Exploring the influence of synaptic density and anxiety on pain perception: evidence from a [11C]UCB-J positron emission tomography imaging study.

Background: Structural and functional brain alterations may be associated with pain and anxiety. We hypothesized that synaptic density (measured in vivo with [11C]UCB-J and positron emission tomography quantification of synaptic vesicle glycoprotein 2A, SV2A) alterations may play a role in higher pain sensitivity and that this relationship may be mediated by anxiety symptoms.

Methods: Twenty-one mentally and medically healthy subjects (11 males, 10 females; age 45.

Network-based Molecular Constraints on Synaptic Density Alterations in Schizophrenia.

Converging neuroimaging, genetic, and post-mortem evidence show a fundamental role of synaptic deficits in schizophrenia pathogenesis. However, the underlying molecular and cellular mechanisms that drive the onset and progression of synaptic pathology remain to be established. Here, we used synaptic density positron emission tomography (PET) imaging using the [C]UCB-J radiotracer to reveal a prominent widespread pattern ( < 0.

Generating synthetic brain PET images of synaptic density based on MR T1 images using deep learning.

Purpose: Synaptic vesicle glycoprotein 2 A (SV2A) in human brains is an important biomarker of synaptic loss associated with several neurological disorders. However, SV2A tracers, such as [C]UCB-J, are less available in practice due to constrains such as cost, radiation exposure and onsite cyclotron. We therefore aim to generate synthetic [C]UCB-J PET images based on MRI in this study.

Psychological Resilience of Mental Health Workers During the Russia-Ukraine War: Implications for Clinical Interventions.

To examine the prevalence and key correlates of psychological resilience in Ukrainian mental health workers (MHWs), using a novel discrepancy-based psychiatric resilience (DBPR) analytic approach. A total of 178 Ukrainian MHWs, recruited via convenience sampling from July to August 2023, completed a survey assessing their war-related exposures, occupational stress, and mental health symptoms and sociodemographic and psychosocial characteristics. DBPR scores were computed by regressing composite distress scores onto measures of war- and work-related stressors.

Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.

Background: Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology.

Methods: Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55).

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.

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 [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.

Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression.

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.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder.

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 [F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task.

Synaptic loss and its association with symptom severity in Parkinson's disease.

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 [C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain.

Preliminary Study of White Matter Abnormalities and Associations With the Metabotropic Glutamate Receptor 5 to Distinguish Bipolar and Major Depressive Disorders.

Background: Understanding distinct neurobiological mechanisms underlying bipolar disorder (BD) and major depressive disorder (MDD) is crucial for accurate diagnosis and the discovery of novel and more effective targeted treatments. Previous diffusion-weighted MRI studies have suggested some common frontotemporal corticolimbic system white matter (WM) abnormalities across the disorders. However, critical to the development of more precise diagnosis and treatment is identifying distinguishing abnormalities.

Examining mGlu5 Receptor Availability as a Predictor of Vulnerability to PTSD: An [F]FPEB and PET Study in Male and Female Rats.

Background: Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females.

Methods: Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female).

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments.

Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [C]UCB-J.

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. [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.

Evaluating infusion methods and simplified quantification of synaptic density with [C]UCB-J and [F]SynVesT-1 PET.

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [C]UCB-J and [F]SynVesT-1.

Linking resting-state network fluctuations with systems of coherent synaptic density: A multimodal fMRI and C-UCB-J PET study.

Resting-state network (RSN) connectivity is a widely used measure of the brain's functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand C-UCB-J PET. Independent component analyses (ICA) were performed on resting-state fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of C-UCB-J variability (medial prefrontal, striatal, and medial parietal).

The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders.

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).

Nicotine Use and Metabotropic Glutamate Receptor 5 in Individuals With Major Depressive and Posttraumatic Stress Disorders.

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 [F]FPEB to measure mGluR5 availability in vivo in 6 groups: (1) nicotine users (NUs) without other psychiatric comorbidities (=23); (2) comparison controls (CCs) without nicotine use or psychiatric comorbidities (=38); (3) major depressive disorder subjects with concurrent nicotine use (MDD-NU; =19); (4) MDD subjects without concurrent nicotine use (MDD-CC; =20); (5) posttraumatic stress disorder subjects with concurrent nicotine use (PTSD-NU; =17); and (6) PTSD subjects without concurrent nicotine use (PTSD-CC; =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).

Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT receptor occupancy from non-human primates to humans.

PF-05212377 (SAM760) is a potent and selective 5-HT antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (C /C ) of 0.