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Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

Purpose: To assess the impact of a pharmacist-led warfarin to DOAC conversion initiative during the COVID-19 pandemic. Methods: Patients who were prescribed warfarin and followed with the anticoagulation clinic for INR monitoring were assessed by outpatient clinical pharmacists as potential candidates for transition to DOACs from March-August 2020. Results: 530 patients were assessed for transition to DOACs, of which 373 (70.4%) were deemed by clinical pharmacists to be candidates for DOACs. Of the patients who were candidates for DOACs, 66 (17.7%) were transitioned from warfarin to a DOAC. Of the patients who transitioned to a DOAC, 59 (89.4%) remained on a DOAC after one year. Conclusion: Outpatient clinical pharmacists are an effective resource to help identify patients who are candidates for DOACs and assist with transition from warfarin. Further, high persistence rates with DOAC therapy after one year demonstrate the positive impact of the clinical pharmacist on medication adherence.

Human alteration of the nitrogen cycle exceeds the safe planetary boundary for the use of reactive nitrogen (Nr). We complement global analysis by analyzing regional mass flows and the relative consequences of multiple chemical forms of Nr as they ‘cascade’ through multiple environmental media. The goals of this paper are (1) to identify the amounts of Nr that flow through a specific nitrogen rich region, (2) develop multiple metrics to characterize and compare multiple forms of Nr and the different damages that they cause, and (3) to use these metrics to assess the most societally acceptable and cost effective means for addressing the many dimensions of Nr damage. This paper uses a multiple metrics approach that in addition to mass flows considers economic damage, health and mitigation costs and qualitative damages to evaluate options for mitigating Nr flows in California’s San Joaquin Valley (SJV). Most analysis focuses attention on agricultural Nr because it is the largest flow in terms of mass. In contrast, the multiple metrics approach identifies mobile source Nr emissions as creating the most economic and health damage in the SJV. Emissions of Nr from mobile sources are smaller than those from crop agriculture and dairy in the SJV, but the benefits of abatement are greater because of reduced health impacts from air pollution, and abatement costs are lower. Our findings illustrate the benefit of a comprehensive multiple metrics approach to Nr management.

We estimate the economic value of birding, which is an important ecosystem service produced by bird populations in recreation areas. Our research identifies the link between values and species richness as well as the abundance of the sandhill crane (Grus canadensis), which migrates each year through our study area. Sandhill crane stopovers at state and federal wildlife areas can attract many birders. We estimate this nonmarket value using the zonal travel cost method and data from the eBird project on wildlife areas in Indiana. We compare crane counts based on eBird with those from the Indiana Department of Natural Resources (DNR). We find important differences depending on whether we use eBird or DNR counts. On average, birders are willing to pay $28 per trip to sites in the study area and less than $1 per trip to see an additional species, while the value of 1000 more cranes is either about $1 or $10 per trip depending on how abundance is measured.

Quantitative molecular imaging with PET can offer insights into physiologic and pathologic processes and is widely used for studying brain disorders. The NeuroEXPLORER is a recently developed dedicated brain PET system offering high spatial resolution and high sensitivity with an extended axial length. This study evaluated the quantitative precision and accuracy of the NeuroEXPLORER with phantom and human data for a variety of imaging conditions that are relevant to dynamic neuroimaging studies. Methods: Thirty-minute scans of an image quality (IQ) phantom and a 3-dimensional Hoffman brain phantom filled with [ 18 F]FDG were performed over 13 h, covering phantom activities of 1.3-177 MBq. Furthermore, a uniform cylindric phantom filled with 558 MBq of 11 C was scanned for 4 h. Quantitative accuracy was assessed using the contrast recovery coefficient (CRC), background variability, and background bias in the IQ phantom, the recovery coefficients (RCs) in the Hoffman phantom, and the bias in the uniform phantom. Results were compared at delayed time points, with different reconstruction parameters and frame lengths down to 1 s. Moreover, randomly subsampled frames of 2 imaging time points (0-2 min and 60-90 min) from a dynamic scan of a healthy volunteer with a 177-MBq injected dose of ( R )-4-(3-fluoro-5-(fluoro- 18 F)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidin-2-one ([ 18 F]SynVesT-1) were used to assess quantification of brain uptake and image-derived input function extraction. Results: Negligible effects were observed on CRC and background bias with 3-177 MBq in the IQ phantom, and bias was less than 5% with 1-558 MBq in the uniform phantom. RC variations were within ±1% with 2-169 MBq in the Hoffman phantom, showcasing the system's high spatial resolution and high sensitivity. Short-frame reconstructions of the 60- to 90-min healthy-volunteer scan showed a ±1% mean difference in quantification of brain uptake for frame lengths down to 30 s and demonstrated the feasibility of measuring image-derived input function with mean absolute differences below 10% for frame lengths down to 1 s. Conclusion: The NeuroEXPLORER, with its high detection sensitivity, maintains high precision and accuracy across a wide range of imaging conditions beyond those evaluated in standard performance tests. These results demonstrate its potential for quantitative neuroimaging applications., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: [ 18 F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [ 11 C]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 k 2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [ 11 C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [ 18 F]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 [ 18 F]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 DVR CER (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 k 2 (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 BP ND (ref: CS) and DVR CER by an average of 3% and 1% across regions, respectively, due to similar bias in k 2 and [Formula: see text] estimation. SRTM underestimated BP ND (ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVR CER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BP ND and DVR CER showed the best agreement with 1TC estimates., Conclusion: Our findings support the use of population [Formula: see text] value in SRTM2 with [ 18 F]SynVesT-1 for the estimation of [Formula: see text] or DVR CER , regardless of the choice of reference region., Competing Interests: Declarations. Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Yale University Human Investigation Committee and the Yale‑New Haven Hospital Radiation Safety Committee. Consent to participate: Written informed consent was obtained from all subjects. Competing interests: The radioligand [18F]SynVesT-1 (formerly referred to as [18F]SDM-8) is contained in the international patent application PCT/US2018/018388, “Radiolabeled Pharmaceuticals and Methods of Making and Using Same,” filed on February 15, 2018 (inventors: Yiyun Huang, Zhengxin Cai, Songye Li, Nabeel Nabulsi, and Richard E. Carson). No other potential conflict of interest relevant to this article was reported., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Borderline Personality Disorder (BPD) is a serious psychiatric condition, associated with a high risk for suicide attempts and death by suicide. However, relatively little is known about the pathophysiology of BPD. The metabotropic glutamate receptor type 5 (mGlu5) has been specifically implicated in the pathophysiology of BPD and suicide attempts, with more general roles in emotion regulation, social and cognitive functioning, and pain processing. Here, we examined the relationship between mGlu5 availability, BPD, and suicide attempts in vivo for the first time., Methods: Eighteen individuals with BPD, and 18 age-, sex-, and smoking-status matched healthy (HC) and 18 clinical comparison controls with major depressive disorder (MDD) completed comprehensive clinical assessments and participated in an [ 18 F]FPEB positron emission tomography (PET) scan to measure mGlu5 availability. Volume of distribution (V T ) in the frontolimbic circuit implicated in BPD pathophysiology was the PET outcome measure., Results: We observed significantly higher frontolimbic mGlu5 availability in BPD compared to both HC (p=.009, d=0.84, 18.43% difference), and MDD (p=.03, d=0.69, 15.21% difference). In the BPD, but not MDD group, higher mGlu5 availability was also associated with history of suicide attempts (SA; 19-25% higher, p's=.005-.02). Further, mGlu5 availability was positively correlated with risk factors for suicide (e.g., sexual victimization, perceived burdensomeness) in BPD-SA group., Conclusions: Results show higher mGlu5 availability in BPD and suicide attempt for the first time. Our preliminary findings suggest mGlu5 may be a critical treatment target for BPD symptoms, including suicide attempts, and warrant further investigation in larger samples., (Copyright © 2024. Published by Elsevier Inc.)

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [ 11 C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60-90 or 70-90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a review of our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms and the use of a ketamine drug challenge to examine synaptogenesis in vivo. We then highlight the importance of performing translational PET imaging in animal models in conjunction with clinical imaging. We consider the ongoing challenges, possible solutions, and present preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress. Finally, we discuss methodological improvements and future directions for SV2A imaging, potentially in conjunction with other neural markers., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D 2 /D 3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans., Methods: Healthy, vitamin D-sufficient adults (N = 18, 32.8 ± 6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving 4 total scans over 2 visits consisting of same-day preamphetamine and postamphetamine (0.3 mg/kg) [ 11 C]-PHNO positron emission tomography scanning to examine D 2 /D 3 receptor availability (nondisplaceable binding potential [BP ND ]) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least 6 days apart. Parametric images of [ 11 C]-PHNO positron emission tomography BP ND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra., Results: For preamphetamine scans, there was a medication × region of interest interaction (F 4,153  = 2.59, p = .039) and a main effect of medication (F 1,153  = 4.88, p = .029) on BP ND , with higher BP ND values on calcitriol in the ventral striatum (t 153  = 2.89, p = .004) and dorsal putamen (t 153  = 2.15, p = .033). There was a main effect of medication on postamphetamine change in BP ND (F 4,153  = 5.93, p = .016), with greater decreases in calcitriol in the ventral striatum (t 153  = 3.00, p = .003), substantia nigra (t 153  = 2.49, p = .014), and dorsal caudate (t 153  = 2.29, p = .023)., Conclusions: Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders that involve dysregulated dopamine function., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11 C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a 11 C-UCB-J PET scan. Binding potential, BP ND , was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower 11 C-UCB-J BP ND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

[ 18 F]FE-PE2I PET is a promising alternative to single positron emission computed tomography-based dopamine transporter (DAT) imaging in Parkinson's disease. While the excellent discriminative power of [ 18 F]FE-PE2I PET has been established, so far only one study has reported meaningful associations between motor severity scores and DAT availability. In this study, we use high-resolution (∼3 mm isotropic) PET to provide an independent validation for the clinical correlates of [ 18 F]FE-PE2I imaging in separate cross-sectional (28 participants with Parkinson's disease, Hoehn-Yahr: 2 and 14 healthy individuals) and longitudinal (initial results from 6 participants with Parkinson's disease with 2-year follow-up) cohorts. In the cross-sectional cohort, DAT availability in the putamen and substantia nigra of patients with Parkinson's disease showed a significant negative association with total motor severity ( r = -0.59, P = 0.002 for putamen; r = -0.46, P = 0.018 for substantia nigra), but not tremor severity. To our knowledge, this is the first observed association between motor severity in Parkinson's disease and DAT availability in the substantia nigra. The associations with motor severity in most nigrostriatal regions improved if tremor scores were excluded from motor scores. Further, we found significant asymmetry in DAT availability in the putamen (∼28% lower DAT availability within the more-affected side of the putamen), and DAT-based asymmetry index for the putamen was correlated with asymmetry in motor severity ( r = -0.60, P = 0.001). In the longitudinal study, [ 18 F]FE-PE2I PET detected significant annual percentage reduction of DAT availability at the individual level in the putamen (9.7 ± 2.6%), caudate (10.5 ± 3.8%) and ventral striatum (5.5 ± 2.7%), but not the substantia nigra. Longitudinal per cent reduction in DAT availability within the putamen was strongly associated with increase in motor severity ( r = 0.91, P = 0.011) at follow-up, demonstrating the high sensitivity of [ 18 F]FE-PE2I PET in tracking longitudinal changes. These results provide further evidence for the utility of [ 18 F]FE-PE2I as an important in vivo PET biomarker in future clinical trials of Parkinson's disease., Competing Interests: R.C. and S.J.F. are full-time employees of AbbVie, but their employment does not constitute any competing interest for the content presented in this article. All other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Rubidium-82 ( 82 Rb) is a radioactive isotope widely used for cardiac PET imaging. Despite numerous benefits of 82 Rb, there are several factors that limits its image quality and quantitative accuracy. First, the short half-life of 82 Rb results in noisy dynamic frames. Low signal-to-noise ratio would result in inaccurate and biased image quantification. Noisy dynamic frames also lead to highly noisy parametric images. The noise levels also vary substantially in different dynamic frames due to radiotracer decay and short half-life. Existing denoising methods are not applicable for this task due to the lack of paired training inputs/labels and inability to generalize across varying noise levels. Second, 82 Rb emits high-energy positrons. Compared with other tracers such as 18 F, 82 Rb travels a longer distance before annihilation, which negatively affect image spatial resolution. Here, the goal of this study is to propose a self-supervised method for simultaneous (1) noise-aware dynamic image denoising and (2) positron range correction for 82 Rb cardiac PET imaging. Tested on a series of PET scans from a cohort of normal volunteers, the proposed method produced images with superior visual quality. To demonstrate the improvement in image quantification, we compared image-derived input functions (IDIFs) with arterial input functions (AIFs) from continuous arterial blood samples. The IDIF derived from the proposed method led to lower AUC differences, decreasing from 11.09% to 7.58% on average, compared to the original dynamic frames. The proposed method also improved the quantification of myocardium blood flow (MBF), as validated against 15 O-water scans, with mean MBF differences decreased from 0.43 to 0.09, compared to the original dynamic frames. We also conducted a generalizability experiment on 37 patient scans obtained from a different country using a different scanner. The presented method enhanced defect contrast and resulted in lower regional MBF in areas with perfusion defects. Lastly, comparison with other related methods is included to show the effectiveness of the proposed method., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chi Liu reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [ 18 F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [ 11 C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [ 18 F]FPEB and [ 11 C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD., Methods: Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [ 18 F]FPEB to measure mGluR5 and [ 11 C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [ 18 F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [ 11 C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.., Result: A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD ( r = 0.81, p < 0.001) and in the CN group ( r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group ( r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group ( r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions., Conclusion: Medial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated Aβo toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss., Competing Interests: Competing interests Adam P. Mecca, Richard E. Carson, and Christopher H. van Dyck report grants from the National Institutes of Health for the conduct of the study. Adam P. Mecca reports grants for clinical trials from Eli Lilly and Janssen Pharmaceuticals outside the submitted work. Yiyun Huang reports research grants from UCB and Eli Lilly outside the submitted work. Yiyun Huang, Nabeel B. Nabulsi, and Richard E. Carson have a patent for a newer version of the tracer. Richard E. Carson is a consultant for Rodin Therapeutics and has received research funding from UCB. Richard E. Carson reports having received grants from AstraZeneca, Astellas, Eli Lilly, Pfizer, Taisho, and UCB outside the submitted work. Ryan S. O’Dell reports grants for clinical trials from Cognition Therapeutics and Bristol-Myers Squibb outside of the submitted work. Christopher H. van Dyck reports consulting fees from Kyowa Kirin, Roche, Merck, Eli Lilly, and Janssen and grants for clinical trials from Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, Toyama, and Biohaven outside the submitted work.

Background: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD., Methods: Positron emission tomography (PET) with [ 18 F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25)., Results: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028)., Limitations: The modest sample size is the primary limitation., Conclusions: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [ 11 C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease., Competing Interests: Competing interests statement:J.H.K.: (consultations less than $5,000/y) Aptinyx, Inc., BioXcel, Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cerevel Pharmaceuticals, Epiodyne, Inc., Esai, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., PsychoGenics, Inc., Sunovion Pharmaceuticals, Inc., Takeda Pharmaceuticals (Stock/Options) Biohaven Pharmaceuticals, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, Inc., EpiVario, Inc., Freedom Biosciences, Neumora Therapeutics, Inc., Response Pharmaceuticals, Rest Therapeutics, Spring Health, Inc., Tempero Bio, Inc., Terran Biosciences, Tetricus Inc. (nonmonetary support, i.e., provision of drug) Cerevel Pharmaceuticals, Novartis. J.H.K. stands to benefit from patents held by Yale University that were licensed to Janssen Pharmaceuticals (ketamine), Biohaven Pharmaceuticals (riluzole), Freedom Biosciences (NMDA-R antagonist plus MTORC inhibitor), and Spring Health (precision medicine strategy).

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 18 F-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 18 F-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., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The sphingosine-1-phosphate receptor-1 (S1PR 1 ) is involved in regulating responses to neuroimmune stimuli. There is a need for S1PR 1 -specific radioligands with clinically suitable brain pharmcokinetic properties to complement existing radiotracers. This work evaluated a promising S1PR 1 radiotracer, [ 18 F]TZ4877, in nonhuman primates., Procedures: [ 18 F]TZ4877 was produced via nucleophilic substitution of tosylate precursor with K[ 18 F]/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 [ 18 F]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 S1PR 1 inhibitor ponesimod, 33 min after 0.4-0.8 mg/kg of the S1PR 1 -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: [ 18 F]TZ4877 exhibited fast kinetics that were described by the reversible 2-tissue compartment model. Baseline [ 18 F]TZ4877 f P was low (< 1%), and [ 18 F]TZ4877 V T / f P values were 233-866 mL/cm 3 . TZ82112 dose-dependently reduced [ 18 F]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: [ 18 F]TZ4877 exhibits reversible kinetic properties, but the low f P value limits quantification with this radiotracer. S1PR 1 is a compelling PET imaging target, and these data support pursuing alternative F-18 labeled radiotracers for potential future human studies., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Long-lasting vaginal dosage forms could improve the therapeutic efficacy of vaginal microbicides, but achieving long-term delivery to the vaginal canal has been a significant challenge. To advance understanding of vaginal dosage retention and biodistribution, we describe a method of noninvasive imaging with 89 Zr-labeled bioadhesive nanoparticles (BNPs) in non-human primates. We additionally examined the safety of repeated BNP application. BNPs administered vaginally to cynomolgus monkeys were still detected after 24 h (1.7% retention) and 120 h (0.1% retention). BNPs did not translocate to the uterus or into systemic circulation. Analysis of inflammatory biomarkers in the vaginal fluid and plasma suggest that BNPs are safe and biocompatible, even after multiple doses. BNPs are a promising delivery vehicle for vaginally administered therapeutics. Further studies using the non-human primate imaging materials and methods developed here could help advance clinical translation of BNPs and other long-lasting vaginal dosage forms., Competing Interests: YW, MK, HWS, and WMS are inventors on patent applications related to bioadhesive PLA‐HPG nanoparticles. WMS is a founder and consultant to Stradefy Biosciences, which is developing bioadhesive nanoparticles for other applications., (© 2024 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [ 11 C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [ 11 C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [ 11 C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes ( r = -0.54, P = 0.0019), Mini-Mental State Examination ( r = 0.48, P = 0.0055) and Logical Memory II score ( r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score ( r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes ( r = -0.54, P = 0.0019) and Mini-Mental State Examination ( r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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. [ 11 C]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 [ 11 C]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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [ 11 C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [ 11 C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions., (© 2024. The Author(s).)

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-( 18 F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one ( 18 F-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 18 F-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: 18 F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18 F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18 F-SynVesT-2 entered the brain quickly, with an SUV peak 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/cm 3 in CS to 7.6 ± 0.8 mL/cm 3 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: 18 F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18 F-SynVesT-2 is faster than the kinetics of 11 C-UCB-J and 18 F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

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 ( k 2 , 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 [ 11 C]LSN3172176, healthy controls and Parkinson's disease subjects for [ 18 F]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 ∼25% 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 [ 11 C]LSN3172176, 20% for [ 18 F]FE-PE2I). Future work should investigate the benefits of using corrected SUVR in other populations and with different tracers., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Effective, disease-modifying therapeutics for the treatment of Alzheimer's disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among the most toxic forms of Aβ. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aβ oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aβ oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients., Methods: The present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration., Results: No treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated., Conclusions: The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development., Trial Registration: The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282)., (© 2024. The Author(s).)