BPND Values Research Articles

Cross-validation study between the HRRT and the PET component of the SIGNA PET/MRI system with focus on neuroimaging

BackgroundThe Siemens high-resolution research tomograph (HRRT - a dedicated brain PET scanner) is to this day one of the highest resolution PET scanners; thus, it can serve as useful benchmark when evaluating performance of newer scanners. Here, we report results from a cross-validation study between the HRRT and the whole-body GE SIGNA PET/MR focusing on brain imaging.Phantom data were acquired to determine recovery coefficients (RCs), % background variability (%BG), and image voxel noise (%). Cross-validation studies were performed with six healthy volunteers using [11C]DTBZ, [11C]raclopride, and [18F]FDG. Line profiles, regional time-activity curves, regional non-displaceable binding potentials (BPND) for [11C]DTBZ and [11C]raclopride scans, and radioactivity ratios for [18F]FDG scans were calculated and compared between the HRRT and the SIGNA PET/MR.ResultsPhantom data showed that the PET/MR images reconstructed with an ordered subset expectation maximization (OSEM) algorithm with time-of-flight (TOF) and TOF + point spread function (PSF) + filter revealed similar RCs for the hot spheres compared to those obtained on the HRRT reconstructed with an ordinary Poisson-OSEM algorithm with PSF and PSF + filter. The PET/MR TOF + PSF reconstruction revealed the highest RCs for all hot spheres. Image voxel noise of the PET/MR system was significantly lower. Line profiles revealed excellent spatial agreement between the two systems. BPND values revealed variability of less than 10% for the [11C]DTBZ scans and 19% for [11C]raclopride (based on one subject only). Mean [18F]FDG ratios to pons showed less than 12% differences.ConclusionsThese results demonstrated comparable performances of the two systems in terms of RCs with lower voxel-level noise (%) present in the PET/MR system. Comparison of in vivo human data confirmed the comparability of the two systems. The whole-body GE SIGNA PET/MR system is well suited for high-resolution brain imaging as no significant performance degradation was found compared to that of the reference standard HRRT.

Effect of Shortening the Scan Duration on Quantitative Accuracy of [18F]Flortaucipir Studies

PurposeDynamic positron emission tomography (PET) protocols allow for accurate quantification of [18F]flortaucipir-specific binding. However, dynamic acquisitions can be challenging given the long required scan duration of 130 min. The current study assessed the effect of shorter scan protocols for [18F]flortaucipir on its quantitative accuracy.ProceduresTwo study cohorts with Alzheimer’s disease (AD) patients and healthy controls (HC) were included. All subjects underwent a 130-min dynamic [18F]flortaucipir PET scan consisting of two parts (0–60/80–130 min) post-injection. Arterial sampling was acquired during scanning of the first cohort only. For the second cohort, a second PET scan was acquired within 1–4 weeks of the first PET scan to assess test-retest repeatability (TRT). Three alternative time intervals were explored for the second part of the scan: 80–120, 80–110 and 80–100 min. Furthermore, the first part of the scan was also varied: 0–50, 0–40 and 0–30 min time intervals were assessed. The gap in the reference TACs was interpolated using four different interpolation methods: population-based input function 2T4k_VB (POP-IP_2T4k_VB), cubic, linear and exponential. Regional binding potential (BPND) and relative tracer delivery (R1) values estimated using simplified reference tissue model (SRTM) and/or receptor parametric mapping (RPM). The different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, TRT of the RPM BPND and R1 values estimated using the optimal shortest scan duration was also assessed.ResultsRPM BPND and R1 obtained using 0–30/80–100 min scan and POP-IP_2T4k_VB reference region interpolation had an excellent correlation with the respective parametric values estimated using the original scan duration (r2 > 0.95). The TRT of RPM BPND and R1 using the shortest scan duration was − 1 ± 5 % and − 1 ± 6 % respectively.ConclusionsThis study demonstrated that [18F]flortaucipir PET scan can be acquired with sufficient quantitative accuracy using only 50 min of dual-time-window scanning time.

Assessment of test-retest reproducibility of [18F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A.

Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [18F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [11C]UCB-J. Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (VT) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BPND) was calculated using centrum semiovale as the reference region. The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [18F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC VT values (mL/cm3) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [11C]UCB-J. Regional BPND values were 2.7-4.7 in gray matter areas, and mean BPND values across all ROIs were ~ 21% higher than those of [11C]UCB-J. The absolute test-retest variability of VT and BPND was excellent (< 9%) across all brain regions. [18F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [18F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.

Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study.

Introduction:A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers.Methods:Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration.Results:Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus.Conclusions:We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

Quantitative accuracy remains after shortening of dynamic [18F]flortaucipir PET protocol

AbstractBackgroundTau pathology can be assessed by [18F]flortaucipir positron emission tomography (PET). Dynamic PET protocols allow for accurate quantification of [18F]flortaucipir specific binding. However, dynamic acquisitions can be challenging or burdensome to patients given the long required scan duration of 130 min, especially in persons with cognitive impairment due to Alzheimer’s disease (AD). Therefore, the current study assessed the effect of shorter scan protocols for [18F]flortaucipir PET on its quantitative accuracy.MethodFor this study, two study samples were used: 10 Alzheimer disease (AD) patients and 10 healthy controls (HC) with arterial blood sampling, and 8 AD patients and 6 HCs with a test‐retest scan protocol but without arterial sampling. All subjects underwent a 130‐minute dynamic [18F]flortaucipir PET scan with a 20 min break after 60 minutes. First, the second part of the scan was shortened to 80‐120, 80‐110 and 80‐100 minutes p.i.. Second, the first part of the scan was shortened to 0‐50, 0‐40, and 0‐30 min p.i.. To fill the gap of missing time frames in the reference region (i.e. grey matter cerebellum) time activity curves, four different interpolation methods were tested: 2T4k_VB model using population‐based input‐function (2T4k_POP‐IP), cubic, linear and exponential interpolations. Regional BPND values estimated using SRTM and/or RPM and different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, test‐retest repeatability (TRT) of the RPM BPND values estimated using the optimal shortest scan duration was assessed.ResultRPM BPND values obtained using a shortened second part of the PET scan had negligible effect on the accuracy of parameter estimates (Table 1). The RPM BPND values using 0‐30/80‐100 min with 2T4k_POP‐IP interpolation had the best correlation with original DVR‐1, SRTM and RPM BPND (r2=0.95, slope=0.91; r2=0.97, slope=0.88; r2=0.99, slope=0.96). The TRT remained similar using the shortest scan duration (Figure 1).ConclusionThe current study demonstrated that accurate [18F]flortaucipir quantification can be obtained using a scan protocol of 0‐30/80‐100 min p.i.. With this reduction in total scan duration the scan will be less burdensome while remaining quantitatively accurate.

Low convergent validity of [11C]raclopride binding in extrastriatal brain regions: A PET study of within-subject correlations with [11C]FLB 457

Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test–retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [11C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30–0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82–0.98). In comparison, correlations between repeated [11C]raclopride measurements were low to moderate (Pearson's R: 0.28–0.75). These results are likely related to low signal to noise ratio of [11C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]raclopride should be interpreted with caution.

Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy.

We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. Nondisplaceable binding potential (BPND ) for each ligand was quantified in 83 regions of interest (ROIs). The [11 C]PK11195 and [18 F]AV-1451 BPND values were correlated across all regions. The spatial distributions of [11 C]PK11195 and [18 F]AV-1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients' clinical severity (using the PSP rating scale). Regional [11 C]PK11195 and [18 F]AV-1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11 C]PK11195 and [18 F]AV-1451 components' loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP. ANN NEUROL 2020;88:1194-1204.

Reduced synaptic vesicle protein 2A binding in temporal lobe epilepsy: A [11 C]UCB-J positron emission tomography study.

In this positron emission tomography (PET) study with [11 C]UCB-J, we evaluated synaptic vesicle glycoprotein 2A (SV2A) binding, which is decreased in resected brain tissues from epilepsy patients, in subjects with temporal lobe epilepsy (TLE) and compared the regional binding pattern to [18 F]fluorodeoxyglucose (FDG) uptake. Twelve TLE subjects and 12 control subjects were examined. Regional [11 C]UCB-J binding potential (BPND ) values were estimated using the centrum semiovale as a reference region. [18 F]FDG uptake in TLE subjects was quantified using mean radioactivity values. Asymmetry in outcome measures was assessed by comparison of ipsilateral and contralateral regions. Partial volume correction (PVC) with the iterative Yang algorithm was applied based on the FreeSurfer segmentation. In 11 TLE subjects with medial temporal lobe sclerosis (MTS), the hippocampal volumetric asymmetry was 25±11%. After PVC, [11 C]UCB-J BPND asymmetry indices were 37±19% in the hippocampus, with very limited asymmetry in other brain regions. Reductions in [11 C]UCB-J BPND values were restricted to the sclerotic hippocampus when compared to control subjects. The corresponding asymmetry in hippocampal [18 F]FDG uptake was 22±7% and correlated with that of [11 C]UCB-J BPND across subjects (R2 =.38). Hippocampal asymmetries in [11 C]UCB-J binding were 1.7-fold larger than those of [18 F]FDG uptake. [11 C]UCB-J binding is reduced in the seizure onset zone of TLE subjects with MTS. PET imaging of SV2A may be a promising biomarker approach in the presurgical selection and evaluation of TLE patients and may improve the sensitivity of molecular imaging for seizure focus detection.

Low dopamine transporter binding in the nucleus accumbens in geriatric patients with severe depression.

Dysfunction of dopaminergic neurons in the central nervous system is considered to be related to major depressive disorder (MDD). Especially, MDD in geriatric patients is characterized by anhedonia, which is assumed to be associated with reduced dopamine neurotransmission in the reward system. Dopamine transporter (DAT) is considered to reflect the function of the dopamine nerve system. However, previous DAT imaging studies using single photon emission computed tomography or positron emission tomography (PET) have shown inconsistent results. The radioligand [18 F]FE-PE2I for PET enables more precise evaluation of DAT availability. Hence, we aimed to evaluate the DAT availability in geriatric patients with MDD using [18 F]FE-PE2I. Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [18 F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BPND ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BPND values were compared between MDD patients and healthy controls. MDD patients showed significantly lower DAT BPND in the NAc (P = 0.009), and there was a trend of lower BPND in the putamen (P = 0.032) compared to controls. We found low DAT in the NAc and putamen in geriatric patients with severe MDD, which could be related to dysregulation of the reward system.

MGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [11C]ABP688 binding potential (BPND) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.

Extra-striatal D2/3 receptor availability in youth at risk for addiction

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA2/3R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [18F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [18F]fallypride binding potential (BPND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BPND values were associated with low SP scores. Together, the results suggest that altered DA2/3R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).

A strategy to account for noise in the X-variable to reduce underestimation in Logan graphical analysis for quantifying receptor density in positron emission tomography

BackgroundThe Logan graphical analysis (LGA) algorithm is widely used to quantify receptor density for parametric imaging in positron emission tomography (PET). Estimating receptor density, in terms of the non-displaceable binding potential (BPND), from the LGA using the ordinary least-squares (OLS) method has been found to be negatively biased owing to noise in PET data. This is because OLS does not consider errors in the X-variable (predictor variable). Existing bias reduction methods can either only reduce the bias slightly or reduce the bias accompanied by increased variation in the estimates. In this study, we addressed the bias reduction problem by applying a different regression method.MethodsWe employed least-squares cubic (LSC) linear regression, which accounts for errors in both variables as well as the correlation of these errors. Noise-free PET data were simulated, for 11C-carfentanil kinetics, with known BPND values. Statistical noise was added to these data and the BPNDs were re-estimated from the noisy data by three methods, conventional LGA, multilinear reference tissue model 2 (MRTM2), and LSC-based LGA; the results were compared. The three methods were also compared in terms of beta amyloid (A β) quantification of 11C-Pittsburgh compound B brain PET data for two patients with Alzheimer’s disease and differing A β depositions.ResultsAmongst the three methods, for both synthetic and actual data, LSC was the least biased, followed by MRTM2, and then the conventional LGA, which was the most biased. Variations in the LSC estimates were smaller than those in the MRTM2 estimates. LSC also required a shorter computational time than MRTM2.ConclusionsThe results suggest that LSC provides a better trade-off between the bias and variability than the other two methods. In particular, LSC performed better than MRTM2 in all aspects; bias, variability, and computational time. This makes LSC a promising method for BPND parametric imaging in PET studies.

Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain.

Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [18F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls. Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [18F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (Vt) and binding potentials (BPnd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications. [18F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated Vts in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BPnd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification. [18F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable Vts or BPnds, and good test-retest reliability for precise quantification of DAT in human subjects.

Ethnic disparities in pain processing among healthy adults: μ-opioid receptor binding potential as a putative mechanism.

Although ethnic differences in pain perception are well documented, the underlying mechanism for these outcomes has not been established. µ-opioid receptor (MOR) function might contribute to this disparity, given that MORs play a key role in pain sensitivity and modulation. However, no study has characterized ethnic differences in MOR physiology. This study sought to address this knowledge gap by examining differences in µ-selective agonist binding potential (BPND; [C]-Carfentanil) between 27 non-Hispanic black (NHB) and 27 demographically similar, non-Hispanic white participants. Participants completed questionnaires and two 90-minute high-resolution research tomograph positron emission tomography (PET) imaging sessions. During PET imaging, a capsaicin or control cream was applied to individuals' arms, and pain ratings were collected. Bonferroni-corrected PET volumes of interest analyses revealed significantly greater [C]-Carfentanil BPND among NHB participants in bilateral ventral striatum ([left]: F1,52 = 16.38, P < 0.001; [right]: F1,52 = 21.76, P < 0.001), bilateral dorsolateral prefrontal cortex ([left] F1,52 = 17.3, P < 0.001; [right]: F1,52 = 14.17, P < 0.001), bilateral subgenual anterior cingulate cortex ([left]: F1,52 = 10.4, P = 0.002; [right]: F1,52 = 12.91, P = 0.001), and right insula (F1,52 = 11.0, P = 0.002). However, there were no significant main effects of condition or ethnicity × condition interaction effects across models, likely attributable to individual variability in the direction of change within groups. BPND values were significantly correlated with pain ratings collected during the capsaicin condition (r range = 0.34-0.46, P range = 0.01-0.001). Results suggest that NHB individuals might have generally greater unoccupied MOR density than non-Hispanic white peers. Findings have implications for physiological differences underlying ethnicity-related pain disparities. If replicated, these results further emphasize the need for tailored treatments in historically underserved populations.

Correction of head movement by frame-to-frame image realignment for receptor imaging in positron emission tomography studies with [11C]raclopride and [11C]FLB 457

Positron emission tomography (PET) scans of imaging receptors require 60-90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantitative parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [11C]raclopride and [11C]FLB 457 acquired by an Eminence SET-3000GCT/X and investigated the effect of this correction on the quantitative outcomes. First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emission sinograms were reconstructed to the PET images with or without attenuation correction using a µ-map of the transmission scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [11C]raclopride and [11C]FLB 457 studies in normal volunteers, six motion parameters for each frame were estimated by the registration method determined from the simulation results. Head movement was corrected by realigning the PET images reconstructed with a motion-included µ-map in which a mismatch between the transmission and emission scans was corrected. After this correction, time-activity curves (TAC) for the striatum or cerebral cortex were obtained and the binding potentials of the receptors (BPND) were estimated using the simplified reference tissue model. In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenuation-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BPND values in these regions increased. Compared to the motion-corrected PET images reconstructed using the measured µ-map, the images reconstructed using the motion-included µ-map did not result in a remarkable improvement of BPND in the striatum of [11C]raclopride studies, while the BPND in the cerebral cortex changed in some [11C]FLB 457 studies in which large head movement was observed. In PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realignment. This method is easily applicable to clinical studies and provides reliable TACs and BPND.

High long-term test–retest reliability for extrastriatal 11C-raclopride binding in healthy older adults

In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test–retest reliability in a sample of younger adults. The present work demonstrates high seven-month test–retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64–78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85–0.96), absolute variability was low (mean: 4–8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.

PET quantification of [18F]MPPF in the canine brain using blood input and reference tissue modelling.

Numerous studies have shown that the serotonin1A (5-HT1A) receptor is implicated in the pathophysiology and treatment of several psychiatric and neurological disorders. Furthermore, functional imaging studies in a variety of species have demonstrated that 4-(2´-Methoxyphenyl)-1-[2´-(N-2´´-pyridinyl)-p- [18F]fluorobenzamidoethylpiperazine ([18F]MPPF) is a valid and useful PET tracer to visualize the 5HT1A receptor. However, to our knowledge, [18F]MPPF has never been demonstrated in the canine brain. The ability to image the 5HT1A receptor with PET in dogs could improve diagnosis and therapy in both canine and human behavioural and neuropsychiatric disorders. To examine the potential use of [18F]MPPF in dogs, five healthy adult laboratory beagles underwent a 60-minutes dynamic PET scan with [18F]MPPF while arterial blood samples were taken. For each region of interest, total distribution volume (VT) and corresponding binding potential (BPND) were calculated using the 1-tissue compartment model (1-TC), 2-Tissue compartment model (2-TC) and Logan plot. The preferred model was chosen based on the goodness-of-fit, calculated with the Akaike information criterium (AIC). Subsequently, the BPND values of the preferred compartment model were compared with the estimated BPND values using three reference tissue models (RTMs): the 2-step simplified reference tissue model (SRTM2), the 2-parameter multilinear reference tissue model (MRTM2) and the Logan reference tissue model. According to the lower AIC values of the 2-TC model compared to the 1-TC in all ROIs, the 2-TC model showed a better fit. Calculating BPND using reference tissue modelling demonstrated high correlation with the BPND obtained by metabolite corrected plasma input 2-TC. This first-in-dog study indicates the results of a bolus injection with [18F]MPPF in dogs are consistent with the observations presented in the literature for other animal species and humans. Furthermore, for future experiments, compartmental modelling using invasive blood sampling could be replaced by RTMs, using the cerebellum as reference region.

Optimized dual-time-window protocols for quantitative [18F]flutemetamol and [18F]florbetaben PET studies

BackgroundA long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load. However, such a protocol results in a lower patient comfort and scanning efficiency compared to static scans. A compromise can be achieved by implementing dual-time-window protocols. This study aimed to optimize these protocols for quantitative [18F]flutemetamol and [18F]florbetaben studies.MethodsRate constants for subjects across the Alzheimer’s disease spectrum (i.e., non-displaceable binding potential (BPND) in the range 0.02–0.77 and 0.02–1.04 for [18F]flutemetamol and [18F]florbetaben, respectively) were established based on clinical [18F]flutemetamol (N = 6) and [18F]florbetaben (N = 20) data, and used to simulate tissue time-activity curves (TACs) of 110 min using a reference tissue and plasma input model. Next, noise was added (N = 50) and data points corresponding to different intervals were removed from the TACs, ranging from 0 (i.e., 90–90 = full-kinetic curve) to 80 (i.e., 10–90) minutes, creating a dual-time-window. Resulting TACs were fitted using the simplified reference tissue method (SRTM) to estimate the BPND, outliers (≥ 1.5 × BPND max) were removed and the bias was assessed using the distribution volume ratio (DVR = BPND + 1). To this end, acceptability curves, which display the fraction of data below a certain bias threshold, were generated and the area under those curves were calculated.Results[18F]Flutemetamol and [18F]florbetaben data demonstrated an increased bias in amyloid estimate for larger intervals and higher noise levels. An acceptable bias (≤ 3.1%) in DVR could be obtained with all except the 10–90 and 20–90-min intervals. Furthermore, a reduced fraction of acceptable data and most outliers were present for these two largest intervals (maximum percentage outliers 48 and 32 for [18F]flutemetamol and [18F]florbetaben, respectively).ConclusionsThe length of the interval inversely correlates with the accuracy of the BPND estimates. Consequently, a dual-time-window protocol of 0–30 and 90–110 min (=maximum of 60 min interval) allows for accurate estimation of BPND values for both tracers.[18F]flutemetamol: EudraCT 2007-000784-19, registered 8 February 2007, [18F]florbetaben: EudraCT 2006-003882-15, registered 2006.

Unchanged type 1 metabotropic glutamate receptor availability in patients with Alzheimer's disease: A study using 11C-ITMM positron emission tomography.

Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). To date, little evidence exists on the role of mGluR1 in the pathophysiology of Alzheimer's disease (AD). We aimed to examine mGluR1 availability in patients with AD. Ten patients with AD (78.9 ± 5.9 years) and 12 age-matched volunteers (74.6 ± 2.6 years) underwent PET using an mGluR1 radiotracer. All patients were anti-dementia drug-naive. Volumes-of-interest were placed on the anterior and posterior lobes and vermis in the cerebellum and frontal, parietal, and temporal cortices. The binding potential (BPND) was calculated to estimate mGluR1 availability, and partial volume correction was applied to the BPND values. Mini Mental State Examination (MMSE) scores were also obtained (22.0 ± 4.8). No significant difference was observed in BPND between the AD and control groups in the anterior lobe (p = .30), posterior lobe (p = .95), vermis (p = .96), frontal cortex (p = .61), parietal cortex (p = .59), or temporal cortex (p = .27). No significant correlation was observed between BPND and MMSE scores in the anterior lobe (p = .59), posterior lobe (p = .35), vermis (p = .92), frontal cortex (p = .78), parietal cortex (p = .83), or temporal cortex (p = .82). In conclusions, this study suggests that mGluR1 availability is unchanged in the relatively early stage of AD. However, because regional mGluR1 availability may change with the progression of AD, further longitudinal follow-up is necessary.

MR-based spatial normalization improves [18F]MNI-659 PET regional quantification and detectability of disease effect in the Q175 mouse model of Huntington’s disease

The positron emission tomography (PET) tracer [18F]MNI-659, selective for phosphodiesterase 10A (PDE10A), is a promising tool to assess an early biomarker for Huntington’s disease (HD). In this study we investigated [18F]MNI-659 uptake in the Q175 mouse model of HD. Given the focal striatal distribution of PDE10A as well as the striatal atrophy occurring in HD, the spatial normalization approach applied during the processing could sensibly affect the accuracy of the regional quantification. We compared the use of a magnetic resonance images (MRI) template based on individual MRI over a PET and CT templates for regional quantification and spatial normalization of [18F]MNI-659 PET images. We performed [18F]MNI-659 PET imaging in six months old heterozygous (HET) Q175 mice and wild-type (WT) littermates, followed by X-ray computed tomography (CT) scan. In the same week, individual T2-weighted MRI were acquired. Spatial normalization and regional quantification of the PET/CT images was performed on MRI, [18F]MNI-659 PET, or CT template and compared to binding potential (BPND) using volumes manually delineated on the individual MR images. Striatal volume was significantly reduced in HET mice (-7.7%, p<0.0001) compared to WT littermates. [18F]MNI-659 BPND in striatum of HET animals was significantly reduced (p<0.0001) when compared to WT littermates using all three templates. However, BPND values were significantly higher for HET mice using the PET template compared to the MRI and CT ones (p<0.0001), with an overestimation at lower activities. On the other hand, the CT template spatial normalization introduced larger variability reducing the effect size. The PET and CT template-based approaches resulted in a lower accuracy in BPND quantification with consequent decrease in the detectability of disease effect. This study demonstrates that for [18F]MNI-659 brain PET imaging in mice the use of an MRI-based spatial normalization is recommended to achieve accurate quantification and fully exploit the detectability of disease effect.