Antisocial personality disorder (ASPD) imposes a high societal burden given the repetitive reactive aggression that affected individuals perpetrate. Since the brain endocannabinoid system (ECS) has been implicated in ASPD and aggressive behavior, we utilized [11C]CURB positron emission tomography to investigate fatty acid amide hydrolase (FAAH), an enzyme of the ECS that degrades anandamide, in 16 individuals with ASPD and 16 control participants. We hypothesized that FAAH density would be lower in the amygdala for several reasons. First, decreased FAAH expression is associated with increased cannabinoid receptor 1 stimulation, which may be responsible for amygdala hyper-reactivity in reactive aggression. Second, the amygdala is the seat of the neural circuit mediating reactive aggression. Third, other PET studies of externalizing populations show reduced brain FAAH density. Conversely, we hypothesized that FAAH expression would be greater in the orbitofrontal cortex. Consistent with our hypothesis, we found that amygdala FAAH density was lower in the amygdala of ASPD (p = 0.013). Cerebellar and striatal FAAH expression were inversely related with impulsivity (cerebellum: r = −0.60, p = 0.017; dorsal caudate: r = −0.58, p = 0.023; dorsal putamen: r = −0.55, p = 0.034), while cerebellar FAAH density was also negatively associated with assaultive aggression (r = −0.54, p = 0.035). ASPD presents high levels of disruptive behavior with few, if any, efficacious treatment options. Novel therapeutics that increase FAAH brain levels in a region-specific manner could hold promise for attenuating certain symptom clusters of ASPD, although our results require replication.
Background: Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration.Methods: This study included 54 retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181. A portion (N=21) of retired athletes came for a 2-year follow-up visit. All participants had completed a neuropsychological battery and MRI imaging.Results: Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.945.08 pg/mL vs. 6.002.53 pg/mL; 95% CI 0.87-5.01; p=.02). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) and entorhinal volumes were significantly lower in high pTau181 compared to older healthy controls (1.570.19 vs. 2.020.32, p=.002; and 2.070.35 vs. 2.820.51, p=.003, respectively). Lower white matter integrity was observed in the high pTau181 group in comparison to healthy controls (CC medial diffusivity: 0.960.04 x10 -3 mm 2 /s vs. 0.900.03 x10 -3 mm 2 /s, p=.003; CC axial diffusivity: 1.490.04 x10 -3 mm 2 /s vs. 1.410.02 x10 -3 mm 2 /s, p<.001, respectively). Conclusions:Although high plasma pTau181 levels was associated with lower regional brain volumes and decreased white matter integrity, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white matter integrity in retired contact sport athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.
Gliosis is implicated in the pathophysiology of many neuropsychiatric diseases, including treatment-resistant major depressive disorder (TRD). Translocator protein total distribution volume (TSPO VT), a brain marker mainly reflective of gliosis in disease, can be measured using positron emission tomography (PET). Minocycline reduces gliosis and translocator protein binding in rodents, but this is not established in humans. Here, the ability of oral minocycline to reduce TSPO VT was assessed in TRD. To determine whether oral minocycline, as compared to placebo, can reduce prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula TSPO VT in TRD, twenty-one TRD participants underwent two [18F]FEPPA PET scans to measure TSPO VT. These were completed before and after either oral minocycline 100 mg bid or placebo which was administered in a randomized double-blinded fashion for 8 weeks. There was no significant difference between the minocycline and placebo groups on change in TSPO VT within the PFC, ACC, and insula (repeated measures ANOVA, effect of group interaction, PFC: F1,19 = 0.28, P = 0.60; ACC: F1,19 = 0.54, P = 0.47; insula F1,19 = 1.6, P = 0.22). Oral minocycline had no significant effect on TSPO VT which suggests that this dosage is insufficient to reduce gliosis in TRD. To target gliosis in TRD either alternative therapeutics or intravenous formulations of minocycline should be investigated. These results also suggest that across neuropsychiatric diseases in humans, it should be assumed that oral minocycline will not reduce TSPO VT or gliosis unless empirically demonstrated.
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 (F 1,26 = 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 λk 3 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.
Background: Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels as compared to healthy control subjects. Methods: PubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (V T ), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no-change of TSPO levels in patients as compared to healthy controls. Results: Five studies, with 75 patients with first-episode psychosis or schizophrenia and 77 healthy control subjects were included. BF showed strong support for lower patient V T relative to no-change (all BF>32) or relative to an increase (all BF>422) in all brain regions. From the posterior distributions, mean patient-control differences in standardized V T values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25). Discussion: The observed reduction of TPSO in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.Keywords: positron emission tomography, psychosis, schizophrenia, translocator protein, microglia, immuneactivation, meta-analysis *Corresponding author: pontus.plaven-sigray@ki.se. 1. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/228742 doi: bioRxiv preprint first posted online Dec. 5, 2017; IntroductionGenetic, epidemiological and biomolecular data suggest that the immune system is involved in the pathophysiology of schizophrenia (1-3). When translating these findings into clinical trials, initial studies have shown positive effect of medication targeting the immune system when used as addon treatment to antipsychotics (4-6). To aid further development of this therapeutic approach, tools for directly assessing the status of the brain immune system are needed to allow for patient stratification and monitoring of treatment effects.Using Positron Emission Tomography (PET), the localization and activation state of central nervous system (CNS) immune response modulators can be assessed with radioligands targeting the glial cell marker 18 kDa translocator protein (TSPO) (7-9). During the last decade, a handful of TSPO PET studies have been performed in patients with early-sta...
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