ABSTRACT
PURPOSE: [18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions. METHOD: Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated. RESULTS: The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates. CONCLUSION: Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.
ABSTRACT
PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.
Subject(s)
Gray Matter , Membrane Glycoproteins , Humans , Aged, 80 and over , Gray Matter/diagnostic imaging , Gray Matter/metabolism , Membrane Glycoproteins/metabolism , Positron-Emission Tomography/methods , Brain/diagnostic imaging , Brain/metabolism , Synapses/metabolismABSTRACT
The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.
Subject(s)
Depressive Disorder, Major , Ketamine , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Brain/diagnostic imaging , Brain/metabolism , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/metabolism , Humans , Ketamine/metabolism , Ketamine/pharmacology , Macaca mulatta/metabolism , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography/methodsABSTRACT
Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (18F-FDG, N = 15; 11C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (18F-FDG, N = 10; 11C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for 18F-FDG (-3.4 ± 1.7% for 11C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for 11C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for 18F-FDG (-0.4 ± 3.2% for 11C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.
Subject(s)
Image Processing, Computer-Assisted , Positron-Emission Tomography , Algorithms , Brain/diagnostic imaging , Humans , Image Processing, Computer-Assisted/methods , Kinetics , Motion , Movement , Positron-Emission Tomography/methodsABSTRACT
Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain-wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = -0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = -0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL- and MRP-DA release patterns (ΔR2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL- and MRP-induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern-based characterization of drug-induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.
Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Morphine/pharmacology , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Narcotics/pharmacology , Receptors, Opioid/metabolism , Adult , Corpus Striatum/diagnostic imaging , Female , Humans , Male , Positron-Emission Tomography , Retrospective StudiesABSTRACT
Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [11C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [11C]UCB-J binding, an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using [11C]UCB-J and high-resolution research tomography (HRRT). [11C]UCB-J distribution volume (VT) and binding potential (BPND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [11C]UCB-J BPND with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen's d = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85) and temporal cortex (-11%, Cohen's d = 1.23). These differences remained significant after partial volume correction. [11C]UCB-J BPND did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that [11C]UCB-J PET is a sensitive tool to detect lower synaptic density in SCZ and holds promise for future studies of early detection and disease progression.
Subject(s)
Schizophrenia , Synaptic Vesicles , Brain/diagnostic imaging , Brain/metabolism , Humans , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography/methods , Schizophrenia/diagnostic imaging , Schizophrenia/metabolism , Synaptic Vesicles/metabolismABSTRACT
Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [11C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BPND) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [11C]UCB-J BPND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BPND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study.
Subject(s)
Marijuana Abuse , Animals , Brain/metabolism , Hippocampus/metabolism , Marijuana Abuse/diagnostic imaging , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography , PyridinesABSTRACT
Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4ß2* nicotinic ligand (-)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p < 0.0001; α4ß2*/nicotine scans, 67 ± 15% vs. 74 ± 16%, p = 0.0065), indicating higher striatal ACh concentration. Subject-level measures of these concentration differences were estimated, and whole-brain images of regional ACh concentration gradients were generated. These results constitute the first in vivo estimates of regional variation in ACh concentration in the living brain and offer a novel experimental method to assess potential ACh imbalances in clinical populations.
Subject(s)
Acetylcholine/metabolism , Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals/metabolism , Adult , Animals , Brain/drug effects , Female , Humans , Indoles/metabolism , Indoles/pharmacology , Macaca mulatta , Male , Middle Aged , Piperidines/metabolism , Piperidines/pharmacology , Radiopharmaceuticals/pharmacology , Receptor, Muscarinic M1/agonists , Receptor, Muscarinic M1/metabolism , Receptors, Nicotinic/metabolism , Scopolamine/metabolism , Scopolamine/pharmacology , Young AdultABSTRACT
Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.
Subject(s)
Cocaine , Synaptic Vesicles , Brain/metabolism , Cocaine/metabolism , Humans , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography/methods , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/metabolism , Pyridines/metabolism , Synaptic Vesicles/metabolismABSTRACT
INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Positron-Emission Tomography/methods , Synapses/pathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Cognition , Brain/diagnostic imaging , Brain/pathologyABSTRACT
BACKGROUND: Synaptic injury is a pathological hallmark of neurological impairment in people living with human immunodeficiency virus (HIV, PLWH), a common complication despite viral suppression with antiretroviral therapy (ART). Measurement of synaptic density in living humans may allow better understanding of HIV neuropathogenesis and provide a dynamic biomarker for therapeutic studies. We applied novel synaptic vesical protein 2A (SV2A) positron emission tomographic (PET) imaging to investigate synaptic density in the frontostriatalthalamic region in PLWH and HIV-uninfected participants. METHODS: In this cross-sectional pilot study,13 older male PLWH on ART underwent magnetic resonance imaging (MRI) and PET scanning with the SV2A ligand [11C]UCB-J with partial volume correction and had neurocognitive assessments. SV2A binding potential (BPND) in the frontostriatalthalamic circuit was compared to 13 age-matched HIV-uninfected participants and assessed with respect to neurocognitive performance in PLWH. RESULTS: PLWH had 14% lower frontostriatalthalamic SV2A synaptic density compared to HIV-uninfected (PLWH: mean [SD], 3.93 [0.80]; HIV-uninfected: 4.59 [0.43]; Pâ =â .02, effect size 1.02). Differences were observed in widespread additional regions in exploratory analyses. Higher frontostriatalthalamic SV2A BPND associated with better grooved pegboard performance, a measure of motor coordination, in PLWH (râ =â 0.61, Pâ =â .03). CONCLUSIONS: In a pilot study, SV2A PET imaging reveals reduced synaptic density in older male PLWH on ART compared to HIV-uninfected in the frontostriatalthalamic circuit and other cortical areas. Larger studies controlling for factors in addition to age are needed to determine whether differences are attributable to HIV or comorbidities in PLWH. SV2A imaging is a promising biomarker for studies of neuropathogenesis and therapeutic interventions in HIV.
Subject(s)
HIV Infections , Positron-Emission Tomography , Aged , Cross-Sectional Studies , HIV , HIV Infections/complications , HIV Infections/drug therapy , Humans , Male , Pilot ProjectsABSTRACT
PURPOSE: 11C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC). METHODS: We performed two PVC algorithms, Müller-Gärtner (MG) and 'iterative Yang' (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT, the rate constant K1, binding potential BPND (centrum semiovale as reference region), and tissue volume were compared. RESULTS: In most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT, BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions. CONCLUSION: 11C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For 11C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.
Subject(s)
Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Image Processing, Computer-Assisted/methods , Positron-Emission Tomography/methods , Cerebrovascular Circulation/physiology , Humans , RadiopharmaceuticalsABSTRACT
OBJECTIVE: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. METHODS: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. RESULTS: A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). INTERPRETATION: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.
Subject(s)
Early Diagnosis , Parkinson Disease/diagnostic imaging , Parkinson Disease/pathology , Putamen/pathology , Substantia Nigra/pathology , Synapses/pathology , Autoradiography , Case-Control Studies , Female , Functional Neuroimaging , Humans , Locus Coeruleus/pathology , Male , Membrane Glycoproteins/metabolism , Middle Aged , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography , Putamen/metabolism , Pyridines , Pyrrolidines , Red Nucleus/pathology , Substantia Nigra/metabolismABSTRACT
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: [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.
Subject(s)
Positron-Emission Tomography , Synaptic Vesicles , Animals , Brain/diagnostic imaging , Fluorine Radioisotopes , Glycoproteins , Pyridines , Pyrrolidinones , Radiopharmaceuticals , Reproducibility of ResultsABSTRACT
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: [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.
Subject(s)
Epilepsy, Temporal Lobe/diagnostic imaging , Epilepsy, Temporal Lobe/metabolism , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Positron-Emission Tomography/methods , Pyridines/metabolism , Pyrrolidinones/metabolism , Adult , Carbon Radioisotopes/metabolism , Female , Fluorodeoxyglucose F18/metabolism , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Humans , Male , Middle Aged , Protein Binding/physiology , Temporal Lobe/diagnostic imaging , Temporal Lobe/metabolism , Young AdultABSTRACT
INTRODUCTION: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. METHODS: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio. RESULTS: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. CONCLUSION: We were able to measure widespread synaptic loss due to AD using [11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.
Subject(s)
Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Cognitive Dysfunction/diagnostic imaging , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Synapses/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Biomarkers , Brain/metabolism , Cognitive Dysfunction/metabolism , Disease Progression , Female , Humans , Male , Middle Aged , Neurons/metabolism , Positron-Emission TomographyABSTRACT
OBJECTIVE: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11 C-UCB-J (EP0074; NCT02602860). METHODS: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO. RESULTS: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 µg/mL) was 8.7-fold lower than of LEV (4.02 µg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough). SIGNIFICANCE: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.
Subject(s)
Anticonvulsants/pharmacokinetics , Levetiracetam/pharmacokinetics , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Neuroimaging/methods , Positron-Emission Tomography , Pyrrolidinones/pharmacokinetics , Administration, Oral , Anticonvulsants/administration & dosage , Anticonvulsants/blood , Anticonvulsants/metabolism , Carbon Radioisotopes , Female , Healthy Volunteers , Humans , Inhibitory Concentration 50 , Injections, Intravenous , Levetiracetam/administration & dosage , Levetiracetam/blood , Levetiracetam/metabolism , Magnetic Resonance Imaging , Male , Protein Binding , Pyrrolidinones/administration & dosage , Pyrrolidinones/blood , Pyrrolidinones/metabolismABSTRACT
The kappa opioid receptor (KOR) is involved in depression, alcoholism, and drug abuse. The current agonist radiotracer 11C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties. A novel compound FEKAP ((( R))-4-(2-(3,4-dichlorophenyl)acetyl)-3-((ethyl(2-fluoroethyl)amino)methyl) piperazine-1-carboxylate) was designed, synthesized, and assayed for in vitro binding affinities. It was then radiolabeled and evaluated in rhesus monkeys. Baseline and blocking scans were conducted on a Focus-220 scanner to assess binding specificity and selectivity. Metabolite-corrected arterial activities over time were measured and used as input functions to analyze the brain regional time-activity curves and derive kinetic and binding parameters with kinetic modeling. FEKAP displayed high KOR binding affinity ( Ki = 0.43 nM) and selectivity (17-fold over mu opioid receptor and 323-fold over delta opioid receptor) in vitro. 11C-FEKAP was prepared in high molar activity (mean of 718 GBq/µmol, n = 19) and >99% radiochemical purity. In monkeys, 11C-FEKAP metabolized fairly fast, with â¼31% of intact parent fraction at 30 min post-injection. In the brain, it exhibited fast and reversible kinetics with good uptake. Pretreatment with the nonselective opioid receptor antagonist naloxone (1 mg/kg) decreased uptake in high binding regions to the level in the cerebellum, and the selective KOR antagonist LY2456302 (0.02 and 0.1 mg/kg) reduced 11C-FEKAP specific binding in a dose-dependent manner. As a measure of specific binding signals, the mean binding potential ( BPND) values of 11C-FEKAP derived from the multilinear analysis-1 (MA1) method were greater than 0.5 for all regions, except for the thalamus. The novel KOR agonist tracer 11C-FEKAP demonstrated binding specificity and selectivity in vivo and exhibited attractive properties of fast tissue kinetics and high specific binding.
Subject(s)
Brain/drug effects , Brain/diagnostic imaging , Piperazines/chemical synthesis , Piperazines/pharmacology , Positron-Emission Tomography/methods , Radioactive Tracers , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Receptors, Opioid, kappa/agonists , Animals , Brain/metabolism , Carbon Radioisotopes/pharmacokinetics , Macaca mulatta , Tissue DistributionABSTRACT
Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.
Subject(s)
Drug Development/methods , Models, Biological , Positron-Emission Tomography/methods , Animals , Binding Sites , Brain/diagnostic imaging , Brain/metabolism , Central Nervous System Agents/pharmacokinetics , Computer Simulation , Drug Development/statistics & numerical data , Humans , Likelihood Functions , Mathematical Concepts , Models, Neurological , Pharmacokinetics , Positron-Emission Tomography/statistics & numerical data , Receptors, Drug/metabolism , Receptors, Opioid, kappa/metabolismABSTRACT
AIMS/HYPOTHESIS: The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [18F]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV). METHODS: Dynamic positron emission tomography (PET) data were obtained for 4 h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test-retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3-4 h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose-enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX. RESULTS: Absolute test-retest variability (aTRV) was ≤15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p = 0.009 and pancreas head p = 0.009; body p = 0.019 and tail p = 0.023). SUVR-1 inversely correlated with HbA1c (all groups) in the whole pancreas (p = 0.033) and pancreas head (p = 0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p = 0.049) and pancreas tail (p = 0.035). CONCLUSIONS/INTERPRETATION: The observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes.