includes one parameter which is the ratio between the real total number of infected and the number of infected that were documented in the official statistics. Due to many factors, like governmental decisions, several variants circulating, opening and closing of schools, the typical assumption that the parameters of the model stay constant for long periods of time is not realistic. Thus our objective is to create a method which works for short periods of time. In this scope, we approach the estimation relying on the previous 7 days of data and then use the identified parameters to make predictions. To perform the estimation of the parameters we propose the average of an ensemble of neural networks. Each neural network is constructed based on a database built by solving the SIRD for 7 days, with random parameters. In this way, the networks learn the parameters from the solution of the SIRD model. Lastly we use the ensemble to get estimates of the parameters from the real data of Covid19 in Romania and then we illustrate the predictions for different periods of time, from 10 up to 45 days, for the number of deaths. The main goal was to apply this approach on the analysis of COVID-19 evolution in Romania, but this was also exemplified on other countries like Hungary, Czech Republic and Poland with similar results. The results are backed by a theorem which guarantees that we can recover the parameters of the model from the reported data. We believe this methodology can be used as a general tool for dealing with short term predictions of infectious diseases or in other compartmental models.
... MOR availability was measured with the radioligand [ 11 C]carfentanil (10), synthesized as described previously (11). Regional time-activity curves were obtained from 21 regions of interest, and regional nondisplaceable binding potential values were obtained for each scan using the simplified reference tissue model with the occipital cortex as a reference (Supplemental Table 1) (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). PET imaging was performed with a Discovery 690 PET/CT scanner. ...
The endogenous μ-opioid receptor (MOR) system plays a key role in the mammalian reward circuit. Human and animal experiments suggest the involvement of MORs in human sexual pleasure, yet this hypothesis currently lacks in vivo support. Methods: We used PET with the radioligand [11C]carfentanil, which has high affinity for MORs, to quantify endogenous opioid release after orgasm in man. Participants were scanned once immediately after orgasm and once in a baseline state. Hemodynamic activity was measured with functional MRI during penile stimulation. Results: The PET data revealed significant opioid release in the hippocampus. Hemodynamic activity in the somatosensory and motor cortices and in the hippocampus and thalamus increased during penile stimulation, and thalamic activation was linearly dependent on self-reported sexual arousal. Conclusion: Our data show that endogenous opioidergic activation in the medial temporal lobe is centrally involved in sexual arousal, and this circuit may be implicated in orgasmic disorders.
... For [ 11 C]raclopride PET, reversible tracer binding was quantified using simplified reference tissue model analysis (SRTM; Lammertsma and Hume 1996). Specifically, a basis function version of the SRTM was applied as previously described (Gunn et al. 1997) with posterior cerebellar gray matter used as the reference region. The SRTM analysis was performed using in-house software provided by Dr. Roger Gunn and MATLAB version 8.2. ...
In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.
... Regional 11 C-PK11195-binding was quantified as distribution volume ratios (DVR) within 20-60 min post injection using a reference tissue input Logan's method with pseudo-reference region extracted using supervised clustering algorithm [38,39]. Voxel-level kinetic modeling for 11 C-PK11195 was carried out using basis function implementation of simplified reference tissue model with respect to the aforementioned clustered pseudo-reference region and with 300 basis functions calculated within the Θ 3 parameter limits 0.06 ≤ Θ 3 ≤ 0.6 [40]. Partial volume effect (PVE)-corrected data was used for all 11 C-PK11195 analysis in order to minimize the effect TSPO uptake in sinuses to cortical regions. ...
Background
Neuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer’s disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD.
Methods
Sixty 60–75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent ¹¹C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), ¹¹C-PiB PET (targeting Aβ), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). ¹¹C-PK11195 distribution volume ratios and ¹¹C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aβ accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aβ1-42/1.40.
Results
In our cognitively unimpaired sample, cortical ¹¹C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38–1.66) in non-carriers, 1.55 (1.43–2.02) in heterozygotes, and 2.13 (1.61–2.83) in homozygotes, P = 0.002). In contrast, cortical composite ¹¹C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aβ-positive and Aβ-negative individuals (P = 0.81) and associated with higher Aβ burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical ¹¹C-PiB (Rho = 0.35, P = 0.040), but not ¹¹C-PK11195-binding (Rho = 0.13, P = 0.47) in Aβ-positive individuals. In the total cognitively unimpaired population, both higher composite ¹¹C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated ¹¹C-PiB-binding was associated with lower APCC scores.
Conclusions
Only Aβ burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ.
... Model fit accuracies were compared using the Akaike Information Criterion (AIC). Two models with reference region were also assessed: the Simplified Reference Tissue Model (SRTM) [31] and the logan reference model (LREF) [30]. Four different reference regions were compared: corpus callosum (CC), cerebellum (CER), white matter cerebellum (CERWM), and frontal lobe white matter (FLWM). ...
Purpose
F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT 1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [ ¹⁸ F]F13640 binds preferentially to functional 5-HT 1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT 1A receptors by [ ¹⁸ F]F13640 in humans and describe a simplified model for its quantification.
Methods
PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) ( n = 9) and test–retest protocol ( n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF).
Results
[ ¹⁸ F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [ ¹⁸ F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions.
Conclusion
The favorable brain labeling and kinetic profile of [ ¹⁸ F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT 1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [ ¹⁸ F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry.
Trial Registration
Trial Registration EudraCT 2017–002,722-21.
... [ 11 C]carfentanil uptake was quantified by non-displaceable binding potential (BPND) in 21 regions (amygdala, caudate, cerebellum, dorsal anterior cingulate cortex, hippocampus, inferior temporal cortex, insula, medulla, midbrain, middle temporal cortex, nucleus accumbens, orbitofrontal cortex, pars opercularis, posterior cingulate cortex, pons, putamen, rostral anterior cingulate cortex, superior frontal gyrus, superior temporal sulcus, temporal pole, and thalamus). BPND was estimated with simplified reference tissue model in regional (Lammertsma & Hume, 1996) and voxel-level (Gunn et al., 1997) by using occipital cortex as the reference region. Due to . ...
Sex is one of the most rewarding and motivating behaviours for humans. Endogenous mu-opioid receptor system (MORs) plays a key role in the mammalian reward circuit. Both human and animal experiments suggest the involvements of MORs in human sexual pleasure, yet this hypothesis currently lacks in vivo support. We used positron emission tomography (PET) with the radioligand [11C]carfentanil, which has high affinity for MORs to quantify endogenous opioid release following orgasm in man. Subjects were scanned twice: Once immediately after reaching an orgasm and once in a baseline state. Haemodynamic activity was measured with functional magnetic resonance imaging during penile stimulation from partner. The PET data revealed significant opioid release in hippocampus. Haemodynamic activity in somatosensory and motor cortices as well as hippocampus and thalamus increased during penile stimulation, and thalamic activation was linearly dependent on self-reported sexual arousal. Altogether these data show that endogenous opioidergic activation in the medial temporal lobe is centrally involved in sexual arousal.
... Preprocessing. Parametric [ 11 C]PE2I binding potential (BP ND ) images were generated using receptor parametric mapping [65] which is based on a simplified reference region compartmental model and [ 11 C]DASB BP ND images were calculated using the reference Logan [66] method. When using reference Logan, BP ND is derived by subtracting 1 from the O. Hjorth et al. distribution volume ratio. ...
Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.
... For parametric approaches using a reference tissue, a Simplified Reference Tissue Model using a set of predefined basis functions (SRTM2) [72], a Multilinear Reference Tissue Model (MRTM2) [30] and a reference Logan Graphical Analysis (rLGA) [31] were considered. For all three approaches, the tracer efflux rate constant k2 from the reference tissue to plasma was assumed to be known and set to a fixed value. ...
... Radiotracer binding potential (BP) in the right striatum was estimated with the simpli ed reference tissue model (SRTM), using left striatum as the reference tissue, implemented in PMOD4.203 (PMOD Technologies, Zurich, Switzerland) [47]. TACs of the left and right hippocampus, which was not affected by LPS injection in the striatum, was analyzed as a control. ...
Introduction: Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[¹⁸F]FDF) was developed for PET imaging of fructose metabolism in breast cancer via the fructose-preferred facilitative hexose transporter, GLUT5. In the brain, GLUT5 is predominantly expressed on microglial cells that are activated in response to inflammatory stimuli. We hypothesize that 6-[¹⁸F]FDF will specifically image microglia following neuroinflammatory insult.
Methods: 6-[¹⁸F]FDF was evaluated in a neuroinflammation model induced by unilateral injection of lipopolysaccharide (LPS) into the right striatum (50 µg/animal) in male and female rats. Comparison of 6-[¹⁸F]FDF and the glucose derivative [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), was performed by longitudinal dynamic PET imaging in vivo. Immunohistochemistry was conducted to examine the presence of activated microglia (Iba-1) and astrocytes (GFAP) in fixed brain tissues.
Results: In LPS-injected rats, increased accumulation of radioactivity from 6-[¹⁸F]FDF was observed in the ipsilateral striatum compared to the contralateral side at 24-48 hr post-LPS injection, with plateaued uptake at 60-120 min significantly higher in the right (0.985 ± 0.047 SUV) vs. left (0.819 ± 0.033 SUV) striatum at 48 h (P = 0.002; n = 4M/3F). The ipsilateral-contralateral difference in striatal 6-[¹⁸F]FDF uptake expressed as binding potential peaked at 48 h (male: 0.25 ± 0.03; female: 0.11 ± 0.03) and was significantly decreased at later time points of one, two and four weeks; and was higher in male rats (P = 0.017). In contrast, increased [¹⁸F]FDG uptake was observed in the ipsilateral striatum compared to the contralateral striatum and was highest at one week post-LPS injection. Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes in the ipsilateral striatum.
Conclusions: This proof-of-concept study revealed an early response of 6-[¹⁸F]FDF to neuroinflammatory stimuli in rat brain. 6-[¹⁸F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in the brain with applications in neuroinflammatory and neurodegenerative diseases.
... Voxel-level kinetic modelling for 11 C-PK11195 was carried out using basis function implementation of simplified reference tissue model with respect to the aforementioned clustered pseudo-reference region and with 300 basis functions calculated within the 3 parameter limits 0.06 3 0.6. 45 Partial volume effect (PVE)-corrected data was used for all 11 C-PK11195 analysis in order to minimize the effect TSPO uptake in sinuses to cortical regions. PVE correction was carried out . ...
Increased reactivity of microglia and astrocytes is known to be present at various stages of the Alzheimer's continuum but their relationship with core Alzheimer's disease pathology in the preclinical stages is less clear. We investigated glial reactivity and β-amyloid pathology in cognitively unimpaired APOE ε4 homozygotes, heterozygotes and non-carriers using 11C-PK11195 PET (targeting 18-kDa translocator protein), 11C-PiB PET (targeting β-amyloid), brain MRI, and a preclinical cognitive composite (APCC). Plasma glial fibrillary acidic protein (GFAP) by and plasma Aβ1-42/1-40 were measured using single molecule array and immunoprecipitation combined with mass spectrometry, respectively. We observed that (i) 11C-PiB-binding was significantly higher in APOE ε4 homozygotes compared with non-carriers in all evaluated regions, (ii) regional 11C-PK11195-binding did not differ between the APOE ε4 gene doses or between Aβ-positive and -negative individuals, and (iii) higher 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, and elevated 11C-PiB-binding and plasma GFAP concentration with lower APCC scores. Increased glial reactivity might emerge in later stages of preclinical Alzheimer's disease in parallel with early neurodegenerative changes.
... receptor availability). The binding potential was calculated by applying the basis function method [32] for each voxel using the simplified reference tissue model [33], with the occipital cortex serving as the reference region [34]. The parametric images were spatially normalized to MNI-space via segmentation and normalization of T1-weighted anatomical images, and finally smoothed with an 8 mm full-width-at-half-maximum (FWHM) Gaussian kernel. ...
Laughter is a contagious prosocial signal that conveys bonding motivation; adult crying conversely communicates desire for social proximity by signalling distress. Endogenous mu-opioid receptors (MORs) modulate sociability in humans and non-human primates. In this combined PET–fMRI study ( n = 17), we tested whether central MOR tone is associated with regional brain responses to social signals of laughter and crying. MOR availability was measured with positron emission tomography (PET) using the high-affinity agonist radioligand [ ¹¹ C]carfentanil. Haemodynamic responses to social laughter and crying vocalizations were measured using functional magnetic resonance imaging (fMRI). Social laughter evoked activation in the auditory cortex, insula, cingulate cortex, amygdala, primary and secondary somatosensory cortex, and primary and secondary motor cortex; crying sounds led to more restricted activation in the auditory cortex and nearby areas. MOR availability was negatively correlated with the haemodynamic responses to social laughter in the primary and secondary somatosensory cortex, primary and secondary motor cortex, posterior insula, posterior cingulate cortex, precuneus, cuneus, temporal gyri and lingual gyrus. For crying-evoked activations, MOR availability was negatively correlated with medial and lateral prefrontal haemodynamic responses. Altogether our findings highlight the role of the MOR system in modulating acute brain responses to both positive and negative social signals.
This article is part of the theme issue ‘Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience’.
... Image analyses including CT to MR brain template co-registration, extraction of regional brain TACs, kinetic modelling, and BP ND map construction were performed using PMOD (version 4.203, Zürich, Switzerland). Modified cerebellar cortex with voxels close to the brainstem removed was used as the reference region for modelling with a simplified reference tissue model [16,17]. ...
Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer’s disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.
... Next, regions of interest (ROIs) were defined on the co-registered MRI using the probabilistic Hammers brain atlas in PVElab [31]. Receptor parametric mapping (RPM) was used to generate parametric BP ND and R 1 images with cerebellar gray matter as a reference region using PPET [25,[32][33][34]. We calculated (volume weighted) mean cortical BP ND and R 1 in the following (bilateral) ROIs: frontal, temporal, parietal, occipital, and a composite ROI consisting of orbitofrontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus regions [35]. ...
Purpose
The role of cerebral blood flow (CBF) in the early stages of Alzheimer’s disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD).
Methods
We included 187 cognitively normal individuals with SCD from the SCIENCe project (65 ± 8 years, 39% F, MMSE 29 ± 1). Each underwent a dynamic (0–70 min) [ ¹⁸ F]florbetapir PET and T1-weighted MRI scan, enabling calculation of mean binding potential (BP ND ; specific amyloid binding) and R 1 (measure of relative (r)CBF). Eighty-three individuals underwent a second [ ¹⁸ F]florbetapir PET (2.6 ± 0.7 years). Participants annually underwent neuropsychological assessment (follow-up time 3.8 ± 3.1 years; number of observations n = 774).
Results
A low baseline R 1 was associated with steeper decline on tests addressing memory, attention, and global cognition (range betas 0.01 to 0.27, p < 0.05). High BP ND was associated with steeper decline on tests covering all domains (range betas − 0.004 to − 0.70, p < 0.05). When both predictors were simultaneously added to the model, associations remained essentially unchanged. Additionally, we found longitudinal associations between R 1 and BP ND . High baseline BP ND predicted decline over time in R 1 (all regions, range betas BP×time − 0.09 to − 0.14, p < 0.05). Vice versa, low baseline R 1 predicted increase in BP ND in frontal, temporal, and composite ROIs over time (range betas R 1×time − 0.03 to − 0.08, p < 0.05).
Conclusion
Our results suggest that amyloid accumulation and decrease in rCBF are two parallel disease processes without a fixed order, both providing unique predictive information for cognitive decline and each process enhancing the other longitudinally.
... Next, regions of interest (ROIs) were defined on the co-registered MRI using the probabilistic Hammers brain atlas [14] in PVElab. Receptor parametric mapping (RPM) was used to generate parametric binding potential (BP ND ) images with cerebellar grey matter as a reference region using PPET [11,[15][16][17]. For [ 18 F]florbetapir, we calculated (volume weighted) mean cortical BP ND in a composite ROI consisting of orbitofrontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus regions [6,18]. ...
Background
Biomarkers for amyloid, tau, and neurodegeneration (ATN) have predictive value for clinical progression, but it is not clear how individuals move through these stages. We examined changes in ATN profiles over time, and investigated determinants of change in A status, in a sample of cognitively normal individuals presenting with subjective cognitive decline (SCD).
Methods
We included 92 individuals with SCD from the SCIENCe project with [ ¹⁸ F]florbetapir PET (A) available at two time points (65 ± 8y, 42% female, MMSE 29 ± 1, follow-up 2.5 ± 0.7y). We additionally used [ ¹⁸ F]flortaucipir PET for T and medial temporal atrophy score on MRI for N. Thirty-nine individuals had complete biomarker data at baseline and follow-up, enabling the construction of ATN profiles at two time points. All underwent extensive neuropsychological assessments (follow-up time 4.9 ± 2.8y, median number of visits n = 4). We investigated changes in biomarker status and ATN profiles over time. We assessed which factors predisposed for a change from A− to A+ using logistic regression. We additionally used linear mixed models to assess change from A− to A+, compared to the group that remained A− at follow-up, as predictor for cognitive decline.
Results
At baseline, 62% had normal AD biomarkers (A−T−N− n = 24), 5% had non-AD pathologic change (A−T−N+ n = 2,) and 33% fell within the Alzheimer’s continuum (A+T−N− n = 9, A+T+N− n = 3, A+T+N+ n = 1). Seventeen subjects (44%) changed to another ATN profile over time. Only 6/17 followed the Alzheimer’s disease sequence of A → T → N, while 11/17 followed a different order (e.g., reverted back to negative biomarker status). APOE ε4 carriership inferred an increased risk of changing from A− to A+ (OR 5.2 (95% CI 1.2–22.8)). Individuals who changed from A− to A+, showed subtly steeper decline on Stroop I ( β − 0.03 (SE 0.01)) and Stroop III (− 0.03 (0.01)), compared to individuals who remained A−.
Conclusion
We observed considerable variability in the order of ATN biomarkers becoming abnormal. Individuals who became A+ at follow-up showed subtle decline on tests for attention and executive functioning, confirming clinical relevance of amyloid positivity.
... Parametric images in MNI 152 space were expressed as z scores to facilitate interpretation of findings across the three radiotracers. [ 11 C]SA4503 and [ 11 C]UCB-J parametric maps were generated with the one tissue reversible compartmental model, solved voxel-wise using the basis function method (61). [ 18 F]BCPP-EF parametric maps were generated using the MA1 method solved at the voxel level, using the same settings as for the associated regional analysis. ...
Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ ¹¹ C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [ ¹⁸ F]BCPP-EF, and the presynaptic vesicular protein SV2A with [ ¹¹ C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ −28%) and SV2A (≥ −25%) radioligand binding, brain volume (≥ −23%), and CBF (≥ −26%). [ ¹⁸ F]BCPP-EF PET MC1 binding (≥ −12%) and brain volumes (≥ −5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.
... Model t accuracy were compared using the Akaike Information Criterion (AIC). Two models with reference region were also assessed: the Simpli ed Reference Tissue Model (SRTM) [30] and the logan reference model (LREF) [29]. The use of four different reference regions were compared: corpus callosum (CC), cerebellum (CER), white matter cerebellum (CERWM) and frontal lobe white matter (FLWM). ...
Purpose:
F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [¹⁸F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here we characterize brain labeling of 5-HT1A receptors by [¹⁸F]F13640 in humans and describe a simplified model for its quantification.
Methods:
PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) and test-retest protocol. Several kinetic models were compared (one tissue compartment model, two-tissue compartment model and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the Logan reference model (LREF).
Results:
[¹⁸F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed excellent correlation with kinetic models using AIF. Considering test-retest parameters and the prolonged binding kinetics of [¹⁸F]F13640, better reproducibility and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions.
Conclusion:
The favorable brain labeling and kinetic profile of [¹⁸F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [¹⁸F]F13640’s kinetic properties allow injection out of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry.
Trial Registration EudraCT 2017-002722-21
... Next, parametric modelling was performed using the basisfunction-based implementation of the two-step simplified reference tissue model (SRTM2) [20], as implemented in the PPET software package [21] and validated previously [22], to compute parametric BP ND and relative tracer delivery (R 1 ) images. For SRTM2, k 2 ' was determined by taking the median k 2 ' across all voxels with a BP ND higher than 0.05 from a first run using receptor parametric mapping (RPM) [23,24]. In addition, SUVR was calculated from 90 to 110 min p.i. ...
Background
Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [ ¹⁸ F]flutemetamol ( N = 90) or [ ¹⁸ F]florbetaben ( N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R 1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland–Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R 1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region.
Results
Despite high correlations (GCA: R ² ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVR bias and R 1, albeit non-significant.
Conclusion
The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018.
... An in-house MNI-based atlas including the whole striatum, its limbic, associative, and sensorimotor functional subdivisions (as defined by Martinez et al. [36]) underwent the same transformation. Then, using a simplified reference tissue model (SRTM) and the voxel time activity curves, the nondisplaceable binding potential (BP ND ) of [ 11 C]-( + )-PHNO was estimated at each voxel [37,38]. The cerebellum was chosen as the reference region due to its low D 2/3 receptor binding [39], and each participant's mean BP ND were calculated for each region-of-interest (ROI). ...
Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [11C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.
... For each subject, an isotropic, skull-stripped IR-FSPGR structural image normalised to the MNI template was co-registered onto an isotropic, motioncorrected integral image created from the PET time series. Binding potential parametric maps were estimated through a simplified reference tissue model using the pons as the reference region and solved with basis function method 73 . The individual parametric maps were averaged using SPM imCalc function and resliced with the Co-register: Reslice function to match the dimensions of the Desikan-Killiany atlas (voxel size 1 × 1 × 1 mm, number of voxels per direction X = 146, Y = 182, Z = 155). ...
Diverse GABAergic interneuron networks orchestrate information processing in the brain. Understanding the principles underlying the organisation of this system in the human brain, and whether these principles are reflected by available non-invasive in vivo neuroimaging methods, is crucial for the study of GABAergic neurotransmission. Here, we use human gene expression data and state-of-the-art imaging transcriptomics to uncover co-expression patterns between genes encoding GABA A receptor subunits and inhibitory interneuron subtype-specific markers, and their association with binding patterns of the gold-standard GABA PET radiotracers [ 11 C]Ro15-4513 and [ 11 C]flumazenil. We found that the inhibitory interneuron marker somatostatin covaries with GABA A receptor-subunit genes GABRA5 and GABRA2, and that their distribution followed [ 11 C]Ro15-4513 binding. In contrast, the inhibitory interneuron marker parvalbumin covaried with GABA A receptor-subunit genes GABRA1, GABRB2 and GABRG2, and their distribution tracked [ 11 C]flumazenil binding. Our findings indicate that existing PET radiotracers may provide complementary information about key components of the GABAergic system.
Background
Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear.
Objective
We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression.
Methods
The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0–17.2) years, 72% females, 74% relapsing–remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [¹¹C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM).
Results
Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs.
Conclusion
We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.
This review summarizes positron emission tomography (PET) and single photon emission tomography (SPECT) studies relating to all levels of alcohol consumption to support the dimensional view of alcohol use disorder (AUD) ranging from acute consumption in social drinkers over individuals at high risk up to severe AUD and the associations with blunted dopaminergic (DA) neurotransmission. Confounding factors of PET and SPECT of the DA system are also discussed. Alcohol-associated alterations of the DA system have been investigated via functional SPECT and PET imaging methods for many years, investigating presynaptic or postsynaptic markers such as DA receptor or transporter availability, both with and without challenge. These studies provided strong evidence that acute alcohol administration in social drinkers is followed by a DA release particularly in the ventral striatum. In AUD subjects, DA release appears to be impaired, as administration of a psychostimulant is followed by a blunted striatal DA. Further, in recently detoxified AUD subjects, in vivo dopamine D2 and D3 receptor availability appears to be reduced, which may be a predisposing factor or the result of a neuroadaptive process influencing drug-induced DA release. DA transporter availability is reduced in AUD, whereas findings with respect to DA synthesis capacity are controversial.
Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson’s disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D 2/3 autoreceptors in mesocorticolimbic circuits. While altered D 2/3 binding is noted in ICB+ PD patients, there is limited prior assessment of the trait impulsivity-D 2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36M; 18F) and 31 sex- and age-matched HC (21M; 10F) subjects using [ ¹⁸ F]fallypride, a high-affinity D 2/3 receptor ligand, to measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). Subcortical and cortical assessment exclusively utilized region-of-interest or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale (BIS-11), a measure of trait impulsivity. Subcortical region-of-interest analyses indicated a negative relationship between trait impulsivity and D 2/3 BP ND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D 2/3 BP ND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD.
Significance Statement
The biologic determinants of impulsivity have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease (PD). This is the first study to evaluate a large cohort of PD patients and age-matched healthy controls with a measure of trait-impulsivity and concurrent [ ¹⁸ F]fallypride positron emission tomography, a method which allows quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in the trait impulsivity-dopamine relationship, including (1) loss of subcortical relationships present in the healthy brain, and (2) emergence of a new relationship in a limbic cortical area. This illustrates the loss of mechanisms of behavioral regulation present in the healthy brain while suggesting a potential compensatory response and target for future investigation.
The use of radiopharmaceuticals and the imaging of their kinetics are key components to successful developments in PET. The state-of-the-art PET systems produce high-quality 3D images providing quantitatively accurate measurements of radioactivity concentration. The application of tracer kinetic modeling techniques can convert these radioactivity values into quantitative and semi-quantitative indices of blood flow, metabolism, and receptor pharmacology. In this chapter, the concepts of mathematical modeling as applied to PET are presented, with a focus on receptor-binding tracers. The commonly used compartment models and their equations are shown, including models using arterial input functions and reference regions. This is followed by alternative approaches including linearized techniques, constant infusion, and model simplifications. Application of models in a voxelwise manner to produce parametric images is then presented. An example of model validation and optimization for SV2A PET tracer is included. Finally, the applications of modeling for quantification of neurotransmitter dynamics and drug-induced target occupancy are presented.KeywordsPositron emission tomographyTracer kinetic modelingCompartment modelingReference region methodsReceptorsParametric imagingDrug occupancyNeurotransmitter dynamics
Background:
Positron emission tomography (PET) scanning is an important diagnostic imaging technique used in disease diagnosis, therapy planning, treatment monitoring, and medical research. The standardized uptake value (SUV) obtained at a single time frame has been widely employed in clinical practice. Well beyond this simple static measure, more detailed metabolic information can be recovered from dynamic PET scans, followed by the recovery of arterial input function and application of appropriate tracer kinetic models. Many efforts have been devoted to the development of quantitative techniques over the last couple of decades.
Challenges:
The advent of new-generation total-body PET scanners characterized by ultra-high sensitivity and long axial field of view, i.e., uEXPLORER (United Imaging Healthcare), PennPET Explorer (University of Pennsylvania), and Biograph Vision Quadra (Siemens Healthineers), further stimulates valuable inspiration to derive kinetics for multiple organs simultaneously. But some emerging issues also need to be addressed, e.g., the large-scale data size and organ-specific physiology. The direct implementation of classical methods for total-body PET imaging without proper validation may lead to less accurate results.
Conclusions:
In this contribution, the published dynamic total-body PET datasets are outlined, and several challenges/opportunities for quantitation of such types of studies are presented. An overview of the basic equation, calculation of input function (based on blood sampling, image, population or mathematical model), and kinetic analysis encompassing parametric (compartmental model, graphical plot and spectral analysis) and non-parametric (B-spline and piece-wise basis elements) approaches is provided. The discussion mainly focuses on the feasibilities, recent developments, and future perspectives of these methodologies for a diverse-tissue environment.
The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [11C]PE2I (n = 20) and [18F]FE-PE2I (n = 20) and the D2/3 tracer [11C]raclopride (n = 18). Subjects with a [11C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [11C]DASB. Binding potential (BPND) and relative tracer delivery (R1) values were calculated on regional and voxel-level. Striatal R1 and BPND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BPND image. An inter-tracer comparison between [11C]PE2I BPND and [11C]DASB R1 was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BPND and R1 for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [11C]PE2I BPND and [11C]DASB R1. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.
The amyloid cascade hypothesis has strongly impacted the Alzheimer’s disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual-level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau-PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association.
We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume), and cognitive data (composite memory). Associations between each modality were tested at the individual-level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis.
At the individual-level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual-level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β=0.68, p < 0.001), and moderately associated with within-pair differences in hippocampal volume (β=-0.37, p = 0.03) and memory functioning (β=-0.57, p < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β=-0.53, p < 0.001) and strongly associated with within-pair differences in memory functioning (β=-0.68, p < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated: 51.6%).
Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.
Importance:
Although dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown.
Objective:
To assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms.
Design, setting, and participants:
This cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021.
Main outcomes and measures:
DAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD.
Results:
Of 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]-corrected P < .001) as well as left putamen and caudate (MR = 24%; cluster level FWE-corrected P < .001). The reduction in BPND was more extensive and pronounced in patients with current mania, while patients with recently remitted mania had lower BPND in the left striatum but not the right. There was a significant negative correlation between YMRS scores and MP BPND in the right striatum in patients with current mania (ρ = -0.93; 95% CI, -0.99 to -0.69; P < .001) and those with recently remitted mania (ρ = 0.64; 95% CI, -0.86 to -0.23; P = .005) but not in the left striatum in either group.
Conclusions and relevance:
These findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.
The authors present the results of testing an algorithm for
three-dimensional image reconstruction that uses all gamma-ray
coincidence events detected by a PET (positron emission tomography)
volume imaging scanner. By using two iterations of an analytic
filter-backprojection method, the algorithm is not constrained by the
requirement of a spatially invariant detector point spread function,
which limits normal analytic techniques. Removing this constraint allows
the incorporation of all detected events, regardless of orientation,
which improves the statistical quality of the final reconstructed image
Performance characteristics of a new design of positron tomograph with automatically retractable septa for brain imaging have been studied. The device, consisting of block BGO detectors (8 x 8 elements per block), has a ring diameter of 76 cm and an axial FOV of 106.5 mm. The in-plane resolution is on average 5.8 mm and 5.0 mm (FWHM) for stationary and wobble sampling, respectively, over the central 18 cm of the transaxial FOV. Its unique feature is the capability of data acquisition both in the 'conventional' 2D mode (with septa) or 3D mode (septa retracted) where coincidences between any of the 16 detector rings are acquired. When scattered events are subtracted, the efficiency for a 20 cm diameter uniform cylinder increases overall by a factor of 4.8 between 2D (septa extended) and 3D modes. For a 20 cm phantom the trues/singles ratio is higher for 3D than for 2D but for a given unscattered trues rate, the randoms rate in 3D is higher. At 380 keV the scatter fraction within a 20 cm cylinder is 10% (septa extended) and 36% (retracted). In spite of the increase in scatter when septa are retracted, the increased efficiency in the 3D mode of acquisition yields distinct advantages, particularly in the many studies where tracer concentration is low and consequently where dead time and random rates are less important.
The regional binding of the opiate receptor ligand diprenorphine has been examined in rat brain both in vivo and in vitro. The time course of total label in specific brain regions was followed up to 2 h after intravenous bolus injection of [3H]diprenorphine, with or without a pulse chase of unlabelled diprenorphine at 30 min. In addition, total label was measured 30 min after injection of labelled diprenorphine at nontracer concentrations over a range of specific activities. Total data sets for each region were fitted simultaneously to a compartmental model to give estimates of maximal binding capacity (Bmax), the second-order apparent association rate constant, and the first-order dissociation rate constant of the receptor-ligand complex. The model incorporated the use of a reference region with low specific binding (cerebellum). The binding of diprenorphine to rat brain homogenates was measured in vitro under equilibrium conditions at 37 degrees C, pH 7.4, in the presence and absence of naloxone, to give corresponding regional estimates of Bmax and the half-saturation constant Kd. The results showed a close correlation between in vitro and in vivo regional estimates of Bmax over a wide range. There were no significant interregional differences either in Kd in vitro or in the Kd derived from the in vivo analysis, although in vitro and in vivo estimates differed by an order of magnitude. This work was carried out as part of a validation study with a view to the application of the compartmental model to data obtained in vivo in humans using positron emission tomography, when successive studies over a range of specific activities are not feasible.(ABSTRACT TRUNCATED AT 250 WORDS)
Local CBF (LCBF) can be quantitated from positron computed tomographic (PCT) data and physiologically based mathematical models by several general methods. Those using a dynamic sequence of PCT scans allow the simultaneous estimation of both LCBF and p, the indicator's tissue-blood partition coefficient. This article presents a comparison of three rapid estimation techniques for use with inert diffusible radioindicators and serial PCT, each of which is based on the original Kety model. One method, developed in our laboratory, involves minimizing the mean squared discrepancy between measured data and model predictions, whereas the other two methods, recently reported in the literature, are weighted integration techniques that involve multiplying the measured data by time-dependent weighting functions. Simulation studies of noise propagation and other sources of error were performed under a variety of simulated conditions. Functional images of LCBF and p were calculated using each method for both phantom and human subject data. Errors can differ by as much as a factor of 2-3 between methods, with each having its own unique advantages and disadvantages.
This chapter reports on the use of a system to quantify specific binding of three positron-emitting tracers in rat striatum in vivo: [11C]SCH 23390 (D1 receptor antagonist), [11C]raclopride (D2 receptor antagonist), and the recently described dopamine transporter ligand [11C]RTI-121. A dedicated small-diameter positron emission tomography (PET) scanner has been used to quantify binding of three positron-emitting tracers in rat striatum in vivo: [11C]SCH 23390 (D1 receptor antagonist), [11C]-raclopride (D2 receptor antagonist), and the dopamine transporter ligand [11C]RTI-121. As the sizes of the striatal regions of interest used for analysis are of the same order as the dimensions of a detector element (3–4 mm), slight differences in the position of the rat within the scanner significantly affected the final images. Rats therefore were held in a perspex stereotaxic frame during scanning, thus abolishing movement and allowing precise positioning such that the striata were at the center of the field of view. Data are reported from a total of 31 previously untreated rats scanned over a period of 17 months. In addition, for each radioligand, groups of three rats were scanned after pretreatment with a blocking dose of the stable compound. Specific binding was quantified from the kinetic data using a reference tissue compartment model, with the cerebellum as an indirect input function. The results demonstrate that regional time-radioactivity data acquired using small animal positron emission tomography (PET) can provide reproducible and consistent quantitative information on pre- and postsynaptic dopaminergic function in rat striatum and that the system is sufficiently sensitive to allow the study of animal models of disease.
We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD−1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD−1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added [18F]spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability–surface area product) to be in the range of 0.025 to 0.036 cm3/(s·ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favourably to in vitro values in the literature. To our knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.
A method is described for the minimization of a function of n variables, which depends on the comparison of function values at the (n + 1) vertices of a general simplex, followed by the replacement of the vertex with the highest value by another point. The
simplex adapts itself to the local landscape, and contracts on to the final minimum. The method is shown to be effective and
computationally compact. A procedure is given for the estimation of the Hessian matrix in the neighbourhood of the minimum,
needed in statistical estimation problems.
Using conventional autoradiographic and tissue counting techniques, the experimental quantitation of in vivo kinetics of prospective or established radioligands for PET is animal and labour intensive. The present study tested the feasibility of using PET itself to quantitate the specific binding of [11C] raclopride to rat striatum and to study the effects of experimental manipulation of endogenous dopamine on binding parameters.
Carbon-11-labeled raclopride was given i. v. to anaesthetised rats, positioned in a PET camera and dynamic emission scans acquired over 60 min. Time-activity curves were generated for selected regions of interest, representing striatum and cerebellum and the striatal data fitted to a compartmental model, using cerebellum as the input function, thus circumventing the need for individual metabolite-corrected plasma curves. In control rats, the binding potential (BP), defined as the ratio of the rate constants for transfer from “free to bound” and “bound to free” compartments, was of the order of 0.6. This was reduced threefold by predosing with nonraioactive raclopride. Increasing extracellular dopamine levels by predosing with d -amphetamine resulted in a significant decrease in BP whereas reducing extracellular dopamine by predosing with γ-butyrolactone caused a significant increase.
Thus, despite the limitation in spatial resolution of PET, specific binding of raclopride could be assessed from regional time-activity curves from individual rats. The system was sufficiently sensitive that changes in BP could be detected following modulation of endogenous dopamine levels, a finding of potential relevance to the interpretation of clinical PET data.
A comprehensive software system called ANALYZE has been developed which permits detailed investigation and evaluation of 3-D biomedical images. The software can be used with any 2-D or 3-D imaging modality, including x-ray computed tomography, radionuclide emission tomography, ultrasound tomography, magnetic resonance imaging, and both light and electron microscopy. The package is unique in its synergistic integration of fully interactive modules for direct display, manipulation and measurement of multidimensional image data. Several original algorithms are included which improve image display efficiency and quality. One of the most versatile and powerful algorithms is interactive volume rendering, which is optimized to be fast without compromising image quality. An important advantage of this technique is to display 3-D images directly from the original data and to provide on-the-fly combinations of selected image transformations and/or volume set operations (union, intersection, difference, etc.). The inclusion of a variety of interactive editing and quantitative mensuration tools significantly extends the usefulness of the software. Any curvilinear path or region-of-interest can be manually specified and/or automatically segmented for numerical determination and statistical analyses of distances, areas, volumes, shapes, densities and textures.
Central to several current theories of the etiology of Parkinson's disease is the premise that the nigrostriatal dopaminergic system degenerates with normal aging. Much of the evidence for this assertion has come from postmortem neurochemical studies. We have used L-6-[18F] fluoro-Dopa and positron emission tomography in 26 healthy volunteers (age range, 27-76 years) to examine striatal and frontal cortical tracer uptake. Data have been analyzed by using a graphical approach to calculate an influx constant (Ki) for L-6-[18F]fluoro-Dopa uptake into the caudate, putamen, and medial frontal cortex of each subject. In the population studied, there was no decline in Ki with age for any of these structures. A series of physiological measurements made on the older subjects also showed few significant changes with age. The positron emission tomographic findings demonstrate preservation of nigrostriatal dopaminergic function in normal aging. The pathological process causing Parkinson's disease may operate closer to the time of presentation than has been suggested.
A small diameter positron emission tomography, designed specifically for small animal studies, was constructed from existing, commercially available, bismuth germanate (BGO) detectors and electronics. The scanner consists of 16 BGO detector blocks arranged to give a tomograph with a diameter of 115 mm and an axial field of view (FOV) of 50 mm. Each block is cut to produce eight (axial) by seven (radial) individual detector elements. The absence of interplane septa enables the acquisition of 3D data sets consisting of 64 sinograms. A 2D data set of 15 sinograms, consisting of eight direct and seven adjacent cross planes, can be extracted from the 3D data set. Images are reconstructed from the 2D sinograms using a conventional filtered backprojection algorithm. Two methods of normalization were investigated, based on either a rotating 68Ge rod source, or a uniform 68Ge plane source, with a uniform cylindrical 18F phantom. Attenuation of the emitted photons was estimated using a rotating 68Ge rod source. The transaxial resolution of the tomograph was measured as 2.3 mm full width at half maximum (FWHM) and 5.6 mm full width at tenth maximum (FWTM) at the centre of the FOV, degrading to 6.6 mm (radial) and 4.4 mm (tangential) FWHM and 10.4 mm (radial) and 14.4 mm (tangential) FWTM at 40.0 mm from the centre of the FOV. The axial slice width was 4.3 mm FWHM, 10.3 mm FWTM at the centre of the transaxial field of view and 4.4 mm FWHM, 10.6 mm FWTM at 20.0 mm from the centre of the FOV. A scatter fraction of 31.0% was measured at 250-850 keV, for an 18F line source centred in a 60 mm diameter, water-filled phantom, reducing to 20.4% and 13.8% as the lower energy discrimination was increased to 380 keV and 450 keV, respectively. The count rate performance was measured using a noise equivalent count rate method, and the linearity of the dead time correction was confirmed over the count rates encountered during routine scanning. In 2D mode, the absolute sensitivity of the tomograph was measured as 9948 counts s-1 MBq-1 at 250-850 keV, 8284 counts s-1 MBq-1 at 380-850 keV and 6280 counts s-1 MBq-1 at 450-850 keV.
Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.
Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.
The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.
Recently, the initial 2D physical characterization of a small-diameter positron emission tomograph, designed specifically for scanning of small laboratory animals, was reported. The physical characteristics of the tomograph operating in 3D mode have now been measured and compared to those obtained in 2D mode.
In 3D, the transaxial resolution was measured as full width at half maximum (FWHM) and full width at tenth maximum (FWTM) at the centre of the transaxial field of view (FOV). These values degraded to (tangential) and (radial) FWHM and (tangential) and (radial) FWTM, respectively, at a radial distance of 40 mm from the centre of the transaxial FOV. The axial resolution was measured as FWHM and FWTM at the centre of the transaxial FOV, increasing to FWHM and FWTM at a radial distance of 40 mm from the centre of the transaxial FOV. These resolutions are similar to those obtained for the tomograph operating in 2D mode.
The sensitivity of the tomograph operating in 3D was at 250 - 850 keV compared to in 2D at the same energy thresholds. In this energy window the noise equivalent count rate peaked at , compared to in 2D. A scatter fraction of 30.2% at 250 - 850 keV was measured for a line source centred in a 60 mm diameter water filled phantom in 3D, compared to 31.0% in 2D for the same scanning geometry and energy thresholds.
A comparison was made between 2D and 3D kinetic analyses for a group of five anaesthetized rats scanned using [] SCH 23390, a marker of dopamine receptors. The integrity of the results was maintained between 2D and 3D data sets, though in 3D there was a significant reduction in the standard error of the fitted parameter. The results demonstrate that, with regard to sensitivity, there are significant gains in the physical performance of this tomograph when operating in 3D compared to 2D mode and that the quantification of PET studies of small animals using the 3D data reflects this.
The reference tissue model allows for quantification of receptor kinetics without measuring the arterial input function, thus avoiding arterial cannulation and time-consuming metabolite measurements. The model contains four parameters, of which the binding potential (BP) is the parameter of interest. Although BP is robust, convergence rates are slow and the other parameters can have large standard errors. To overcome this problem, a simplified reference tissue containing only three parameters was developed. This new three-parameter model was compared with the previous four-parameter model using a variety of PET studies: [11C]SCH 23390 (D1 receptor) and [11C]raclopride (D2 receptor) in humans, and [11C]SCH 23390, [11C]raclopride and [11C]RTI-121 (dopamine transporter) in rats. The BP values obtained from both models were essentially the same for all cases. In addition, the three-parameter model was insensitive to starting values, produced stable results for the other parameters (small standard errors), and converged rapidly. In conclusion, for the ligands tested the three-parameter model is a better choice, combining increased convergence rate with increased stability.
3D acquisition and reconstruction in positron emission tomography (PET) produce data with improved signal-to-noise ratios compared with conventional 2D slice-oriented methods. However, the sensitivity increase is accompanied by an increase in the number of scattered photons and random coincidences detected. This paper presents a scatter correction technique for 3D PET data where an estimate of the scattered photon distribution is subtracted from the data before reconstruction. The scatter distribution is estimated by iteratively convolving the photopeak projections with a mono-exponential kernel. The method accounts for the 3D acquisition geometry and nature of scatter by performing the scatter estimation on 2D projections. The assumptions of the method have been investigated by measuring the variation in the scatter fraction and the scatter function at different positions in a cylinder. Both parameters were found to vary by up to 50% from the centre to the edge of a large water-filled cylinder. Despite this, in a uniform cylinder containing water with different concentrations of radioactivity, scatter was reduced from 25% in a non-radioactive region to less than 5% using the convolution-subtraction method. In addition, the relative concentration of a cylinder containing an increased concentration, which was underestimated by almost 50% without scatter correction, was within 5% of the true concentration after correction.
Mathematical modelling and identifiability applied to positron emission tomography data
- R N Gunn
Gunn, R. N. 1996. Mathematical modelling and identifiability ap-plied to positron emission tomography data. Ph.D. Thesis, Univer-sity of Warwick.
Dynamic models of reversible ligand binding
- G Blomqvist
- S Pauli
- L Farde
- L Ericksson
- A Persson
- C Halldin
Blomqvist, G., Pauli, S., Farde, L., Ericksson, L., Persson, A., and Halldin, C. 1989. Dynamic models of reversible ligand binding. In Clinical Research and Clinical Diagnosis (C. Beckers, A. Goffinet, and A. Bol, Eds). Kluwer Academic Publishers.
A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography
- M A Mintun
- M E Raichle
- M R Kilbourn
- G F Wooten
- M J Welch
Mintun, M. A., Raichle, M. E., Kilbourn, M. R., Wooten, G. F., and
Welch, M. J. 1984. A quantitative model for the in vivo assessment
of drug binding sites with positron emission tomography. Ann.
Neurol. 15:217–227.
Dose dependent occupancy of central dopamine D211
- Bench
Dynamic models of reversible ligand binding
- Blomqvist
A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography
- Mintun
A software system for interactive and quantitative visualization of multidimensional biomedical images
- Robb
Physical performance of a positron tomograph for brain imaging with retractable septa
- Spinks