Tobacco smoking, a major cause of preventable mortality, upregulates β2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in most brain regions. Although the α4 subunit most frequently co-assembles with β2, other subunits likely assemble with β2 and contribute to distinct aspects of nicotine-mediated behaviors, but these factors are poorly understood in people. This work performed independent component analysis (ICA) of [18F]Flubatine positron emission tomography (PET) image data to identify maximally independent sources of specific binding to β2*-nAChRs. We then compared their magnitudes (loading coefficients) in people who recently stopped smoking cigarettes (abstinent smokers; n = 26) and people who never smoked cigarettes (non-smokers; n = 20). ICA identified 3 reproducible components: IC1 (36% of variance) in medial thalamus, lateral thalamus, and red nucleus; IC2 (18% of variance) in ventral thalamus, lateral geniculate, and midbrain; IC3 (19% of variance) in cerebellum and optic circuitry in midbrain. Nicotine challenge in an independent sample (n = 9) reduced loading coefficients of all components, confirming specific binding to nAChRs. Post-mortem autoradiography of cerebellum showed greatest [18F]Flubatine displacement by α3/α6β2*-nAChR blocker (α-Conotoxin MII) but low displacement by α6β2*-nAChR blocker (α-Conotoxin PIA), suggesting that IC3 measures α3β2*-nAChRs specific binding – a novel finding in living people. Loading coefficients of IC1 and IC2 were significantly lower in abstinent smokers compared to non-smokers. IC3 loading coefficients were significantly higher during extended smoking abstinence, and exploratory analyses suggested initial evidence for daily smoking amount correlating with nicotine dependence severity. These results could inform novel treatment development to help people quit smoking.

[11C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [11C]UCB-J reference region (CS2mL); however, due to its small volume, its high variability resulted in reduced reliability. Herein, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinson's disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n = 10 same-day and n = 20 longitudinal scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n = 25) and PD (n = 20); 10 mL was the optimal reference region volume, yielding [11C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10 mL: 1.2 ± 5.7%, same-day: CS2mL: -0.9 ± 9.2% longitudinal: 10 mL: 1.5 ± 7.0%, CS2mL: 1.6 ± 11.9%), while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10 mL, with greater effect size (Cohen's d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).

This study discusses social determinants of health and suicide risk in US military veterans.

Converging neuroimaging, genetic, and post-mortem evidence highlights the fundamental role of synaptic density reductions in schizophrenia pathogenesis. However, the brain-wide spatial pattern of these alterations and the mechanisms underlying this patterning remain to be established. Here, using [11C]UCB-J radiotracer positron emission tomography (PET) imaging in individuals with schizophrenia (n = 29) and healthy controls (n = 93), we find a prominent and widespread pattern of lower synaptic density (0.58 < Cohen's D < 1.47; pFWE < 0.05) in patients. The left hemisphere is substantially more impacted than the right (Cohen's D = 1.14; p < 0.001), with frontal, temporal, cingulate, thalamic, striatal and hippocampal areas particularly affected. Synaptic density alterations were not spatially aligned with grey matter volume alterations indexed using anatomical Magnetic Resonance Imaging. Lower synaptic density in the left hemisphere is associated with higher normative concentrations of GABAA/BZ, 5HT2A, mGluR5 and 5HT1B (rcca = 0.68; p = 0.022). Simulation-based network diffusion models identified regions that may represent the initial sources of pathology, nominating left inferior frontal areas (pFWE < 0.05) as potential foci from which synaptic pathology initiates and then propagates to structurally connected and molecularly similar areas. Overall, our findings provide in vivo evidence for widespread synaptic density deficits in schizophrenia that are left-lateralised, independent of grey matter volume alterations, aligned to specific neurochemical systems, and suggest that such synaptic pathology may propagate in a pattern consistent with axonal networks.

Bipolar disorder (BD) is a neuropsychiatric condition associated with affective and cognitive symptoms, impulsivity, and suicidality. The metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in BD, but the relationship between psychiatric medication use and mGlu5 availability remains unclear. Using [18F]FPEB positron emission tomography (PET), we measured mGlu5 in ventromedial prefrontal (vmPFC), orbitofrontal (OFC), and dorsolateral prefrontal (dlPFC) cortices, amygdala, and hippocampus in 48 individuals with BD (21 medicated) and 48 age and sex-matched healthy controls (HC). Group differences in mGlu5 availability were tested with analysis of covariance, controlling for cannabis and nicotine use. Clinical assessments of depression (MADRS), anhedonia (SHAPS), attention (Barratt Impulsiveness Scale), and cognition (Groton Maze Learning Test) were examined in relation to regional mGlu5 availability using linear regression. Significant group effects were observed across ROIs, showing lower mGlu5 in unmedicated BD relative to medicated BD and HC, with effects in the vmPFC (p = 0.003), OFC (p = 0.006), dlPFC (p = 0.007), amygdala (p = 0.009), and hippocampus (p = 0.010). Across the full sample, lower OFC mGlu5 was associated with poorer executive function (β = -0.25, p = 0.044). In unmedicated BD, lower mGlu5 correlated with greater attentional difficulties (r's = -0.52 - -0.54, all p's < 0.05). In medicated BD, worse anhedonia correlated with lower mGlu5 (r's = -0.41-0.43, all p's < 0.05). These associations remained statistically significant after adjustment for depressive symptom severity, nicotine, and cannabis use. Findings indicate that medication status is associated with differences in mGlu5 availability in BD. mGlu5 availability in medicated participants was closer to that of HC, supporting further investigation of glutamatergic mechanisms as potential therapeutic targets in BD.

Depression in Parkinson's disease is often reported as being more debilitating than the motor symptoms and has been shown to accelerate disease progression. Identifying its underlying neurobiology is crucial in the discovery of mechanism-informed treatments. We hypothesize that lower synaptic density in mood circuitry drives symptoms of depression in Parkinson's disease. To test this hypothesis, we used PET imaging and [11C]UCB-J-a radiotracer that binds to synaptic vesicle protein 2A (SV2A) to image synaptic density across patients with Parkinson's disease and depressive symptoms (PDd; n = 10), Parkinson's disease patients without depressive symptoms (PDnd; n = 20) and healthy controls (HCs; n = 18). The primary outcome was binding potential (BPND) in mood circuitry. Participants with PDd exhibited significantly lower synaptic density compared to HC and PDnd in the dorsolateral prefrontal cortex (dlPFC) (-22.0%, P < 0.001; -19.9%, P = 0.002), anterior cingulate cortex (ACC) (-27.9%, P < 0.001; -24.0%, P = 0.002), amygdala (-25.1%, P < 0.001; -18.9%, P = 0.006) and hippocampus (-28.1%, P < 0.001; -20.3%, P = 0.003). Synaptic density was significantly and negatively correlated with the severity of depressive symptoms across all participants with Parkinson's disease (n = 30) in the dlPFC (r = -0.59, P = 0.002), ACC (r = -0.68, P < 0.001), amygdala (r = -0.53, P = 0.004) and hippocampus (r = -0.56, P = 0.003). These findings provide the first in vivo evidence that lower synaptic density in mood-related brain regions may contribute to depression in Parkinson's disease. If confirmed, they would support the evaluation of interventions that target synaptic loss/induce synaptic plasticity in individuals with Parkinson's disease and comorbid depression.

Chronic pain (CP) is a significant source of personal and public health burden with high prevalence (up to one in five in the United States) and few safe, effective treatment options. This study examined relationships between metabotropic glutamate receptor 5 (mGlu5) availability and CP in vivo for the first time. A transdiagnostic sample of individuals (major depressive disorder; bipolar disorder; healthy controls; N = 112) with and without CP or acute pain completed clinical assessments and participated in an [18F]FPEB positron emission tomography (PET) scan. Results indicated that mGlu5 availability was 13.5-15.7% lower in individuals with pain relative to those with no pain (p's = -0.002-0.029) in brain regions implicated in the neurophysiology of pain. Results did not change when controlling for demographics or psychiatric diagnosis. Exploratory analyses demonstrated lower mGlu5 availability in individuals with CP (10.3-14.2% difference) or both acute and CP (15.9-21.1% difference) than those with acute pain only, suggesting specific associations between mGlu5 and CP. Individuals with pain reported more severe depression (p's = 0.008-0.022) and anxiety (p = 0.009), sleep disturbances (p < 0.001), and worse cognitive functioning (p's = 0.009-0.025). Across various regions, mGlu5 availability was negatively associated with depression (r's = -0.24-0.33), anxiety (r = -0.27), and executive dysfunction (r's = -0.24-0.33); mGlu5 was not related to sleep disturbance. This study demonstrated lower mGlu5 availability in individuals with pain across psychiatric groups and presents mGlu5 as a promising treatment target for pain with low abuse potential, warranting future research examining mGlu5 for pain reduction.

BACKGROUND: Borderline personality disorder (BPD) is a serious psychiatric condition that is associated with a high risk for suicide attempts (SAs) and death by suicide. However, relatively little is known about the pathophysiology of BPD. The metabotropic glutamate 5 receptor (mGlu5) has been specifically implicated in the pathophysiology of BPD and SAs, with more general roles in emotion regulation, social and cognitive functioning, and pain processing. Here, we examined the relationship between mGlu5 availability, BPD, and SAs in vivo for the first time. METHODS: Eighteen individuals with BPD, 18 healthy control participants matched on age, sex, and smoking status, and 18 clinical comparison control participants with major depressive disorder completed comprehensive clinical assessments and participated in an [18F]FPEB positron emission tomography scan to measure mGlu5 availability. The volume of distribution (VT) in the frontolimbic circuit implicated in BPD pathophysiology was the positron emission tomography outcome measure. RESULTS: We observed significantly higher frontolimbic mGlu5 availability in the BPD group than in both the healthy control group (p = .009, d = 0.84, 18.43% difference) and the major depressive disorder group (p = .03, d = 0.69, 15.21% difference). In the BPD, but not the major depressive disorder group, higher mGlu5 availability was also associated with a history of SAs (19-25% higher, ps = .02-.005). Furthermore, mGlu5 availability was positively correlated with risk factors for suicide (e.g., sexual victimization, perceived burdensomeness) in individuals with BPD and a history of SA. CONCLUSIONS: Results show higher mGlu5 availability in BPD and SA for the first time. Our preliminary findings suggest that mGlu5 may be a critical treatment target for BPD symptoms, including SAs, and warrant additional investigation in larger samples.

BACKGROUND: Preclinical research indicates that chronic stress can induce synaptic loss in corticolimbic brain regions regulating mood and cognition. Presynaptic density can now be measured in vivo using radioligands targeting synaptic vesicle protein 2A (SV2A) and positron emission tomography (PET). We conducted the first in vivo PET study to investigate chronic stress-induced synaptic density changes in rats and examined correlates with behavior and protein expression. METHODS: Male and female Long Evans rats were exposed to chronic unpredictable stress (CUS) (n = 24/sex) and compared with controls (n = 12/sex). Sucrose preference and novel object recognition (NOR) were used to assess stress-related behavioral phenotypes. PET with [18F]SynVesT-1 was used to measure synaptic density in a subset of rats (n = 8-9/group/sex). Prefrontal cortex (PFC) and hippocampal proteins were quantified via liquid chromatography-tandem mass spectrometry (n = 5/group/sex), followed by pathway analysis and linear regression to examine molecular profiles associated with CUS and correlated with synaptic density as measured by PET. RESULTS: Synaptic density was lower in the PFC of CUS rats relative to controls (d = 0.94, p = .012) and correlated with sucrose preference (r = 0.35, p = .042). Synaptic density was also lower in the hippocampus (d = 0.55, p = .017), which correlated with NOR (r = 0.35 p = .045). Differentially expressed proteins were enriched for transcriptional regulation and metabolic pathways. Proteins implicated in synaptogenesis and neurodegeneration were positively and negatively correlated, respectively, with synaptic density. CONCLUSIONS: We demonstrated that [18F]SynVesT-1 PET can be used for in vivo quantification of synaptic density in a rodent model of chronic stress. Therefore, this method can facilitate translational research investigating synaptic mechanisms in stress-related pathology and treatment response.

OBJECTIVE:Autism spectrum disorder is a prevalent and heterogeneous condition with features ranging from social and communication differences to sensory sensitivities. Differences in excitatory neurotransmission have been identified in autism, but the molecular underpinnings are poorly understood. To investigate the mechanism underlying these observed differences, the authors assessed glutamatergic receptor density in autistic adults using positron emission tomography (PET) and related it to a functional EEG measure of excitatory activity. METHODS:Metabotropic glutamate receptor 5 (mGlu5) availability was compared in autistic (N=16) and neurotypical (N=16) adults between 18 and 36 years of age, using the PET tracer 3-[18F]fluoro-5-(2-pyridinylethynyl) benzonitrile ([18F]FPEB). The PET outcome measure was volume of distribution (VT) computed with equilibrium analysis using a venous input function and partial volume correction. Group differences were quantified using mixed-model analyses. Heterogeneity was further parsed within the autistic group by quantifying the relationship between receptor availability and the slope of the EEG power spectrum, an index of excitatory-inhibitory balance. Correlations between EEG and VT were calculated using Spearman's rho. RESULTS:Across all brain regions, mGlu5 availability was significantly lower (by ~15%) in autistic relative to neurotypical control participants. Group differences were generally greatest in the cerebral cortex. Within the autistic group, mGlu5 availability in all regions was significantly correlated with the slope of the EEG (e.g., cerebral cortex, r=0.67), such that shallower slope was associated with lower mGlu5 availability. CONCLUSIONS:This brain-wide investigation of mGlu5 availability with PET revealed pervasive lower mGlu5 availability across multiple brain areas in autism. Additionally, multimethod analyses revealed associations with a noninvasive electrophysiological index of excitatory neurotransmission. These results indicate that lower brain-wide mGlu5 availability may represent a molecular mechanism underlying altered excitatory neurotransmission that has the potential to stratify the heterogeneous autism phenotype.

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 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 45.1 ± 16.9 years) participated in imaging, acute pain [cold pressor test (CPT)] and anxiety (State–Trait Anxiety Inventory) assessments. SV2A density was quantified as regional volumes of distribution (VT) using a one-tissue compartment model with a plasma input function. SV2A density was assessed in five regions of interest (ROIs) that were previously shown to be associated with pain: dorsolateral prefrontal cortex (DLPFC), amygdala, anterior cingulate cortex (ACC), fusiform gyrus, and cerebellum. Results State anxiety was positively correlated with pain sensitivity (r = 0.60, p=.004). Significant negative correlations were observed between pain sensitivity and SV2A density in cerebellum (r = -0.67, p=.001), fusiform gyrus (r = -0.66, p=.001), DLPFC (r = -0.63, p=.002), and ACC (r = -0.58, p=.006). Mediation analysis revealed a significant indirect effect of cerebellar synaptic density on pain sensitivity through state anxiety symptoms (B = -0.77, 95% CI [-1.89, -0.04]), accounting for 33% of the total effect. For the fusiform gyrus, the direct effect on pain sensitivity remained significant after controlling for anxiety symptoms (B = -1.67, p=.020), while the indirect effect through anxiety symptoms was not significant (B = -0.43, 95% CI [-1.44, 0.37]). Conclusion Results provide the first known in vivo evidence that lower synaptic (SV2A) density is associated with greater pain sensitivity, particularly in the fusiform gyrus and cerebellum. Mediation analyses revealed that state anxiety partially mediated the relationship between cerebellar synaptic density and pain sensitivity, while having an additive - but not mediating - effect on the relationship between fusiform synaptic density and pain sensitivity.

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 [11C]UCB-J radiotracer to reveal a prominent widespread pattern (p FWE < 0.05) of lower synaptic density in individuals with schizophrenia (n=29), compared to a large sample of healthy controls (n=93). We found that the spatial pattern of lower synaptic density in schizophrenia is spatially aligned (r cca = 0.67; p < 0.001) with higher normative distributions of GABAA/BZ, 5HT1B, 5HT2A, and 5HT6, and lower levels of CB1 and 5HT1A. Competing neighborhood deformation network models revealed that regional synaptic pathology strongly correlated with estimates predicted using a model constrained by both interregional structural connectivity and molecular similarity (.42 < r < .61; p FWE < 0.05). These data suggest that synaptic pathology in schizophrenia is jointly constrained by both global axonal connectivity and local molecular vulnerability. Simulation-based network diffusion models were used to identify regions that may represent the initial sources of pathology, nominating left prefrontal areas (p FWE < 0.05) as potential foci from which synaptic pathology initiates and propagates to molecularly similar areas. Overall, our findings provide in vivo evidence for widespread deficit in synaptic density in schizophrenia that is jointly constrained by axonal connectivity and molecular similarity between regions, and that synaptic deficits spread from initial source regions to axonally connected and molecularly similar territories.