Regional Binding Potential Research Articles

Trait-anxiety and glial-related neuroinflammation of the amygdala and its associated regions in Alzheimer's disease: A significant correlation

BackgroundPositron emission tomography, which assesses the binding of translocator protein radiotracers, 11C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional 11C-DPA713 binding potential (BPND) and anxiety in patients with Alzheimer's disease (AD) continuum. MethodsNineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]). Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI). A whole-brain voxel-based analysis was performed to examine the relationship between 11C-DPA-713-BPND values at each voxel and the STAI score. Stepwise multiple regression analysis was performed to determine the predictors of STAI scores using independent variables, including 11C-DPA-713-BPND values within significant clusters. 11C-DPA-713-BPND values were compared between patients with AD continuum with low-to-moderate and high STAI scores. ResultsVoxel-based analysis revealed a positive correlation between trait anxiety severity and 11C-DPA713-BPND values in the centromedial amygdala and the left inferior occipital area [P < 0.001 (uncorrected) at the voxel-level]. 11C-DPA713-BPND values in these regions were a strong predictor of the STAI trait anxiety score. Specifically, patients with AD continuum and high trait anxiety had increased 11C-DPA713-BPND values in these regions. ConclusionsThe amygdala–occipital lobe circuit influences the control of emotional generation, and disruption of this network by AD pathology-induced inflammation may contribute to the expression of anxiety. Our findings suggest that suppression of inflammation can help effectively treat anxiety by attenuating damage to the amygdala and its associated areas.

First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

Association of protein distribution and gene expression revealed by positron emission tomography and postmortem gene expression in the dopaminergic system of the human brain.

The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution. We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman's rank correlation. We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140). We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.

Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats.

Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron emission tomography (PET) to examine the relationship between mGluR5 availability and differences in the response of rats to repeated footshock exposure (FE). Specifically, on day 1, male (n = 16) and female (n = 12) rats received 15 footshocks and were compared with control rats who did not receive footshocks (n = 7 male; n = 4 female). FE rats were classified as low responders (LR) or high responders (HR) based on freezing to the context the following day (day 2). PET with [18F]FPEB was used to calculate regional mGluR5 binding potential (BPND) at two timepoints: prior to FE (i.e., baseline), and post-behavioral testing. Additionally, we used an unbiased proteomics approach to assess group and sex differences in prefrontal cortex (PFC) protein expression. Post-behavioral testing we observed decreased BPND in LR females, but increased BPND in HR males relative to baseline. Further, individuals displaying the greatest freezing during the FE context memory test had the largest increases in PFC BPND. Males and females displayed unique post-test molecular profiles: in males, the greatest differences were between FE and CON, including upregulation of mGluR5 and related molecular networks in FE, whereas the greatest differences among females were between the LR and HR groups. These findings suggest greater mGluR5 availability increases following footshock exposure may be related to greater contextual fear memory. Results additionally reveal sex differences in the molecular response to footshock, including differential involvement of mGluR5-related molecular networks.

Synthesis and Preclinical Evaluation of [11C]AZ11895530 for PET Imaging of the Serotonin 1A Receptor

The serotonin 1A (5-HT1A) receptor is a G-protein-coupled receptor implicated in the pathophysiology of several neuropsychiatric and neurodegenerative disorders. We here report the preparation of two candidate 5-HT1A radioligands, [11C]AZ11132132 ([11C]3) and [11C]AZ11895530 ([11C]4), and their subsequent evaluation in vitro using autoradiography and in vivo using positron emission tomography (PET). Compounds 3 and 4 were radiolabeled at high radiochemical purity (>99%) and high molar activity (>38 GBq/μmol) by heteroatom methylation with [11C]methyl iodide. Autoradiography on whole hemispheres from post-mortem human brain revealed substantial nonspecific binding of [11C]3, while the binding of [11C]4 to brain tissue was consistent with the distribution of 5-HT1A receptors and sensitive to co-incubation with the reference 5-HT1A antagonist WAY-100635 (10 μM). Following intravenous injection of [11C]4 into a cynomolgus monkey, brain radioactivity concentration (Cmax ∼ 2.2 SUV) was high whereafter it decreased rapidly. The regional binding potential (BPND) values were calculated using the simplified reference tissue model with cerebellum as reference region. The values varied between 0.2 and 1.0 for temporal cortex, raphe nuclei, frontal cortex, and hippocampus which is consistent with the known 5-HT1A expression pattern. After pretreatment with WAY100635 (0.5 mg/kg), a homogeneous distribution of radioactivity was observed in non-human primate (NHP) brain. Although [11C]4 fulfilled important criteria for successful in vivo neuroimaging, including good blood-brain-barrier permeability and high specific binding in vitro to human brain tissue, the regional BPND values for [11C]4 in NHP brain were low when compared to those obtained with existing radioligands and thus do not merit further investigation of [11C]4. Evaluation of structurally related analogues is underway in our laboratory to identify improved candidates for clinical imaging.

Evaluation of (rac)-, (R)-, and (S)-18F-OF-NB1 for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors in Nonhuman Primates.

Despite 2 decades of research, no N-methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on (rac)-18F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the invivo characterization of (rac)-, (R)-, and (S)-18F-OF-NB1 in nonhuman primates. Methods: PET scans were performed on rhesus monkeys. Plasma profiling was used to obtain the arterial input function. Regional brain time-activity curves were generated and fitted with the 1- and 2-tissue-compartment models and the multilinear analysis 1 method, and the corresponding regional volumes of distribution were calculated. Blocking studies with the GluN1/2B ligand Co 101244 (0.25 mg/kg) were performed for the enantiopure radiotracers. Receptor occupancy, nonspecific volume of distribution, and regional binding potential (BP ND) were obtained. Potential off-target binding toward σ1 receptors was assessed for (S)-18F-OF-NB1 using the σ1 receptor ligand FTC-146. Results: Free plasma fraction was moderate, ranging from 12% to 16%. All radiotracers showed high and heterogeneous brain uptake, with the highest levels in the cortex. (R)-18F-OF-NB1 showed the highest uptake and slowest washout kinetics of all tracers. The 1-tissue-compartment model and multilinear analysis 1 method fitted the regional time-activity curves well for all tracers and produced reliable regional volumes of distribution, which were higher for (R)- than (S)-18F-OF-NB1. Receptor occupancy by Co 101244 was 85% and 96% for (S)-18F-OF-NB1 and (R)-18F-OF-NB1, respectively. Pretreatment with FTC-146 at both a low (0.027 mg/kg) and high (0.125 mg/kg) dose led to a similar reduction (48% and 49%, respectively) in specific binding of (S)-18F-OF-NB1. Further, pretreatment with both Co 101244 and FTC-146 did not result in a further reduction in specific binding compared with Co 101244 alone in the same monkey (82% vs. 81%, respectively). Regional BP ND values ranged from 1.3 in the semiovale to 3.4 in the cingulate cortex for (S)-18F-OF-NB1. Conclusion: Both (R)- and (S)-18F-OF-NB1 exhibited high binding specificity to GluN2B subunit-containing NMDA receptors. The fast washout kinetics, good regional BP ND values, and high plasma free fraction render (S)-18F-OF-NB1 an attractive radiotracer for clinical translation.

In Alzheimer's disease, amyloid beta accumulation is a protective mechanism that ultimately fails.

Here, we claim that amyloid beta (Aβ) accumulation is a protective mechanism that ultimately fails. We predict that more Aβ accumulates in regions with higher rates of glucose metabolism, reaching a maximum followed by progression of pathology. Aβ accumulation is characteristic of Alzheimer's disease (AD) but the accumulation does not correlate with cognitive decline, unlike the rates of glucose metabolism. We compared averaged and individual estimates of regional binding potentials of [11C]Pittsburgh compound B to regionally averaged and individual values of metabolism of [18F]fluorodeoxyglucose in brain regions of volunteers with AD. The claim explains the cognitive decline in some patients at a significantly lower level of Aβdeposition than in other patients, as well as the presence of cognitively healthy individuals with high Aβaccumulation. With further support of the hypothesis, the significance of Aβaccumulation in brains of patients with AD may require revision.

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: (R)-[11C]NR2B-Me, (R)-[18F]of-Me-NB1, and (S)-[18F]of-NB1

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo. Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R)-[11C]NR2B-Me, (R)-[18F]OF-Me-NB1, and (S)-[18F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R)-[11C]NR2B-Me and (R)-[18F]OF-Me-NB1 and higher for (S)-[18F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20–40 mL/cm3 for (R)-[11C]NR2B-Me, 8–16 mL/cm3 for (R)-[18F]OF-Me-NB1, and 15–35 mL/cm3 for (S)-[18F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2–3 for (R)-[11C]NR2B-Me and (S)-[18F]-OF-NB1, and 0.5-1 for (R)-[18F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S)-[18F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.

InVivo 18F-Flortaucipir PET Does Not Accurately Support the Staging of Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET.MethodsN=42 patients with probable PSP and N=39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N=9 patients who also had post-mortem confirmation of the diagnosis and stage.ResultsStage assignment was estimable in 41 patients: N=10 patients were classified in stage I/II, N=26 in stage III/IV, N=5 in stage V/VI, while N=1 was not classifiable. An explorative sub-staging identified N=2 patients in stage I, N=8 in stage II, N=9 in stage III, N=17 in stage IV and N=5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem.Conclusion18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.

Molecular pathology and synaptic loss in primary tauopathies: an 18F-AV-1451 and 11C-UCB-J PET study.

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration as a function of disease severity.Twenty-three patients with progressive supranuclear palsy and 12 patients with corticobasal syndrome were recruited from a tertiary referral centre. Nineteen education-, sex- and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands 11C-UCB-J and 18F-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with 11C-PiB to exclude those with likely Alzheimer’s pathology—we refer to the amyloid-negative cohort as having corticobasal degeneration, although we acknowledge other underlying pathologies exist. Disease severity was assessed with the progressive supranuclear palsy rating scale; regional non-displaceable binding potentials of 11C-UCB-J and 18F-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for 18F-AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions and synaptic density in subcortical areas.Across brain regions, there was a positive correlation between 11C-UCB-J and 18F-AV-1451 non-displaceable binding potentials (β = 0.4, t = 3.6, P = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (β = −0.02, t = −2.9, P = 0.007, R = −0.41). Between regions, cortical 18F-AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher 18F-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical 18F-AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to the molecular pathology.Given the importance of synaptic function for cognition and action, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

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.

Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease.

ABSTRACTBackgroundGlucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.MethodsWe performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as 11C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with 18F‐dopa influx constants.ResultsThe 11C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased 11C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral 11C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal 18F‐dopa uptake was similar to healthy controls.ConclusionsIn vivo 11C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Neuroinflammation in Children With Infantile Spasms: A Prospective Study Before and After Treatment With Acthar Gel (Repository Corticotropin Injection).

The selective effectiveness of adrenocorticotropic hormone (ACTH) in treating infantile spasms suggests an underlying neuroinflammation. Because neuroinflammation is mediated by activated microglia, which express translocator protein (TSPO), we imaged neuroinflammation in children with infantile spasms using positron emission tomography (PET) with 11C-PK11195 (PK), which selectively binds to TSPO. Children were studied prospectively before and following treatment with Acthar Gel (repository corticotropin injection). We hypothesized that PK-PET would show neuroinflammation (increased PET uptake) in cortical and/or subcortical structures before treatment, and that this inflammation will be abolished/reduced following Acthar Gel treatment. Eight children with infantile spasms (5 males; mean age 1.8±1.1, range 0.9-4.1 years) were recruited. After clinical and video electroencephalograph (EEG) evaluation and dynamic PK-PET scan, children underwent treatment with Acthar Gel over 4 weeks, followed by repeat clinical evaluation/video-EEG 2 weeks after initiation of treatment and repeat PK-PET 2 weeks after treatment completion. Visual and quantitative analysis of PK-PET scans were performed. We calculated regional binding potential (measure of receptor-ligand binding) using a reference tissue model. Focal areas of increased PK-binding were found in the pretreatment PK-PET in 5 children. Following treatment, these increases were either reduced or normalized and were associated with cessation (n=4) or significant reduction (n=1) of spasms and complete disappearance of hypsarrhythmia. One child showed increased binding potential in basal ganglia and thalamus, despite normalization of cortical binding potential; however, these increases were likely associated with death-related causes. This study suggests Acthar Gel-responsive neuroinflammatory changes in children with infantile spasms, supporting a potential role of neuroinflammation in the pathogenesis of infantile spasms.

Positron Emission Tomography Imaging Evaluation of a Novel 18F-Labeled Sigma-1 Receptor Radioligand in Cynomolgus Monkeys.

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [18F]FBFP as a potent sigma-1 (σ1) receptor radioligand with advantageous characteristics. [18F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [18F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis. It exhibited heterogeneous distribution with higher regional volume of distribution (VT) values in the amygdala, hippocampus, insula, and frontal cortex. Pretreatment with the σ1 receptor agonist SA4503 (0.5 mg/kg) significantly reduced radioligand uptake in the monkey brain (>95%), indicating high binding specificity of [18F]FBFP in vivo. Compared with (S)-[18F]fluspidine, [18F]FBFP possessed higher regional nondisplaceable binding potential (BPND) values across the brain regions. These findings demonstrate that [18F]FBFP is a highly promising PET radioligand for imaging and quantification of σ1 receptors in humans.

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

PurposeAlpha-synuclein often co-occurs with Alzheimer’s disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. MethodsEighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. ResultsRegional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ = 0.72) and category fluency (stβ = 0.69) tests. Lower parietal R1 was related to lower delayed (stβ = 0.50) and immediate (stβ = 0.48) recall, VOSP number location (stβ = 0.70) and fragmented letters (stβ = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ = 0.61), all p < 0.05. ConclusionThe amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D2/3R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D2/3R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.

Use of a Tracer-Specific Deep Artificial Neural Net to Denoise Dynamic PET Images

Application of kinetic modeling (KM) on a voxel level in dynamic PET images frequently suffers from high levels of noise, drastically reducing the precision of parametric image analysis. In this paper, we investigate the use of machine learning and artificial neural networks to denoise dynamic PET images. We train a deep denoising autoencoder (DAE) using noisy and noise-free spatiotemporal image patches, extracted from the simulated images of [11C]raclopride, a dopamine D2 receptor agonist. The DAE-processed dynamic and corresponding parametric images (simulated and acquired) are compared with those obtained with conventional denoising techniques, including temporal and spatial Gaussian smoothing, iterative spatiotemporal smoothing/deconvolution, and the highly constrained backprojection processing (HYPR). The simulated (acquired) parametric image non-uniformity was 7.75% (19.49%) with temporal and 5.90% (14.50%) with spatial smoothing, 5.82% (16.21%) with smoothing/deconvolution, 5.49% (13.38%) with HYPR, and 3.52% (11.41%) with DAE. The DAE also produced the best results in terms of the coefficient of variation of voxel values and structural similarity index. Denoising-induced bias in the regional mean binding potential was 7.8% with temporal and 26.31% with spatial smoothing, 28.61% with smoothing/deconvolution, 27.63% with HYPR, and 14.8% with DAE. When the test data did not match the training data, erroneous outcomes were obtained. Our results demonstrate that a deep DAE can provide a substantial reduction in the voxel-level noise compared with the conventional spatiotemporal denoising methods while introducing a similar or lower amount of bias. The better DAE performance comes at the cost of lower generality and requiring appropriate training data.

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity

PurposeThe present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine D2/3R binding in relation to motor and exploratory activity in the rat. MethodsD2/3R binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [123I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region. Results40 mg/kg AMA reduced D2/3R binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased D2/3R binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge. ConclusionsResults showed reductions of D2/3R binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

Novel 18F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates.

The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18F-LY2459989 as the first 18F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11C-LY2459989. Methods: The novel radioligand 18F-LY2459989 was synthesized by 18F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18F-LY2459989 and 11C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.