@article{pmid42432829,

title = {Group Differences of Multiregion Glutamate Concentration in Clinical High Risk and Schizophrenia},

author = {Shue Kit Man and M Belen Blasco and Razieh Alemi and Samira Raminfard and Pablo M Rusjan and Jamie Near and Deepak K Sarpal and Romina Mizrahi},

doi = {10.1111/ejn.70626},

issn = {1460-9568},

year  = {2026},

date = {2026-07-01},

journal = {Eur J Neurosci},

volume = {64},

number = {1},

pages = {e70626},

abstract = {Glutamatergic changes are one of the characteristic features of psychotic disorders, with changes reported in their clinical high-risk states (CHR), first episode psychosis (FEP), and schizophrenia. Despite the abundance of literature using proton magnetic resonance (H-MRS) to quantify glutamate, the general pattern of changes across different brain regions is not well studied. We investigated the presence of diagnosis group effects on glutamate concentrations in 99 participants in the left dorsal lateral prefrontal cortex, anterior cingulate cortex, associative striatum, and hippocampus using H-MRS in individuals with CHR (n = 31), schizophrenia spectrum psychotic disorder individuals (SCZ) with minimal antipsychotic exposure (n = 30), and healthy controls (n = 38). H-MRS data were normalized against white matter, gray matter, and cerebrospinal fluid fractions within regions of interest (ROI) to quantify local glutamate concentration. Our results showed no significant group differences in glutamate concentration across the four ROIs. Exploratory analyses showed a significant relationship between region and positive symptom severity on glutamate concentration. Post hoc regression analyses revealed that higher positive symptom severity was significantly associated with higher hippocampal glutamate concentrations. We conclude that glutamate concentrations may be related to positive symptoms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42106478,

title = {PET imaging of FAAH in chronic Cannabis users: longitudinal assessment during short-term abstinence},

author = {Claudia Poluga and Shahtaj S Dheda and Nadia Boachie and Tina McCluskey and Lucas Narciso and Maia Zilberman and Cassie Côté and Marilyn A Huestis and Rachel F Tyndale and Stefan Kloiber and Nathan J Kolla and Pablo M Rusjan and Bernard Le Foll and Jerry J Warsh and Tony P George and Isabelle Boileau},

doi = {10.1038/s41386-026-02438-7},

issn = {1740-634X},

year  = {2026},

date = {2026-05-01},

journal = {Neuropsychopharmacology},

abstract = {Cannabis withdrawal in cannabis use disorder (CUD) increase the risk of relapse and lacks effective treatments. The endocannabinoid enzyme fatty acid amide hydrolase (FAAH) may influence cannabis use and withdrawal, but the relationship between FAAH levels and withdrawal symptoms remains unclear. This study aims to investigate changes in FAAH levels during short-term abstinence from cannabis and their relationship with withdrawal symptoms. FAAH levels were measured in whole-brain regions of interest using positron emission tomography (PET) with the FAAH-specific probe [C]CURB. An irreversible two-tissue compartment model determined [C]CURB binding. Participants with CUD were scanned once after overnight abstinence (T1) and ~3-7 days after monitored last use (T2). FAAH polymorphism (rs324420) was determined from blood samples, and mood, cognition, withdrawal symptoms, and craving were assessed. In a sample of 14 participants (N = 17 prior to attrition) who completed both scans, FAAH binding in whole-brain increased between T1 and T2 (n = 14; %ΔFAAH = 10%; p = 0.003), with the largest change in the ventral striatum (11%, p = 0.026). Increases in FAAH (%ΔFAAH whole-brain) were significantly associated with longer cannabis abstinence, greater baseline depression severity, and tendency to act without thinking (p < 0.001). Short-term cannabis abstinence is associated with increases in brain FAAH levels. These changes are linked to traits and symptoms associated with relapse vulnerability, including negative mood and impulsivity. These preliminary findings suggest that FAAH may play a key role in the neurobiological response to short-term abstinence and could represent a potential target for interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41291188,

title = {MAO-B status in alcohol use disorder: a [C]SL25.1188 PET imaging study of putative astrogliosis},

author = {Laura M Best and Jennifer Truong and Tina McCluskey and Jeffrey H Meyer and Pablo Rusjan and Shahtaj S Dheda and Jerlene Pandian and Vitor S Tardelli and Dafna Sara Rubin-Kahana and Shawn G Rhind and Bernard Le Foll and Jerry Warsh and Stephen J Kish and Isabelle Boileau},

doi = {10.1038/s41380-025-03355-9},

issn = {1476-5578},

year  = {2026},

date = {2026-04-01},

journal = {Mol Psychiatry},

volume = {31},

number = {4},

pages = {2191--2201},

abstract = {Chronic alcohol exposure may trigger astrogliosis-a process involving hypertrophy and upregulation of astrocyte-specific markers following neuronal stress or injury-as suggested by trends in preclinical studies. However, in vivo evidence of astrogliosis in alcohol use disorder (AUD) is lacking. Here, we investigated the status of the astrocyte marker MAO-B -an enzyme predominantly expressed in astrocytes and upregulated during astrogliosis - using [C]SL25.1188 positron emission tomography imaging in healthy controls (n = 28) and people with AUD after 3.5 ± 3.7 (n = 24) and 24 ± 7 days (in a subset: n = 8) of abstinence. Clinical symptoms of AUD were assessed, alongside peripheral markers of astrocyte activation and neuronal injury: glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L), respectively. While mean [C]SL25.1188 binding did not differ significantly between people with and without AUD at either abstinence time-point, binding was notably more variable in AUD and inversely correlated with AUD severity, withdrawal and anxiety (p < 0.05). Plasma GFAP and NF-L were elevated in people with AUD. Daily cigarette use was associated with lower [C]SL25.1188 binding in people with AUD (-40%) and control participants (-33%). These findings reflect variability in MAO-B binding in AUD and support a potential link between lower MAO-B and greater clinical severity. The observed association between cigarette use and lower MAO-B binding replicates prior reports and extends this observation to AUD. The relationship between higher MAO-B binding and lower AUD severity may reflect compensatory reactive astrogliosis. Understanding whether MAO-B status reflects a beneficial or detrimental astrocytic response in AUD may be important for glial-targeted treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41986308,

title = {Stress and synaptic density in psychosis and clinical high risk: evidence from [F]SynVesT-1 PET},

author = {M Belen Blasco and Kankana Nisha Aji and Christian Ramos-Jiménez and Daniel Chartrand and Chris Hung-Hsin Hsiao and Robert Hopewell and Gassan Massarweh and Johan Cohen and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1038/s41398-026-03993-9},

issn = {2158-3188},

year  = {2026},

date = {2026-04-01},

journal = {Transl Psychiatry},

volume = {16},

number = {1},

abstract = {Synaptic dysfunction is implicated in the pathophysiology of schizophrenia, and positron emission tomography (PET) studies demonstrate in vivo reductions in synaptic density across illness stages. Stress is a key modifiable risk factor, and while animal studies show it disrupts synaptic function, its effects on humans remain unclear. We examined the relationship between stress and synaptic density in individuals with first-episode psychosis (FEP) and those at clinical high risk (CHR). Seventy-eight participants, including 25 FEP, 32 CHR, and 21 healthy controls (HC), underwent 90-min [F]SynVesT-1 PET scans to quantify synaptic density measured as SV2A binding across prioritized brain regions. Stress-related measures included the Hassles and Uplifts Scale and the Trier Inventory for Chronic Stress (TICS). Depressive symptoms were evaluated using the Hamilton Depression Rating Scale (HDRS). Across all participants, greater acute stress was associated with lower [F]SynVesT-1 binding (F = 12.0, p < 0.001), with no significant group interaction (F = 2.44, p = 0.09). Group differences emerged for chronic stress and depressive symptoms (TICS × Group: F = 3.87, p = 0.02; sqHDRS × Group: F = 4.47, p = 0.01). Post hoc analyses revealed that higher chronic stress was associated with lower synaptic density in HC (F = 7.07, p = 0.009) but not in clinical groups. Lower mood symptoms were associated with lower synaptic density in FEP (F = 5.19, p = 0.02) only. These findings indicate that the relationship between stress and synaptic density differs between clinical and healthy groups. The changes in the relationship between stress and synaptic density in FEP may reflect impaired adaptive neuroplasticity, providing a potential mechanism by which stress contributes to psychosis vulnerability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41611659,

title = {Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development},

author = {Bernard Le Foll and Mickael Naassila and Jérôme Jeanblanc and Christian S Hendershot and Jesus Chavarria and Thierry Calmels and Stéphane Krief and Isabelle Berrebi-Bertrand and Marilyne Uguen and David Perrin and Xavier Ligneau and Isabelle Boileau and Pablo M Rusjan and Patricia Di Ciano and Pamela Sabioni and Marc Capet and Philippe Robert and Olivier Finance and Jeanne-Marie Lecomte and Jean Charles Schwartz},

doi = {10.1038/s41398-026-03807-y},

issn = {2158-3188},

year  = {2026},

date = {2026-01-01},

journal = {Transl Psychiatry},

volume = {16},

number = {1},

pages = {55},

abstract = {There is an important need to advance medication development for alcohol use disorder (AUD). BP1.3656B, a highly potent and selective histamine H3 receptor inverse agonist/antagonist, has been developed. Preclinical studies revealed high affinity, good pharmacokinetic profile, good brain penetration, and favorable safety. BP1.3656B reduced alcohol drinking and alcohol-seeking behavior in rodents. Phase I studies revealed good tolerability/pharmacokinetic in humans. Positron emission tomography revealed high brain occupancy in humans. Based on this favorable profile, two trials were conducted in subjects with AUD. In non-treatment seekers, BP1.3656B had no impact on intravenous alcohol self-administration (IV-ASA). A randomized clinical trial testing three doses of BP1.3656B versus placebo in treatment-seekers with AUD showed no reduction of heavy drinking days. Collective results illustrate the challenges inherent to clinical translation of AUD therapies, and reinforce the use of Phase IIa human laboratory paradigms as an important tool to de-risk translation of innovative drug targets for AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40158843,

title = {Fatty acid amide hydrolase in comorbid borderline personality disorder and major depressive disorder: Imaging with [C]CURB PET},

author = {Michelle A De Pol and Dorsa Rafiei and Jeffrey H Meyer and Kimberly L Desmond and Shelley McMain and Isabelle Boileau and Jerry Warsh and Pablo Rusjan and Christian Schmahl and Neil Vasdev and Lauren R Gray and Ryan Aloysius and Nathan J Kolla},

doi = {10.1016/j.neuropharm.2025.110436},

issn = {1873-7064},

year  = {2025},

date = {2025-08-01},

journal = {Neuropharmacology},

volume = {273},

pages = {110436},

abstract = {Borderline personality disorder (BPD) is highly comorbid with major depressive disorder (MDD), and the comorbid condition is associated with poorer treatment outcomes, which necessitates the investigation of transdiagnostic biomarkers. Previous research suggests that fatty acid amide hydrolase (FAAH), an endocannabinoid enzyme, is elevated in the prefrontal cortex (PFC) in BPD; however, no study has examined FAAH density in individuals with comorbid conditions. We hypothesized that FAAH level would be elevated in the prefrontal cortex, anterior cingulate cortex and hippocampus of comorbid BPD + MDD compared to healthy controls, as these brain regions are linked to the pathobiology of both disorders. For an exploratory analysis, we hypothesized that brain FAAH would be positively correlated with symptom severity, aggression, and impulsivity. Fifteen unmedicated BPD + MDD cases and 15 age- and sex-matched healthy controls underwent a [C]CURB positron emission tomography scan to measure λk, an index of available FAAH. No significant group differences in [C]CURB λk were observed between BPD + MDD patients and controls. Negative correlations were found between [C]CURB λk and physical aggression scores in the dorsolateral PFC (r = -0.64, p = 0.04), ventrolateral PFC (r = -0.75, p = 0.01), medial PFC (r = -0.64, p = 0.03), and orbitofrontal cortex (r = -0.66, p = 0.03) in the BPD + MDD group. A positive correlation was found between [C]CURB λk and impulsivity, as measured by the Barratt Impulsiveness Scale-11, in the ventrolateral PFC (r = 0.62, p = 0.04) of the BPD + MDD group. We suggest that the negative correlations between [C]CURB λk and physical aggression could reflect a relationship between FAAH and planned aggression whereas the latter findings may reflect a positive relationship with impulsivity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40550956,

title = {Fatty acid amide hydrolase in major depressive episodes: A [C]CURB positron emission tomography study},

author = {Dorsa Rafiei and Michelle De Pol and Jeffrey H Meyer and Kimberly Desmond and Ruth Ross and Isabelle Boileau and Jerry Warsh and Pablo Rusjan and Neil Vasdev and Ryan Aloysius and Lauren Gray and Nathan J Kolla},

doi = {10.1038/s41386-025-02150-y},

issn = {1740-634X},

year  = {2025},

date = {2025-06-01},

journal = {Neuropsychopharmacology},

abstract = {The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [C]CURB λk, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [C]CURB λk were observed between MDD participants and controls (F = 0.32; p = 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [C]CURB λk binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F = 6.75; p = 0.02). Depressive severity and anxiety did not have a significant relationship to [C]CURB λk binding. The relationship of greater fronto-limbic [C]CURB λk to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39632555,

title = {Impact of Stress on the Endocannabinoid System: A [C]-CURB Positron Emission Tomography Study in Early Psychosis: Les effets du stress sur le système endocannabinoïde : étude par tomographie par émission de positons avec l'indicateur radioactif [11C-CURB] dans la psychose précoce},

author = {Ana Weidenauer and Ranjini Garani and Paula Campos Oller and Maira Belén Blasco and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1177/07067437241300958},

issn = {1497-0015},

year  = {2025},

date = {2025-03-01},

journal = {Can J Psychiatry},

volume = {70},

number = {3},

pages = {251--259},

abstract = {BACKGROUND: Stress and traumatic experiences are well-established risk factors for psychiatric disorders. Stressful events can induce symptoms of anxiety and depression and may lead to overt psychosis, especially when there is an innate biological vulnerability. This study explores the role of the stress-regulating endocannabinoid system, specifically the activity of the enzyme fatty acid amid hydrolase (FAAH), a key regulatory enzyme for endocannabinoids, in association with stress by analysing data from healthy individuals and patients with psychosis.nnMETHODS: We performed a post-hoc exploratory analysis on 65 positron emission tomography scans using the selective FAAH radioligand [C]CURB, encompassing 30 patients with psychosis (6 female) and 35 healthy controls (19 female). The study aimed to examine the association between FAAH activity and stressful life events, assessed through the Recent Life Events, Survey of Life Experiences, and Hassles and Uplifts Scale.nnRESULTS: There was a significant difference regarding the number of recent stressors with higher levels in patients compared to healthy subjects (Survey of Life Experiences: = 4.88,  < 0.001, hassles: = 3.14,  = 0.003), however there was no significant relationship of brain FAAH activity and stressful life events in any of the applied scales across groups (Recent Life Events: = 0.07,  = 0.80; Survey of Life Experiences: = 1.75,  = 0.19; hassles: = 1.06,  = 0.31). Linear mixed models performed separately for each group revealed that there was a positive association between FAAH activity and Recent Life Events in patients with psychosis only (= 8.07,  = 0.009).nnCONCLUSIONS: Our data reveal a significant disparity in recent stressors between the two groups, and a correlation between brain FAAH activity and stressful life events in patients with psychosis only. This suggests a complex interplay between stress and the endocannabinoid system.nnPLAIN LANGUAGE SUMMARY TITLE: How Stress Affects the Brain’s Endocannabinoid System in Early Psychosis: A PET Study.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39535765,

title = {Synaptic Density in Early Stages of Psychosis and Clinical High Risk},

author = {M Belen Blasco and Kankana Nisha Aji and Christian Ramos-Jiménez and Ilana Ruth Leppert and Christine Lucas Tardif and Johan Cohen and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1001/jamapsychiatry.2024.3608},

issn = {2168-6238},

year  = {2025},

date = {2025-02-01},

journal = {JAMA Psychiatry},

volume = {82},

number = {2},

pages = {171--180},

abstract = {IMPORTANCE: Synaptic dysfunction is involved in schizophrenia pathophysiology. However, whether in vivo synaptic density is reduced in early stages of psychosis, including its high-risk states, remains unclear.nnOBJECTIVE: To investigate whether synaptic density (synaptic vesicle glycoprotein 2A [SV2A] binding potential) is reduced in first-episode psychosis (FEP) and in clinical high risk (CHR) and investigate the effect of cannabis use on synaptic density and examine its relationship with psychotic symptoms and gray matter microstructure across groups.nnDESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was performed in a tertiary care psychiatric hospital from July 2021 to October 2023. Participants were patients with antipsychotic-free or minimally exposed FEP or CHR and healthy controls with a clean urine drug screen (except cannabis).nnMAIN OUTCOMES AND MEASURES: Synaptic density was quantified with dynamic 90-minute [18F]SynVesT-1 positron emission tomography (PET) scans across prioritized brain regions of interest (ROIs) delineated in individual magnetic resonance images (MRIs). Cannabis use was confirmed with urine drug screens. Gray matter microstructure was assessed using diffusion-weighted MRI to estimate neurite density.nnRESULTS: A total of 49 participants were included, including 16 patients with FEP (mean [SD] age, 26.1 [4.6] years; 9 males and 7 females), 17 patients at CHR (mean [SD] age, 21.2 [3.5] years; 8 males and 9 females), and 16 healthy controls (mean [SD] age, 23.4 [3.6] years; 7 males and 9 females). Synaptic density was significantly different between groups (F2,273 = 4.02, P = .02, Cohen F = 0.17; ROI: F5,273 = 360.18, P < .01, Cohen F = 2.55) with a group × ROI interaction (F10,273 = 2.67, P < .01, Cohen F = 0.32). Synaptic density was lower in cannabis users (F1,272 = 5.31, P = .02, Cohen F = 0.14). Lower synaptic density across groups was associated with more negative symptoms (Positive and Negative Syndrome Scale negative scores: F1,81 = 4.31, P = .04, Cohen F = 0.23; Scale of Psychosis-Risk Symptoms negative scores: F1,90 = 4.12, P = .04, Cohen F = 0.21). SV2A binding potential was significantly associated with neurite density index (F1,138 = 6.76, P = .01, Cohen F = 0.22).nnCONCLUSIONS AND RELEVANCE: This study found that synaptic density reductions were present during the early stages of psychosis and its risk states and associated with negative symptoms. The implications of SV2A for negative symptoms in psychosis and CHR warrant further investigation. Future studies should investigate the impact of cannabis use on synaptic density in CHR longitudinally.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39729518,

title = {The Role of Fatty Acid Amide Hydrolase, a Key Regulatory Endocannabinoid Enzyme, in Domain-Specific Cognitive Performance in Psychosis},

author = {Ana Weidenauer and Ranjini Garani and Nittha Lalang and Jeremy Watts and Martin Lepage and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1093/schbul/sbae212},

issn = {1745-1701},

year  = {2024},

date = {2024-12-01},

journal = {Schizophr Bull},

abstract = {BACKGROUND AND HYPOTHESIS: Cognitive impairments are particularly disabling for patients with a psychotic disorder and often persist despite optimization of antipsychotic treatment. Thus, motivating an extension of the research focus on the endocannabinoid system. The aim of this study was to evaluate group differences in brain fatty acid amid hydrolase (FAAH), an endocannabinoid enzyme between first-episode psychosis (FEP), individuals with clinical high risk (CHR) for psychosis and healthy controls (HCs). Furthermore, to test the hypothesis that FAAH is linked with cognition using positron emission tomography (PET).nnSTUDY DESIGN: We analyzed 80 PET scans with the highly selective FAAH radioligand [11C]CURB, including 30 patients with FEP (6 female), 15 CHR (5 female), and 35 HC (19 female). The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Berg Card Sorting Test (BCST) were applied to test cognitive performance.nnSTUDY RESULTS: There was no difference in FAAH activity between groups (F2, 75 = 0.75, P = .48; Cohen's f = 0.141; small effect). Overall, there was a difference in the association between groups regarding FAAH activity and the domain visuospatial construction (F2, 72 = 4.67, P = .01; Cohen's f = .36; medium effect). Furthermore, across the sample, lower FAAH activity was associated with a higher percentage of perseverative responses (F1, 66 = 5.06, P = .03; Cohen's f = 0.28, medium effect).nnCONCLUSIONS: We report evidence for associations between endocannabinoid alterations in FEP and CHR with specific domains of cognition (visuospatial construction and perseverative response), not overall cognition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39511452,

title = {Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state},

author = {Kankana Nisha Aji and Nittha Lalang and Christian Ramos-Jiménez and Reza Rahimian and Naguib Mechawar and Gustavo Turecki and Daniel Chartrand and Isabelle Boileau and Jeffrey H Meyer and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1038/s41380-024-02816-x},

issn = {1476-5578},

year  = {2024},

date = {2024-11-01},

journal = {Mol Psychiatry},

abstract = {A novel radiotracer, [C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [C]SL25.1188, to measure MAO-B V, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B V (F = 4.56, p = 0.02, Cohen's f = 0.49), controlling for tobacco (F  = 5.37, p = 0.03) and cannabis use (F = 5.11, p = 0.03) with significantly lower MAO-B V in CHR compared to HV (Cohen's d = 0.99). We report a significant cannabis effect on MAO-B V (F = 12.57, p = 0.001, Cohen's f = 0.57), with a significant group-by-cannabis interaction (F = 3.82, p = 0.03, Cohen's f = 0.45), indicating lower MAO-B V in cannabis-using clinical groups. Lower MAO-B V levels were more robust in striatal than cortical regions, in both clinical groups (F = 2.08, p = 0.04, Cohen's f = 0.73) and in cannabis users (F = 6.42, p < 0.001, Cohen's f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39395470,

title = {Astrogliosis Marker [C]SL25.1188 After COVID-19 With Ongoing Depressive and Cognitive Symptoms},

author = {Joeffre Braga and Emily J Y Kuik and Mariel Lepra and Pablo M Rusjan and Stephen J Kish and Erica L Vieira and Zahra Nasser and Natasha Verhoeff and Neil Vasdev and Thomas Chao and Michael Bagby and Isabelle Boileau and Stefan Kloiber and M Ishrat Husain and Nathan Kolla and Yuko Koshimori and Khunsa Faiz and Wei Wang and Jeffrey H Meyer},

doi = {10.1016/j.biopsych.2024.09.027},

issn = {1873-2402},

year  = {2024},

date = {2024-10-01},

journal = {Biol Psychiatry},

abstract = {BACKGROUND: After acute COVID-19, 5% of people experience persistent depressive symptoms and reduced cognitive function (COVID-DC). Theoretical models propose that astrogliosis is important in long COVID, but measures primarily indicative of astrogliosis have not been studied in the brain of long COVID or COVID-DC. The objective of the current study was to measure [C]SL25.1188 total distribution volume ([C]SL25.1188 V), an index of monoamine oxidase B density and a marker of astrogliosis, with positron emission tomography in participants with COVID-DC and compare with healthy control participants.nnMETHODS: In 21 COVID-DC cases and 21 healthy control participants, [C]SL25.1188 V was measured in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum. Depressive symptoms were measured with the Beck Depression Inventory-II, and cognitive symptoms were measured with neuropsychological tests.nnRESULTS: [C]SL25.1188 V was higher in participants with COVID-DC in the prefrontal cortex, anterior cingulate cortex, hippocampus, dorsal putamen, and ventral striatum than in healthy control participants. Depressive symptom severity negatively correlated with [C]SL25.1188 V across prioritized brain regions. More recent acute COVID-19 positively correlated with [C]SL25.1188 V, reflecting higher values since predominance of the Omicron variant. Exploratory analyses found greater [C]SL25.1188 V in the hippocampus, dorsal putamen, and ventral striatum of COVID-DC participants than control participants with a major depressive episode with no history of COVID-19, and there was no relationship to cognitive testing in prioritized regions.nnCONCLUSIONS: Results strongly support the presence of monoamine oxidase B-labeled astrogliosis in COVID-DC throughout the regions assessed, although the association of greater astrogliosis with fewer symptoms raises the possibility of a protective role. The magnitude of astrogliosis in COVID-DC is greater since the emergence of the Omicron variant.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39037476,

title = {18F-Flortaucipir (AV1451) imaging identifies grey matter atrophy in retired athletes},

author = {Anna Vasilevskaya and Chloe Anastassiadis and Simrika Thapa and Foad Taghdiri and Mozhgan Khodadadi and Namita Multani and Pablo Rusjan and Miracle Ozzoude and Apameh Tarazi and Asma Mushtaque and Richard Wennberg and Sylvain Houle and Robin Green and Brenda Colella and Neil Vasdev and Kaj Blennow and Henrik Zetterberg and Thomas Karikari and Christine Sato and Danielle Moreno and Ekaterina Rogaeva and David Mikulis and Karen Deborah Davis and Charles Tator and Maria Carmela Tartaglia},

doi = {10.1007/s00415-024-12573-0},

issn = {1432-1459},

year  = {2024},

date = {2024-09-01},

journal = {J Neurol},

volume = {271},

number = {9},

pages = {6068--6079},

abstract = {BACKGROUND: The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed OBJECTIVE: This study aimed (1) to assess the association of imaging evidence of tau pathology with brain volumes in retired athletes and (2) to examine the relationship between tau-PET and neuropsychological functioning.nnMETHODS: Former contact sport athletes were recruited through the Canadian Football League Alumni Association or the Canadian Concussion Centre clinic. Athletes completed MRI, [F]flortaucipir tau-PET, and a neuropsychological battery. Memory composite was created by averaging the Rey Auditory Verbal Learning Test and Rey Visual Design Learning Test z-scores. Grey matter (GM) volumes were age/intracranial volume corrected using normal control MRIs. Tau-PET % positivity in GM was calculated as the number of positive voxels (≥ 1.3 standardized uptake value ratio (SUVR)/total voxels).nnRESULTS: 47 retired contact sport athletes negative for AD (age:51 ± 14; concussions/athlete:15 ± 2) and 54 normal controls (age:50 ± 13) were included. Tau-PET positive voxels had significantly lower GM volumes, compared to tau-PET negative voxels (- 0.37 ± 0.41 vs. - 0.31 ± 0.37, paired p = .006). There was a significant relationship between GM tau-PET % positivity and memory composite score (r =  - .366, p = .02), controlled for age, PET scanner, and PET scan duration. There was no relationship between tau-PET measures and concussion number, or years of sport played.nnCONCLUSION: A higher tau-PET signal was associated with reduced GM volumes and lower memory scores. Tau-PET may be useful for identifying those at risk for neurodegeneration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38495956,

title = {Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk},

author = {Kankana Nisha Aji and Giulia Cisbani and Ana Weidenauer and Alex Koppel and Sina Hafizi and Tania Da Silva and Michael Kiang and Pablo M Rusjan and Richard P Bazinet and Romina Mizrahi},

doi = {10.1016/j.bbih.2024.100742},

issn = {2666-3546},

year  = {2024},

date = {2024-05-01},

journal = {Brain Behav Immun Health},

volume = {37},

pages = {100742},

abstract = {Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37602426,

title = {Astrogliosis marker 11C-SL2511.88 PET in traumatic brain injury with persistent symptoms},

author = {Yuko Koshimori and Michael D Cusimano and Erica L Vieira and Pablo M Rusjan and Stephen J Kish and Neil Vasdev and Sho Moriguchi and Isabelle Boileau and Thomas Chao and Zahra Nasser and M Ishrat Husain and Khunsa Faiz and Joeffre Braga and Jeffrey H Meyer},

doi = {10.1093/brain/awad279},

issn = {1460-2156},

year  = {2023},

date = {2023-08-01},

journal = {Brain},

abstract = {Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B total distribution volume ([11C]SL25.1188 VT), an index of MAO-B density, was measured in 29 TBI and 29 similarly aged healthy control cases with [11C]SL25.1188 PET, prioritizing prefrontal cortex (PFC) and cortex proximal to cortical convexity. Correlations of PFC [11C]SL25.1188 VT with psychomotor and processing speed; and serum blood measures implicated in astrogliosis were determined. [11C]SL25.1188 VT was greater in TBI in PFC (P=0.00064) and cortex (P=0.00038). PFC [11C]SL25.1188 VT inversely correlated with Comprehensive Trail Making Test psychomotor and processing speed (r=-0.48, P=0.01). In participants scanned within two years of last TBI, PFC [11C]SL25.1188 VT correlated with serum glial fibrillary acid protein (r=0.51, P=0.037) and total tau (r=0.74, P=0.001). Elevated [11C]SL25.1188 VT argues strongly for astrogliosis and therapeutics modifying astrogliosis towards curative phenotypes should be tested in TBI with persistent symptoms. Given substantive effect size, astrogliosis PET markers should be applied to stratify cases and/or assess target engagement for putative therapeutics targeting astrogliosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37293440,

title = {Interaction between Peripheral and Central immune markers in Clinical High Risk for Psychosis},

author = {Kankana Nisha Aji and Sina Hafizi and Tania Da Silva and Michael Kiang and Pablo M Rusjan and Cynthia S Weickert and Romina Mizrahi},

doi = {10.1016/j.bbih.2023.100636},

issn = {2666-3546},

year  = {2023},

date = {2023-07-01},

journal = {Brain Behav Immun Health},

volume = {30},

pages = {100636},

abstract = {•Serum IL-8 levels are elevated in individuals at CHR for psychosis.•Positive association between elevated IL-8 and prodromal general symptom severity.•Inflammatory clusters (IL-1β, IL-2, IFN-γ) are identified (entire cohort and CHR).•TSPO levels did not differ between inflammatory clusters (entire cohort or CHR).•CRP, IL-1β, TNF-α and IFN-γ levels are the independent predictors of brain TSPO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37256580,

title = {Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms},

author = {Joeffre Braga and Mariel Lepra and Stephen J Kish and Pablo M Rusjan and Zahra Nasser and Natasha Verhoeff and Neil Vasdev and Michael Bagby and Isabelle Boileau and M Ishrat Husain and Nathan Kolla and Armando Garcia and Thomas Chao and Romina Mizrahi and Khunsa Faiz and Erica L Vieira and Jeffrey H Meyer},

doi = {10.1001/jamapsychiatry.2023.1321},

issn = {2168-6238},

year  = {2023},

date = {2023-05-01},

journal = {JAMA Psychiatry},

abstract = {IMPORTANCE: Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.nnOBJECTIVE: To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.nnDESIGN, SETTING, AND PARTICIPANTS: This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.nnMAIN OUTCOMES AND MEASURES: The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.nnRESULTS: The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).nnCONCLUSIONS AND RELEVANCE: In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36633702,

title = {Development of a minimally invasive simultaneous estimation method for quantifying translocator protein binding with [F]FEPPA positron emission tomography},

author = {Praveen Dassanayake and Udunna C Anazodo and Linshan Liu and Lucas Narciso and Maryssa Iacobelli and Justin Hicks and Pablo Rusjan and Elizabeth Finger and Keith St Lawrence},

doi = {10.1186/s13550-023-00950-1},

issn = {2191-219X},

year  = {2023},

date = {2023-01-01},

journal = {EJNMMI Res},

volume = {13},

number = {1},

pages = {1},

abstract = {BACKGROUND: The purpose of this study was to assess the feasibility of using a minimally invasive simultaneous estimation method (SIME) to quantify the binding of the 18-kDa translocator protein tracer [F]FEPPA. Arterial sampling was avoided by extracting an image-derived input function (IDIF) that was metabolite-corrected using venous blood samples. The possibility of reducing scan duration to 90 min from the recommended 2-3 h was investigated by assuming a uniform non-displaceable distribution volume (V) to simplify the SIME fitting.nnRESULTS: SIME was applied to retrospective data from healthy volunteers and was comprised of both high-affinity binders (HABs) and mixed-affinity binders (MABs). Estimates of global V and regional total distribution volume (V) from SIME were not significantly different from values obtained using a two-tissue compartment model (2CTM). Regional V estimates were greater for HABs compared to MABs for both the 2TCM and SIME, while the SIME estimates had lower inter-subject variability (41 ± 17% reduction). Binding potential (BP) values calculated from regional V and brain-wide V estimates were also greater for HABs, and reducing the scan time from 120 to 90 min had no significant effect on BP. The feasibility of using venous metabolite correction was evaluated in a large animal model involving a simultaneous collection of arterial and venous samples. Strong linear correlations were found between venous and arterial measurements of the blood-to-plasma ratio and the remaining [F]FEPPA fraction. Lastly, estimates of BP and the specific distribution volume (i.e., V = V - V) from a separate group of healthy volunteers (90 min scan time, venous-scaled IDIFs) agreed with estimates from the retrospective data for both genotypes.nnCONCLUSIONS: The results of this study demonstrate that accurate estimates of regional V, BP and V can be obtained by applying SIME to [F]FEPPA data. Furthermore, the application of SIME enabled the scan time to be reduced to 90 min, and the approach worked well with IDIFs that were scaled and metabolite-corrected using venous blood samples.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36928857,

title = {Monoamine Oxidase B (MAO-B): A Target for Rational Drug Development in Schizophrenia Using PET Imaging as an Example},

author = {Kankana Nisha Aji and Jeffrey H Meyer and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1007/978-3-031-21054-9_14},

issn = {2190-5215},

year  = {2023},

date = {2023-01-01},

journal = {Adv Neurobiol},

volume = {30},

pages = {335--362},

abstract = {Monoamine oxidase B (MAO-B) is an important high-density enzyme involved in the generation of oxidative stress and central in the catabolism of dopamine, particularly in brain subcortical regions with putative implications in the pathophysiology of schizophrenia. In this chapter, we review postmortem studies, preclinical models, and peripheral and genetic studies implicating MAO-B in psychosis. A literature search in PubMed was conducted and 64 studies were found to be eligible for systematic review. We found that MAO-B could be identified as a potential target in schizophrenia. Evidence comes mostly from studies of peripheral markers, showing reduced platelet MAO-B activity in schizophrenia, together with preclinical results from MAO-B knock-out mice resulting in a hyperdopaminergic state and behavioral disinhibition. However, whether brain MAO-B is altered in vivo in patients with schizophrenia remains unknown. We therefore review methodological studies involving MAO-B positron emission tomography (PET) radioligands used to quantify MAO-B in vivo in the human brain. Given the limitations of currently available treatments for schizophrenia, elucidating whether MAO-B could be used as a target for risk stratification or clinical staging in schizophrenia could allow for a rational search for newer antipsychotics and the development of new treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}