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Purpose: The sphingosine-1-phosphate receptor-1 (S1PR1) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR1-specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR1 radiotracer, [18F]TZ4877, in nonhuman primates. Procedures: [18F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[18F]/F- followed by deprotection. Brain PET imaging data were acquired with a Focus220 scanner in two Macaca mulatta (6, 13 years old) for 120-180 min following bolus injection of 118-163 MBq [18F]TZ4877, with arterial blood sampling and metabolite analysis to measure the parent input function and plasma free fraction (f P). Each animal was scanned at baseline, 15-18 min after 0.047-0.063 mg/kg of the S1PR1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR1-specific compound TZ82112, and 167-195 min after 1 ng/kg of the immune stimulus endotoxin. Kinetic analysis with metabolite-corrected input function was performed to estimate the free fraction corrected total distribution volume (V T/f P). Whole-body dosimetry scans were acquired in 2 animals (1M, 1F) with a Biograph Vision PET/CT System, and absorbed radiation dose estimates were calculated with OLINDA. Results: [18F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [18F]TZ4877 f P was low (< 1%), and [18F]TZ4877 V T/f P values were 233-866 mL/cm3. TZ82112 dose-dependently reduced [18F]TZ4877 V T/f P, while ponesimod and endotoxin exhibited negligible effects on V T/f P, possibly due to scan timing relative to dosing. Dosimetry studies identified the critical organs of gallbladder (0.42 (M) and 0.31 (F) mSv/MBq) for anesthetized nonhuman primate. Conclusions: [18F]TZ4877 exhibits reversible kinetic properties, but the low f P value limits quantification with this radiotracer. S1PR1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies.
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The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The system's performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications.
Subject(s)
Brain , Phantoms, Imaging , Positron Emission Tomography Computed Tomography , Humans , Brain/diagnostic imaging , Positron Emission Tomography Computed Tomography/instrumentation , Image Processing, Computer-Assisted , Fluorodeoxyglucose F18ABSTRACT
Fluoride is an environmental toxin prevalent in water, soil, and air. A fluoride transporter called Fluoride EXporter (FEX) has been discovered across all domains of life, including bacteria, single cell eukaryotes, and all plants, that is required for fluoride tolerance. How FEX functions to protect multicellular plants is unknown. In order to distinguish between different models, the dynamic movement of fluoride in wildtype (WT) and fex mutant plants was monitored using [18F]fluoride with positron emission tomography. Significant differences were observed in the washout behavior following initial fluoride uptake between plants with and without a functioning FEX. [18F]Fluoride traveled quickly up the floral stem and into terminal tissues in WT plants. In contrast, the fluoride did not move out of the lower regions of the stem in mutant plants resulting in clearance rates near zero. The roots were not the primary locus of FEX action, nor did FEX direct fluoride to a specific tissue. Fluoride efflux by WT plants was saturated at high fluoride concentrations resulting in a pattern like the fex mutant. The kinetics of fluoride movement suggested that FEX mediates a fluoride transport mechanism throughout the plant where each individual cell benefits from FEX expression.
Subject(s)
Arabidopsis , Fluorides , Fluorides/metabolism , Arabidopsis/genetics , Arabidopsis/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Biological TransportABSTRACT
Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11ß-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11ß-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions: This is the first in vivo examination of 11ß-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11ß-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11ß-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.
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INTRODUCTION: In the dopamine system, the mesolimbic pathway, including the dorsal striatum, underlies the reinforcing properties of tobacco smoking, and the mesocortical pathway, including the dorsolateral prefrontal cortex (dlPFC), is critical for cognitive functioning. Dysregulated dopamine signaling has been linked to drug-seeking behaviors and cognitive deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are key regions for cognitive functioning. We recently showed that people who smoke have lower dlPFC dopamine (D2/3R) receptor availability than people who do not, which is related to poorer cognitive function. AIMS AND METHODS: The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. Twenty-nine (18 males) recently abstinent people who smoke and 29 sex-matched healthy controls participated in 2 same-day [11C]-(+)-PHNO positron emission tomography scans before and after amphetamine administration to provoke dopamine release. D2/3R availability (binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND) were calculated. Cognition (verbal learning and memory) was assessed with the CogState computerized battery. RESULTS: There were no group differences in baseline BPND. People who smoke have a smaller magnitude %ΔBPND in dorsal putamen than healthy controls (pâ =â .022). People who smoke perform worse on immediate (pâ =â .035) and delayed (pâ =â .011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (pâ =â .006) and delayed recall (pâ =â .049), and lower %ΔBPND was related to worse delayed recall (pâ =â .022). CONCLUSIONS: Lower dorsal putamen D2/3R availability and function are associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. IMPLICATIONS: This study directly relates dopamine imaging outcomes in the dorsal striatum to cognitive function in recently abstinent people who smoke cigarettes and healthy controls. The current work included a well-characterized subject sample in terms of demographics, smoking characteristics, and a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature relating dopamine imaging outcomes to cognition in recently abstinent people who smoke and people who do not smoke, expanding our understanding of brain-behavior relationships.
Subject(s)
Amphetamine , Cognition , Dopamine , Positron-Emission Tomography , Putamen , Receptors, Dopamine D2 , Receptors, Dopamine D3 , Humans , Male , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Adult , Female , Cognition/drug effects , Dopamine/metabolism , Putamen/metabolism , Putamen/diagnostic imaging , Putamen/drug effects , Amphetamine/pharmacology , Amphetamine/administration & dosage , Case-Control Studies , Young Adult , Middle Aged , Smoking/metabolism , Smoking/psychology , Smoking Cessation/psychologyABSTRACT
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.
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Standardized Uptake Value Ratio (SUVR) is a widely reported semi-quantitative positron emission tomography (PET) outcome measure, partly because of its ease of measurement from short scan durations. However, in brain, SUVR is often a biased estimator of the gold-standard distribution volume ratio (DVR) due to non-equilibrium conditions, i.e., clearance of the radiotracer in relevant tissues. Factors that affect radiotracer metabolism and clearance such as medication or subject groups could lead to artificial differences in SUVR. This work developed a correction that reduces the bias in SUVR (estimated from a short 15-30 min PET imaging session) by accounting for the effects of tracer clearance observed during the late SUVR time window. The proposed correction takes the form of a one-step non-linear algebraic transform of SUVR that is a function of radiotracer dependent parameters such as clearance rates from the reference and target tissues, and population averaged reference region clearance rate (k2,ref). An important observation was the need for accurate estimation of radiotracer clearance rate in target tissue, which was addressed with a regression based model. Simulations and human data from two different radiotracers (healthy controls for [11C]LSN3172176, healthy controls and Parkinson's disease subjects for [18F]FE-PE2I) were used to validate the correction and evaluate its benefits and limitations. SUVR correction in human data significantly reduced mean SUVR bias across brain regions and subjects (from â¼25% for SUVR to <10% for corrected SUVR). This correction also significantly reduced the variability of this bias across brain regions for both tracers (approximately 50% for [11C]LSN3172176, 20% for [18F]FE-PE2I). Future work should investigate the benefits of using corrected SUVR in other populations and with different tracers.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/metabolism , Positron-Emission Tomography/methods , Brain/diagnostic imaging , Brain/metabolism , Radiopharmaceuticals/metabolism , KineticsABSTRACT
In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [11C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25-45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1-3 months before scan day were enrolled. Imaging featured a baseline [11C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [11C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [11C]PBR28 volume of distributions (VT) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [11C]PBR28 VT (n = 8; F(1,49) = 34.72, p > 0.0001; Cohen's d'=0.8-1.7) throughout brain by 9-16%. Alcohol significantly altered plasma cytokines TNF-α (F(2,22) = 17.49, p < 0.0001), IL-6 (F(2,22) = 18.00, p > 0.0001), and MCP-1 (F(2,22) = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [11C]PBR28 VT. These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol.
Subject(s)
Brain , Positron-Emission Tomography , Male , Female , Humans , Positron-Emission Tomography/methods , Brain/metabolism , Radionuclide Imaging , Blood Alcohol Content , Receptors, GABA/metabolism , Immunity , Cytokines/metabolismABSTRACT
The role of glutamate system in the etiology and pathophysiology of psychiatric disorders has gained considerable attention in the past two decades, including dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Thus, mGlu5 may represent a promising therapeutic target for psychiatric conditions, particularly stress-related disorders. Here, we describe mGlu5 findings in mood disorders, anxiety, and trauma disorders, as well as substance use (specifically nicotine, cannabis, and alcohol use). We highlight insights gained from positron emission tomography (PET) studies, where possible, and discuss findings from treatment trials, when available, to explore the role of mGlu5 in these psychiatric disorders. Through the research evidence reviewed in this chapter, we make the argument that, not only is dysregulation of mGlu5 evident in numerous psychiatric disorders, potentially functioning as a disease "biomarker," the normalization of glutamate neurotransmission via changes in mGlu5 expression and/or modulation of mGlu5 signaling may be a needed component in treating some psychiatric disorders or symptoms. Finally, we hope to demonstrate the utility of PET as an important tool for investigating mGlu5 in disease mechanisms and treatment response.
Subject(s)
Mental Disorders , Receptor, Metabotropic Glutamate 5 , Humans , Mood Disorders , Biomarkers , GlutamatesABSTRACT
Metabotropic glutamate receptor 5 (mGluR5) dysregulation has been implicated in the pathophysiology of many psychiatric disorders, as well as nicotine use and dependence. We used positron emission tomography with [18F]FPEB to measure mGluR5 availability in vivo in 6 groups: (1) nicotine users (NUs) without other psychiatric comorbidities (n = 23); (2) comparison controls (CCs) without nicotine use or psychiatric comorbidities (n = 38); (3) major depressive disorder subjects with concurrent nicotine use (MDD-NU; n = 19); (4) MDD subjects without concurrent nicotine use (MDD-CC; n = 20); (5) posttraumatic stress disorder subjects with concurrent nicotine use (PTSD-NU; n = 17); and (6) PTSD subjects without concurrent nicotine use (PTSD-CC; n = 16). The goal of the study was to test the hypothesis that mGluR5 availability in key corticolimbic regions of interest (ROIs) is different in NU with versus without comorbid psychiatric disorders (ROI: dorsolateral prefrontal cortex [dlPFC], orbitofrontal cortex [OFC], ventromedial prefrontal cortex [vmPFC], anterior cingulate cortex [ACC], amygdala, hippocampus). We found that NU had 11%-13% lower mGluR5 availability in OFC, vmPFC, dlPFC, and ACC as compared with CC, while PTSD-NU had 9%-11% higher mGluR5 availability in OFC, dlPFC, and ACC compared with PTSD. Furthermore, relationships between mGluR5 availability and psychiatric symptoms varied as a function of psychiatric diagnosis among NUs. NU showed a negative correlation between mGluR5 and smoking cravings and urges (r's = -0.58 to -0.70, p's = 0.011 - 0.047), while PTSD-NU had the reverse relationship (r's = 0.60-0.71, p's = 0.013-0.035 in ACC, vmPFC, and dlPFC). These findings have substantial implications for our understanding of glutamate homeostasis in psychiatric subgroups and for identifying key neural phenotypes among NU. mGluR5 is a potential treatment target for precision medicine in individuals with nicotine use.
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The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the ß2-subunit containing nicotinic acetylcholine receptor (ß2*-nAChR) partial agonist radioligand (-)-[18F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[18F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (VT) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[18F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[18F]flubatine VT, consistent with increased cortical acetylcholine levels reducing the number of ß2*-nAChR sites available for (-)-[18F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[18F]flubatine VT was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Subject(s)
Acetylcholine , Receptors, Nicotinic , Animals , Male , Female , Acetylcholine/metabolism , Acetylcholinesterase , Physostigmine , Positron-Emission Tomography/methods , Brain/diagnostic imaging , Brain/metabolism , Receptors, Nicotinic/metabolism , Cognition , Cholinergic Agents , Smoking/adverse effectsABSTRACT
The brain's immune system plays a critical role in responding to immune challenges and maintaining homeostasis. However, dysregulated neuroimmune function contributes to neurodegenerative disease and neuropsychiatric conditions. In vivo positron emission tomography (PET) imaging of the neuroimmune system has facilitated a greater understanding of its physiology and the pathology of some neuropsychiatric conditions. This review presents an in-depth look at PET findings from human neuroimmune function studies, highlighting their importance in current neuropsychiatric research. Although the majority of human PET studies feature radiotracers targeting the translocator protein 18 kDa (TSPO), this review also considers studies with other neuroimmune targets, including monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, nitric oxide synthase, and the purinergic P2X7 receptor. Promising new targets, such as colony-stimulating factor 1, Sphingosine-1-phosphate receptor 1, and the purinergic P2Y12 receptor, are also discussed. The significance of validating neuroimmune targets and understanding their function and expression is emphasized in this review to better identify and interpret PET results.
Subject(s)
Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Receptors, GABA/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals/metabolism , Brain/metabolismABSTRACT
BACKGROUND: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity and a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence. METHODS: Forty-eight image data sets were acquired with a multimodal neuroimaging battery that included resting-state functional magnetic resonance imaging (fMRI) and mGlu5 receptor positron emission tomography (PET) with the radiotracer [18 F]FPEB. Participants with AUD (n = 14) were scanned twice, at approximately 1 and 4 weeks after beginning supervised abstinence. [18 F]FPEB PET results were published previously. Primary comparisons of fMRI outcomes were performed between the AUD group and healthy controls (HCs; n = 23) and assessed changes over time within the AUD group. Relationships between resting-state connectivity measures and mGlu5 receptor availability were explored within groups. RESULTS: Compared to HCs, global functional connectivity of the orbitofrontal cortex was higher in the AUD group at 4 weeks of abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses showed that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group at 1 week of abstinence, r = 0.50 and at 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between the DMN and salience networks in HCs (r = 0.60, p = 0.003) but not in the AUD group (p > 0.3). CONCLUSIONS: These preliminary findings of altered global and network connectivity during the first month of abstinence from drinking may reflect the loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence.
Subject(s)
Alcoholism , Alcoholism/diagnostic imaging , Brain/metabolism , Brain Mapping/methods , Glutamic Acid , Humans , Magnetic Resonance Imaging , Neuroimaging , Receptor, Metabotropic Glutamate 5ABSTRACT
Cannabis use peaks in adolescence, and adolescents may be more vulnerable to the neural effects of cannabis and cannabis-related harms due to ongoing brain development during this period. In light of ongoing cannabis policy changes, increased availability, reduced perceptions of harm, heightened interest in medicinal applications of cannabis, and drastic increases in cannabis potency, it is essential to establish an understanding of cannabis effects on the developing adolescent brain. This systematic review aims to: (1) synthesize extant literature on functional and structural neural alterations associated with cannabis use during adolescence and emerging adulthood; (2) identify gaps in the literature that critically impede our ability to accurately assess the effect of cannabis on adolescent brain function and development; and (3) provide recommendations for future research to bridge these gaps and elucidate the mechanisms underlying cannabis-related harms in adolescence and emerging adulthood, with the long-term goal of facilitating the development of improved prevention, early intervention, and treatment approaches targeting adolescent cannabis users (CU). Based on a systematic search of Medline and PsycInfo and other non-systematic sources, we identified 90 studies including 9441 adolescents and emerging adults (n = 3924 CU, n = 5517 non-CU), which provide preliminary evidence for functional and structural alterations in frontoparietal, frontolimbic, frontostriatal, and cerebellar regions among adolescent cannabis users. Larger, more rigorous studies are essential to reconcile divergent results, assess potential moderators of cannabis effects on the developing brain, disentangle risk factors for use from consequences of exposure, and elucidate the extent to which cannabis effects are reversible with abstinence. Guidelines for conducting this work are provided.
Subject(s)
Adolescent Behavior , Cannabis , Adolescent , Adult , Brain/diagnostic imaging , Cannabis/adverse effects , Functional Neuroimaging , HumansABSTRACT
INTRODUCTION: Chronic nicotine exposure desensitizes dopamine responses in animals, but it is not known if this occurs in human tobacco smokers. Deficits in dopamine function are likely to make smoking cessation difficult. We used positron emission tomography (PET) brain imaging with the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO to determine if abstinent smokers exhibit less amphetamine-induced dopamine release in the ventral striatum than nonsmokers, and whether this was associated with clinical correlates of smoking cessation. METHODS: Baseline [11C]-(+)-PHNO scans were acquired from smokers (n = 22, 7 female, abstinent 11 ± 9 days) and nonsmokers (n = 20, 7 female). A subset of thirty-seven participants (18 smokers) received oral amphetamine (0.5 mg/kg) three hours before a second [11C]-(+)-PHNO scan. Binding potential (BPND) (i.e., D2/3 receptor availability) was estimated at baseline and postamphetamine in the ventral striatum. Amphetamine-induced percent change in BPND was calculated to reflect dopamine release. Subjects also completed the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: There were no group differences in baseline BPND. Amphetamine-induced percent change in BPND in the ventral striatum was significantly lower in abstinent smokers compared to nonsmokers (p=0.019; d=0.82). Higher CES-D scores were significantly associated with lower ventral striatal percent change in BPND for abstinent smokers (rs=-0.627, p=0.025). CONCLUSIONS: In conclusion, abstinent smokers exhibited significantly less amphetamine-induced dopamine release in the ventral striatum than nonsmokers. In abstinent smokers, worse mood was significantly associated with less striatal dopamine release. Our findings highlight a potential neural mechanism that may underlie negative mood symptoms during early abstinence. IMPLICATIONS: This study combined quantitative PET imaging and an amphetamine challenge to examine striatal dopamine function during early smoking cessation attempts. The findings demonstrate that recently abstinent tobacco smokers exhibit significant, mood-associated striatal dopamine dysfunction compared to nonsmokers. This study advances our knowledge of the neurobiology underlying early quit attempts, and bridges novel neural findings with clinically relevant symptoms of smoking cessation. These results may explain the challenge of maintaining long-term abstinence from smoking, and can lend insight into the development of treatment strategies for smoking cessation.
Subject(s)
Dopamine , Ventral Striatum , Animals , Carbon Radioisotopes , Dopamine/metabolism , Female , Humans , Non-Smokers , Positron-Emission Tomography/methods , Smokers , Ventral Striatum/diagnostic imaging , Ventral Striatum/metabolismABSTRACT
Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [11C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.5 years, 5 women) and 13 healthy volunteers (34.8 ± 10 years, 6 women). Independent component analysis was performed to identify spatial patterns of coherent variance in KOR binding (tracer volume of distribution, VT) across all subjects. Expression of each component was compared between groups and relationships to symptoms were explored using the 17-item Hamilton Depression Rating Scale (HDRS). Three components of variation in KOR availability across ROIs were identified, spatially characterized by [11C]GR103545 VT in (1) bilateral frontal lobe; (2) occipital and parietal cortices, right hippocampus, and putamen; and (3) right anterior cingulate, right superior frontal gyrus and insula, coupled to negative loading in left middle cingulate. In MDD patients, component 3 was negatively associated with symptom severity on the HDRS (r = -0.85, p = 0.0021). There were no group-wise differences in expression of any component between patients and controls. These preliminary findings suggest that KOR signaling in cortical regions relevant to depression, particularly right anterior cingulate, could reflect MDD pathophysiology.
Subject(s)
Depressive Disorder, Major , Receptors, Opioid, kappa , Adult , Brain/diagnostic imaging , Brain/metabolism , Case-Control Studies , Depressive Disorder, Major/diagnostic imaging , Female , Frontal Lobe/metabolism , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/metabolism , Humans , Positron-Emission TomographyABSTRACT
BACKGROUNDInvestigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD.METHODSSixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [18F]AS2471907, a radioligand for 11ß-HSD1.RESULTSPrefrontal-limbic 11ß-HSD1 availability, estimated as [18F]AS2471907 volume of distribution (VT), was significantly higher in the PTSD group compared with the TC group (ß = 1.16, P = 0.0057). Lower prefrontal-limbic 11ß-HSD1 availability was related to greater overall PTSD severity (R2 = 0.27, P = 0.038) in the PTSD group. 11ß-HSD1 availability was not related to plasma cortisol levels (R2 = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11ß-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (ß = 4.40, P = 0.039).CONCLUSIONHigher brain cortisol-producing 11ß-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11ß-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDINGBrain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Brain/diagnostic imaging , Hydrocortisone/biosynthesis , Positron-Emission Tomography/methods , Stress Disorders, Post-Traumatic/diagnostic imaging , Triazoles/metabolism , Adult , Brain/metabolism , Female , Humans , Male , Middle Aged , Severity of Illness Index , Stress Disorders, Post-Traumatic/metabolismABSTRACT
BACKGROUND: Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D2/3 receptor antagonist [11C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. METHODS: PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [11C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (Kbol = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ9-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [11C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). RESULTS: Cannabis smoking increased plasma Δ9-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [11C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. CONCLUSIONS: These preliminary data support the sensitivity of [11C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.
Subject(s)
Cannabis , Marijuana Smoking , Ventral Striatum , Adult , Corpus Striatum/diagnostic imaging , Dopamine , Humans , Positron-Emission Tomography , Raclopride , Young AdultABSTRACT
Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer's disease or Parkinson's disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.
Subject(s)
Alzheimer Disease , Receptors, GABA , Animals , Brain/diagnostic imaging , Brain/metabolism , Disease Models, Animal , Endothelial Cells/metabolism , Mice , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, GABA/metabolismABSTRACT
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.