In vivo brain endocannabinoid metabolism is related to hippocampus glutamate and structure - a multimodal imaging study with PET, 1H-MRS, and MRI.

Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108-2114; Biol. Psychiatry 88 (9), 727-735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen's f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen's f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.

In vivo imaging translocator protein (TSPO) in autism spectrum disorder.

Converging evidence points to the significant involvement of the immune system in autism spectrum disorders (ASD). Positron emission tomography (PET) can quantify translocator protein 18 kDa (TSPO), a marker with increased expression mainly in microglia and, to some extent astroglia during neuropsychiatric diseases with inflammation. This preliminary analysis explored, for the first time, whether TSPO binding was altered in male and female participants with ASD in vivo using full kinetic quantification. Thirteen individuals with ASD (IQ > 70 [n = 12], IQ = 62 [n = 1]), 5 F, 25 ± 5 years) were scanned with [18F]FEPPA PET. Data from 13 typically developing control participants with matching age and TSPO rs6971 polymorphism (9 F, age 24 ± 5 years) were chosen from previous studies for comparison. The two tissue compartment model (2TCM) was used to determine the total volume of distribution ([18F]FEPPA VT) in four previously identified regions of interest (ROI): prefrontal, temporal, cerebellar, and anterior cingulate cortices. We observe no significant difference in [18F]FEPPA VT relative to controls (F(1,26)= 1.74, p = 0.20). However, 2 ASD participants with higher VT had concurrent major depressive episodes (MDE), which has been consistently reported during MDE. After excluding those 2 ASD participants, in a post-hoc analysis, our results show lower [18F]FEPPA VT in ASD participants compared to controls (F(1,24)= 6.62, p = 0.02). This preliminary analysis provides evidence suggesting an atypical neuroimmune state in ASD.

Fatty acid amide hydrolase is lower in young cannabis users.

We have recently shown that levels of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide, are lower in the brains of adult cannabis users (CUs) (34 ± 11 years of age), tested during early abstinence. Here, we examine replication of the lower FAAH levels in a separate, younger cohort (23 ± 5 years of age). Eighteen healthy volunteers (HVs) and fourteen CUs underwent a positron emission tomography scan using the FAAH radioligand [11 C]CURB. Regional [11 C]CURB binding was calculated using an irreversible two-tissue compartment model with a metabolite-corrected arterial plasma input function. The FAAH C385A genetic polymorphism (rs324420) was included as a covariate. All CUs underwent a urine screen to confirm recent cannabis use and had serum cannabinoids measured. One CU screened negative for cannabinoids via serum and was removed from analysis. All HVs reported less than five lifetime cannabis exposures more than a month prior to study initiation. There was a significant effect of group (F1,26 = 4.31; P = .048) when two A/A (rs324420) HVs were removed from analysis to match the genotype of the CU group (n = 16 HVs, n = 13 CUs). Overall, [11 C]CURB λk3 was 12% lower in CU compared with HV. Exploratory correlations showed that lower brain [11 C]CURB binding was related to greater use of cannabis throughout the past year. We confirmed our previous report and extended these findings by detecting lower [11 C]CURB binding in a younger cohort with less cumulative cannabis exposure.

Peripheral benzodiazepine receptor/18 kDa translocator protein positron emission tomography imaging in a rat model of acute brain injury.

OBJECTIVE: The activation of microglia in various brain pathologies is accompanied by an increase in the expression of peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO). However, whether activated microglia have a neuroprotective or neurotoxic effect on neurons in the brain is yet to be determined. In this study, we investigated the ability of the novel PBR/TSPO ligand FEPPA to detect activated microglia in an animal model of primary neurotoxic microglia activation. METHODS: [18F] FEPPA positron emission tomography (PET) imaging was performed before and after intraperitoneal administration of lipopolysaccharide (LPS) (LPS group) or saline (control group) in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Images were compared between these groups. After imaging, the brains were collected, and the activated microglia at the disease sites were analyzed by the expression of inflammatory cytokines and immunohistochemistry staining. These results were then comparatively examined with those obtained by PET imaging. RESULTS: In the unilateral 6-OHDA lesion rat model, the PBR/TSPO PET signal was significantly increased in the LPS group compared with the saline group. As the increased signal was observed 4 h after the injection, we considered it an acute response to brain injury. In the post-imaging pathological examination, activated microglia were found to be abundant at the site where strong signals were detected, and the expression of the inflammatory cytokines TNF-α and IL-1ß was increased. Intraperitoneal LPS administration further increased the expression of inflammatory cytokines, and the PBR/TSPO PET signal increased concurrently. The increase in inflammatory cytokine expression correlated with enhanced signal intensity. CONCLUSIONS: PET signal enhancement by PBR/TSPO at the site of brain injury correlated with the activation of microglia and production of inflammatory cytokines. Furthermore, because FEPPA enables the detection of neurotoxic microglia on PET images, we successfully constructed a novel PET detection system that can monitor neurodegenerative diseases.

Imaging Brain Fatty Acid Amide Hydrolase in Untreated Patients With Psychosis.

BACKGROUND: The brain's endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms. METHODS: Twenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [11C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function. RESULTS: FAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F1,62.85 = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69 = 12.42, p = .002; Cohen's f = 0.42, large effect). Shorter duration of illness (F1,26.95 = 13.78, p = .001; Cohen's f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95 = 6.03, p = .021, Cohen's f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62 = 175.85, p < 1 × 10-56; Cohen's f > 1). Overall, FAAH was higher in female subjects than in male subjects (F1,62.84 = 10.05, p = .002; Cohen's f = 0.37). CONCLUSIONS: This first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.

Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB.

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = -0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

Stress-induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis.

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBPND ) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11 C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND . Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth.

Replicating predictive serum correlates of greater translocator protein distribution volume in brain.

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO VT, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), and tumor necrosis factor alpha (TNFα)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO VT were measured in 3 cohorts: prefrontal cortex TSPO VT of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO VT of 20 subjects with obsessive-compulsive disorder. Ln(PGE2/CRP) and ln(TNFα/CRP) consistently correlated with TSPO VT (R2 = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO VT, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R2 = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO VT. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder: An [11C]SL25.1188 Positron Emission Tomography Study.

Importance: Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. Objective: To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. Design, Setting, and Participants: This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy. Main Outcomes and Measures: The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness. Results: Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. Conclusions and Relevance: Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Occupancy of dopamine D2 and D3 receptors by a novel D3 partial agonist BP1.4979: a [11C]-(+)-PHNO PET study in humans.

There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.

GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study.

BACKGROUND: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET). METHODS: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism. RESULTS: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (F1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC (F1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition. LIMITATIONS: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression. CONCLUSION: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.

Preliminary data indicating a connection between stress-induced prefrontal dopamine release and hippocampal TSPO expression in the psychosis spectrum.

Prolonged stress can cause neuronal loss in the hippocampus resulting in disinhibition of glutamatergic neurons proposed to enhance dopaminergic firing in subcortical regions including striatal areas. Supporting this, imaging studies show increased striatal dopamine release in response to psychosocial stress in healthy individuals with low childhood maternal care, individuals at clinical high risk for psychosis (CHR) and patients with schizophrenia. The prefrontal cortex (PFC) is connected to the hippocampus and a key region to control neurochemical responses to stressful stimuli. We recently reported a disrupted PFC dopamine-stress regulation in schizophrenia, which was intact in CHR. Given the available evidence on the link between psychosocial stress, PFC dopamine release and hippocampal immune activation in psychosis, we explored, for the first time in vivo, whether stress-induced PFC dopamine release is associated with hippocampal TSPO expression (a neuroimmune marker) in the psychosis spectrum. We used an overlapping sample of antipsychotic-naïve subjects with CHR (n = 6) and antipsychotic-free schizophrenia patients (n = 9) from our previously published studies, measuring PFC dopamine release induced by a psychosocial stress task with [11C]FLB457 positron emission tomography (PET) and TSPO expression with [18F]FEPPA PET. We observed that participants on the psychosis spectrum with lower stress-induced dopamine release in PFC had significantly higher TSPO expression in hippocampus (ß = -2.39, SE = 0.96, F(1,11) = 6.17, p = 0.030). Additionally, we report a positive association between stress-induced PFC dopamine release, controlled for hippocampal TSPO expression, and Global Assessment of Functioning. This is the first exploration of the relationship between PFC dopamine release and hippocampal TSPO expression in vivo in humans.

TSPO expression and brain structure in the psychosis spectrum.

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Interaction between TSPO-a neuroimmune marker-and redox status in clinical high risk for psychosis: a PET-MRS study.

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [18F]FEPPA, and 3T proton magnetic resonance spectroscopy (1H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F(4, 43) = 10.01, p < 0.001), with a significant group interaction (t = -2.10, p = 0.04), suggesting a different relation between [18F]FEPPA VT and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and [18F]FEPPA VT (r = -0.60, p = 0.006). We observed no significant group differences with respect to [18F]FEPPA VT or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.

Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study.

BACKGROUND: People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (VT), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure. METHODS: In this cross-sectional study, we recruited participants aged 18-75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using 18F-FEPPA PET to measure TSPO VT. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO VT, assessing their significance. FINDINGS: Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO VT (p<0·0001), as were total illness duration (p=0·0021) and duration of antidepressant exposure (p=0·037). The combination of these predictors accounted for about 50% of variance in TSPO VT in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO VT was 29-33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO VT was also 31-39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0·00047). INTERPRETATION: Microglial activation, as shown by TSPO VT, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a different illness phase. Consistent with this, the yearly increase in microglial activation is no longer evident when antidepressant treatment is given. FUNDING: Canadian Institutes of Health Research and Neuroscience Catalyst Fund.

Voxel level quantification of [11C]CURB, a radioligand for Fatty Acid Amide Hydrolase, using high resolution positron emission tomography.

[11C]CURB is a novel irreversible radioligand for imaging fatty acid amide hydrolase in the human brain. In the present work, we validate an algorithm for generating parametric map images of [11C]CURB acquired with a high resolution research tomograph (HRRT) scanner. This algorithm applies the basis function method on an irreversible two-tissue compartment model (k4 = 0) with arterial input function, i.e., BAFPIC. Monte Carlo simulations are employed to assess bias and variability of the binding macroparameters (Ki and λk3) as a function of the voxel noise level and the range of basis functions. The results show that for a [11C]CURB time activity curve with noise levels corresponding to a voxel of an image acquired with the HRRT and reconstructed with the filtered back projection algorithm, the implementation of BAFPIC requires the use of a constant vascular fraction of tissue (5%) and a cutoff for slow frequencies (0.06 min-1). With these settings, BAFPIC maintains the probabilistic distributions of the binding macroparameters with approximately Gaussian shape and minimizes the bias and variability for large physiological ranges of the rate constants of [11C]CURB. BAFPIC reduces the variability of Ki to a third of that given by Patlak plot, the standard graphical method for irreversible radioligands. Application to real data demonstrated an excellent correlation between region of interest and BAFPIC parametric data and agreed with the simulations results. Therefore, BAFPIC with a constant vascular fraction can be used to generate parametric maps of [11C]CURB images acquired with an HRRT provided that the limits of the basis functions are carefully selected.

Influence of Nicotine Metabolism Ratio on [11C]-(+)-PHNO PET Binding in Tobacco Smokers.

Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio. Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels. Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences. Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.

Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naïve Schizophrenia.

Background: Striatal dopamine (DA) synthesis capacity and release are elevated in schizophrenia (SCZ) and its putative prodrome, the clinical high risk (CHR) state. Striatal DA function results from the activity of midbrain DA neurons projecting mainly from the substantia nigra (SN). Elevated stress-induced DA release in SCZ and CHR was observed in the striatum; however, whether it is also elevated in the SN is unclear. The current study aims to determine whether nigral DA release in response to a validated stress task is altered in CHR and in antipsychotic-naïve SCZ. Further, we explore how DA release in the SN and striatum might be related. Methods: 24 CHR subjects, 9 antipsychotic-naïve SCZ and 25 healthy volunteers (HV) underwent 2 positron emission tomography (PET) scans using the DA D2/3 agonist radiotracer, [11C]-(+)-PHNO, which allows simultaneous investigations of DA in the SN and striatum. Psychosocial stress-induced DA release was estimated as the percentage differences in BPND (%[11C]-(+)-PHNO displacement) between stress and sensory-motor control sessions. Results: We observed a significant diagnostic group by session interaction, such that SCZ exhibited greater stress-induced [11C]-(+)-PHNO % displacement (25.90% ± 32.2%; mean ± SD), as compared to HVs (-10.94% ± 27.1%). Displacement in CHRs (-1.13% ± 32.2%) did not differ significantly from either HV or SCZ. Conclusion: Our findings suggest that elevated nigral DA responsiveness to stress is observed in antipsychotic-naïve SCZ.

Evaluation of a novel radiotracer for positron emission tomography imaging of reactive oxygen species in the central nervous system.

INTRODUCTION: Few, if any, radiotracers are available for the in vivo imaging of reactive oxygen species (ROS) in the central nervous system. ROS play a critical role in normal cell processes such as signaling and homeostasis but overproduction of ROS is implicated in several disorders. We describe here the radiosynthesis and initial ex vivo and in vivo evaluation of [11C]hydromethidine ([11C]HM) as a radiotracer to image ROS using positron emission tomography (PET). METHODS: [11C]HM and its deuterated isotopologue [11C](4) were produced using [11C]methyl triflate in a one-pot, two-step reaction and purified by high performance liquid chromatography. Ex vivo biodistribution studies were performed after tail vein injections of both radiotracers. To demonstrate sensitivity of uptake to ROS, [11C]HM was administered to rats treated systemically with lipopolysaccharide (LPS). In addition, ex vivo autoradiography and in vivo PET imaging were performed using [11C]HM on rats which had been microinjected with sodium nitroprusside (SNP) to induce ROS. RESULTS: [11C]HM and [11C](4) radiosyntheses were reliable and produced the radiotracers at high specific activities and radiochemical purities. Both radiotracers demonstrated good brain uptake and fast washout of radioactivity, but [11C](4) washout was faster. Pretreatment with LPS resulted in a significant increase in brain retention of radioactivity. Ex vivo autoradiography and PET imaging of rats unilaterally treated with microinjections of SNP demonstrated increased retention of radioactivity in the treated side of the brain. CONCLUSIONS: [11C]HM has the attributes of a radiotracer for PET imaging of ROS in the brain including good brain penetration and increased retention of radioactivity in animal models of oxidative stress.