@article{pmid41935185,

title = {Local chemoarchitecture explains widespread lower cortical thickness associated with clinical high risk for psychosis},

author = {Xi Yang and Ingrid Agartz and Ole Andreassen and Peter Bachman and Inmaculada Baeza and Cali Bartholomeusz and Stefan Borgwardt and Sunah Choi and Tiziano Colibazzi and Rebecca Cooper and Cheryl Corcoran and Camilo de la Fuente-Sandoval and Bjørn Ebdrup and Adriana Fortea and Birte Yding Glenthøj and Louise Birkedal Glenthøj and Shalaila Haas and Holly Hamilton and Rebecca Hayes and Ying He and Karsten Heekeren and Wenche Ten Velden Hegelstad and Christine Hooker and Michael Kaess and Kiyoto Kasai and Naoyuki Katagiri and Minah Kim and Jochen Kindler and Shinsuke Koike and Tina Kristensen and Jun Soo Kwon and Stephen Lawrie and Jimmy Lee and Ashleigh Lin and Rachel Loewy and Daniel Mathalon and Patrick McGorry and Chantal Michel and Paul Møller and Takahiro Nemoto and Marta Pena and Jayachandra Raghava and Francisco Reyes-Madrigal and Luis Rivera-Chávez and Wulf Rössler and Daiki Sasabayashi and Ulrich Schall and Andre Schmidt and Lukasz Smigielski and Mikkel Sørensen and Gisela Sugranyes and Tsutomu Takahashi and Christian Tamnes and Jinsong Tang and Anastasia Theodoridou and Jordina Tor and Peter Uhlhaas and Tor Værnes and Esther Via and Sophia Vinogradov and James Waltz and Lars Westlye and Stephen Wood and Hidenori Yamasue and Alison Yung and Juan Zhou and Paolo Fusar-Poli and Romina Mizrahi and Vanessa Cropley and Paul Thompson and Therese van Amelsvoort and Maria Jalbrzikowski and Benjamin Becker and David E J Linden and Dennis Hernaus and },

doi = {10.1038/s41380-026-03586-4},

issn = {1476-5578},

year  = {2026},

date = {2026-08-01},

journal = {Mol Psychiatry},

volume = {31},

number = {8},

pages = {4716--4726},

abstract = {The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR Working Group's large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest predictors of lower CT in CHR and psychosis transition (total dominance range: 62-69% and 58-87%, respectively), with contributions of monoamine systems being especially sensitive to medication exposure (8-23% change in dominance range). Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and opioid systems (total dominance range: 60-81%), with contributions of histamine being sensitive to medication exposure (9-19% change in dominance range). Combined, these results uniquely identify specific neurochemical systems - particularly monoaminergic, glutamatergic, and GABAergic pathways - as key molecular mechanisms associated with cortical thinning in people at high risk of developing psychosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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{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{pmid41290713,

title = {Glutamate, NAA, and energy metabolism in clinical high risk and first episode psychosis},

author = {Bridget King and Matthew J Kempton and Shue Kit Man and Alice Egerton and Romina Mizrahi},

doi = {10.1038/s41598-025-22845-y},

issn = {2045-2322},

year  = {2025},

date = {2025-11-01},

journal = {Sci Rep},

volume = {15},

number = {1},

pages = {42031},

abstract = {Regulation of brain glutamate is closely related to brain energy metabolism. Changes in both central glutamatergic function and peripheral energy metabolism have been implicated in psychosis risk, onset and long-term illness, but there is a lack of empirical evidence to link these processes. We investigated the relationships between glutamate and N-acetyl-aspartate (NAA, a potential marker of neuronal metabolic integrity) in the anterior cingulate cortex (ACC), measured using proton magnetic resonance spectroscopy (H-MRS), and peripheral markers of energy metabolism (mitochondrial complex I-V content, pyruvate and lactate) in individuals either at clinical high risk for psychosis or in the first episode of psychosis (N = 36) and healthy controls (N = 20). ACC Glx (glutamate + glutamine) levels were positively related with principal components relating to mitochondrial complex content, and this relationship did not differ between groups. These findings are consistent with the importance of mitochondrial ATP generation in regulating glutamatergic neurotransmission. While we did not find evidence that this relationship is disrupted in clinical high risk or first episode psychosis, further work is required to understand the mechanisms linking glutamate and energy metabolism in psychosis, including studies in larger cohorts, later stages of illness or in individuals with greater illness burden.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41125743,

title = {Structural covariance network topology in individuals at clinical high risk for psychosis: the ENIGMA-CHR Study},

author = {Siwei Liu and Ingrid Agartz and Paul Allen and G Paul Amminger and Ole A Andreassen and Peter Bachman and Inmaculada Baeza and Helen Baldwin and Cali F Bartholomeusz and Stefan Borgwardt and Sabrina Catalano and Xiaogang Chen and Kang Ik K Cho and Sunah Choi and Tiziano Colibazzi and Rebecca E Cooper and Cheryl M Corcoran and Vanessa L Cropley and Lieuwe de Haan and Camilo de la Fuente-Sandoval and Montserrat Dolz and Bjørn H Ebdrup and Adriana Fortea and Paolo Fusar-Poli and Louise Birkedal Glenthøj and Birte Yding Glenthøj and Shalaila S Haas and Holly K Hamilton and Kristen M Haut and Rebecca A Hayes and Ying He and Karsten Heekeren and Wenche Ten Velden Hegelstad and Christine I Hooker and Leslie E Horton and Daniela Hubl and Wu Jeong Hwang and Michael Kaess and Kiyoto Kasai and Naoyuki Katagiri and Minah Kim and Jochen Kindler and Mallory J Klaunig and Shinsuke Koike and Tina D Kristensen and Yoo Bin Kwak and Jun Soo Kwon and Stephen M Lawrie and Irina Lebedeva and Imke Lj Lemmers-Jansen and Pablo León-Ortiz and Ashleigh Lin and Rachel L Loewy and Xiaoqian Ma and Daniel H Mathalon and Patrick McGorry and Philip McGuire and Chantal Michel and Romina Mizrahi and Masafumi Mizuno and Paul Møller and Ricardo Mora-Durán and Daniel Muñoz-Samons and Barnaby Nelson and Takahiro Nemoto and Merete Nordentoft and Dorte Nordholm and Maria A Omelchenko and Lijun Ouyang and Christos Pantelis and Jose C Pariente and Jayachandra M Raghava and Paul E Rasser and Franz Resch and Francisco Reyes-Madrigal and Luis F Rivera-Chávez and Jan I Røssberg and Wulf Rössler and Dean F Salisbury and Daiki Sasabayashi and Ulrich Schall and Jason Schiffman and Andre Schmidt and Lukasz Smigielski and Mikkel E Sørensen and Gisela Sugranyes and Michio Suzuki and Tsutomu Takahashi and Christian K Tamnes and Jinsong Tang and Anastasia Theodoridou and Sophia I Thomopoulos and Alexander S Tomyshev and Jordina Tor and Peter J Uhlhaas and Tor G Værnes and Therese Amj van Amelsvoort and Dennis Velakoulis and Esther Via and Sophia Vinogradov and James A Waltz and Christina Wenneberg and Lars T Westlye and Stephen J Wood and Hidenori Yamasue and Liu Yuan and Alison R Yung and Michael Wl Chee and Paul M Thompson and Dennis Hernaus and Maria Jalbrzikowski and Jimmy Lee and Juan H Zhou and },

doi = {10.1038/s41380-025-03304-6},

issn = {1476-5578},

year  = {2025},

date = {2025-10-01},

journal = {Mol Psychiatry},

abstract = {Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen's d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40440822,

title = {The inventory of psychotic-like anomalous self-experiences (IPASE): Stability and relationships with attenuated psychotic symptoms and remission in individuals at-risk for psychosis},

author = {Isabelle Scott and Alexandra Selloni and Zarina Bilgrami and Matthew Cotter and Cansu Sarac and Alessia McGowan and Marija Krcmar and Melanie Formica and Kate Gwyther and Cassandra Wannan and Agrima Srivastava and Guillermo A Cecchi and Romina Mizrahi and Patrick McGorry and Cheryl M Corcoran and Barnaby Nelson},

doi = {10.1016/j.schres.2025.05.003},

issn = {1573-2509},

year  = {2025},

date = {2025-07-01},

journal = {Schizophr Res},

volume = {281},

pages = {286--294},

abstract = {BACKGROUND: The IPASE is a self-report measure of basic self-disturbance, a core feature of schizophrenia and ultra-high risk (UHR) states. However, the extent to which basic self-disturbance-as captured by the IPASE-is stable over time and related to the severity or progression of attenuated psychotic symptoms (APS) remains unclear. We examined the temporal stability of IPASE scores, their correlation with APS, and whether they predict changes in APS over time.nnMETHODS: The baseline sample included 185 participants (healthy controls = 72, UHR = 66, first-episode psychosis = 47), with 29 UHR participants re-assessed at month-12. Correlations between IPASE scores and Comprehensive Assessment of At-Risk Mental States (CAARMS) positive symptom scores were evaluated at baseline and month-12. Stability between baseline and month-12 IPASE scores was examined in the longitudinal subsample. Regression was used to predict remission and change in CAARMS scores.nnRESULTS: Although mean IPASE scores were significantly higher in the UHR group compared to HCs, total IPASE scores were only weakly correlated with CAARMS total scores (ρ=0.27). IPASE subscales showed weak correlations (0.08<ρ<0.27) with CAARMS positive symptom domains. Changes in IPASE and CAARMS scores were not correlated. Moderate stability was found for IPASE total scores (ICC = 0.59) and four subscales (0.58 < ICC < 0.64), excluding the cognition subscale (ICC = 0.3). Baseline IPASE scores did not predict remission (partial R=0.05) or change in CAARMS scores (partial R=0.02).nnCONCLUSION: The IPASE is a moderately stable measure in UHR individuals, correlates with the presence of positive psychotic symptoms but only weakly with severity, and does not strongly predict positive symptom change.},

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{pmid38200701,

title = {Cannabis-induced psychotic disorder with onset during withdrawal: a brief report of emerging evidence},

author = {Johan Cohen and Hugues Petitjean and M Belen Blasco and Romina Mizrahi},

doi = {10.1017/neu.2023.60},

issn = {1601-5215},

year  = {2024},

date = {2024-10-01},

journal = {Acta Neuropsychiatr},

volume = {36},

number = {5},

pages = {325--329},

abstract = {OBJECTIVES: The link between cannabis use and psychotic symptoms or disorders is well known. However, the relation between cannabis withdrawal and psychotic symptoms is less studied.nnMETHODS: To our knowledge, this is the first publication of an observational systematic report of cannabis-induced psychotic disorder with onset during withdrawal. Here, we review patients presenting to a major emergency room in Montreal between January 2020 and September 2023 in a context of psychotic symptoms following cannabis cessation.nnRESULTS: In total, seven male and one female patients presented at the peak of cannabis withdrawal with acute psychotic symptoms, representing less than 1% of all emergency service admissions.nnCONCLUSIONS: We discuss current knowledge regarding the endocannabinoid system and dopamine homeostasis to formulate hypotheses regarding these observations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39404391,

title = {A Systematic Review of Delta-9-Tetrahydrocannabinol (∆9-THC) in Astrocytic Markers},

author = {Christian Ramos-Jiménez and Sarah Petkau and Romina Mizrahi},

doi = {10.3390/cells13191628},

issn = {2073-4409},

year  = {2024},

date = {2024-09-01},

journal = {Cells},

volume = {13},

number = {19},

abstract = {BACKGROUND: Astrocytic reactivity in substance use disorders (SUDs) has been extensively studied, yet the molecular effect of delta-9-tetrahydrocannabinol (∆9-THC, the main psychoactive compound in cannabis) on glial cells, especially astrocytes, remains poorly understood. Exploring ∆9-THC's impact on astrocytic markers can provide insight into its effects on brain functions such as homeostasis, synaptic transmission, and response to neuronal injury. This systematic review synthesizes findings from studies investigating ∆9-THC's impact on astrocytic markers.nnMETHODS: A systematic review was conducted using EMBASE, Medline, and PsychoInfo via the OvidSP platform. Studies reporting astrocytic markers following ∆9-THC exposure in animals and humans were included. Data were extracted from twelve eligible full-text articles, and the risk of bias was assessed using the Systematic Review Center for Laboratory Animal Experimentation.nnRESULTS: This research identified several astrocytic markers, including glial fibrillary acidic protein (GFAP), nestin, and glutamate-aspartate transporter (GLAST). Both GFAP and nestin expressions increased in adulthood following adolescence and adult ∆9-THC exposure. An increase in GLAST expression was also noted during early development after ∆9-THC exposure.nnCONCLUSIONS: This review indicates varying levels of astrocytic reactivity to ∆9-THC across different developmental stages, including adolescence and adulthood. ∆9-THC appears to impact maturation, particularly during early developmental stages, and exhibits sex-dependent effects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38332374,

title = {Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk},

author = {Yinghan Zhu and Norihide Maikusa and Joaquim Radua and Philipp G Sämann and Paolo Fusar-Poli and Ingrid Agartz and Ole A Andreassen and Peter Bachman and Inmaculada Baeza and Xiaogang Chen and Sunah Choi and Cheryl M Corcoran and Bjørn H Ebdrup and Adriana Fortea and Ranjini Rg Garani and Birte Yding Glenthøj and Louise Birkedal Glenthøj and Shalaila S Haas and Holly K Hamilton and Rebecca A Hayes and Ying He and Karsten Heekeren and Kiyoto Kasai and Naoyuki Katagiri and Minah Kim and Tina D Kristensen and Jun Soo Kwon and Stephen M Lawrie and Irina Lebedeva and Jimmy Lee and Rachel L Loewy and Daniel H Mathalon and Philip McGuire and Romina Mizrahi and Masafumi Mizuno and Paul Møller and Takahiro Nemoto and Dorte Nordholm and Maria A Omelchenko and Jayachandra M Raghava and Jan I Røssberg and Wulf Rössler and Dean F Salisbury and Daiki Sasabayashi and Lukasz Smigielski and Gisela Sugranyes and Tsutomu Takahashi and Christian K Tamnes and Jinsong Tang and Anastasia Theodoridou and Alexander S Tomyshev and Peter J Uhlhaas and Tor G Værnes and Therese A M J van Amelsvoort and James A Waltz and Lars T Westlye and Juan H Zhou and Paul M Thompson and Dennis Hernaus and Maria Jalbrzikowski and Shinsuke Koike and },

doi = {10.1038/s41380-024-02426-7},

issn = {1476-5578},

year  = {2024},

date = {2024-05-01},

journal = {Mol Psychiatry},

volume = {29},

number = {5},

pages = {1465--1477},

abstract = {Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.},

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{pmid37819650,

title = {Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis},

author = { and Shalaila S Haas and Ruiyang Ge and Ingrid Agartz and G Paul Amminger and Ole A Andreassen and Peter Bachman and Inmaculada Baeza and Sunah Choi and Tiziano Colibazzi and Vanessa L Cropley and Camilo de la Fuente-Sandoval and Bjørn H Ebdrup and Adriana Fortea and Paolo Fusar-Poli and Birte Yding Glenthøj and Louise Birkedal Glenthøj and Kristen M Haut and Rebecca A Hayes and Karsten Heekeren and Christine I Hooker and Wu Jeong Hwang and Neda Jahanshad and Michael Kaess and Kiyoto Kasai and Naoyuki Katagiri and Minah Kim and Jochen Kindler and Shinsuke Koike and Tina D Kristensen and Jun Soo Kwon and Stephen M Lawrie and Irina Lebedeva and Jimmy Lee and Imke L J Lemmers-Jansen and Ashleigh Lin and Xiaoqian Ma and Daniel H Mathalon and Philip McGuire and Chantal Michel and Romina Mizrahi and Masafumi Mizuno and Paul Møller and Ricardo Mora-Durán and Barnaby Nelson and Takahiro Nemoto and Merete Nordentoft and Dorte Nordholm and Maria A Omelchenko and Christos Pantelis and Jose C Pariente and Jayachandra M Raghava and Francisco Reyes-Madrigal and Jan I Røssberg and Wulf Rössler and Dean F Salisbury and Daiki Sasabayashi and Ulrich Schall and Lukasz Smigielski and Gisela Sugranyes and Michio Suzuki and Tsutomu Takahashi and Christian K Tamnes and Anastasia Theodoridou and Sophia I Thomopoulos and Paul M Thompson and Alexander S Tomyshev and Peter J Uhlhaas and Tor G Værnes and Therese A M J van Amelsvoort and Theo G M van Erp and James A Waltz and Christina Wenneberg and Lars T Westlye and Stephen J Wood and Juan H Zhou and Dennis Hernaus and Maria Jalbrzikowski and René S Kahn and Cheryl M Corcoran and Sophia Frangou},

doi = {10.1001/jamapsychiatry.2023.3850},

issn = {2168-6238},

year  = {2024},

date = {2024-01-01},

journal = {JAMA Psychiatry},

volume = {81},

number = {1},

pages = {77--88},

abstract = {IMPORTANCE: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals.nnOBJECTIVE: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder.nnDESIGN, SETTING, AND PARTICIPANTS: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022.nnMAIN OUTCOMES AND MEASURES: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores.nnRESULTS: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate).nnCONCLUSIONS AND RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37484195,

title = {C-Reactive protein and cognition: Mediation analyses with brain morphology in the UK Biobank},

author = {Daniel Mendelson and Romina Mizrahi and Martin Lepage and Katie M Lavigne},

doi = {10.1016/j.bbih.2023.100664},

issn = {2666-3546},

year  = {2023},

date = {2023-08-01},

journal = {Brain Behav Immun Health},

volume = {31},

pages = {100664},

abstract = {Cognitive impairments and abnormal immune activity are both associated with various clinical disorders. The association between C-Reactive protein (CRP), a marker associated with inflammation, and cognitive performance remains unclear. Further, mechanisms potentially linking CRP to cognition are not yet established. Brain structure may well mediate this relationship: immune processes play crucial roles in shaping and maintaining brain structure, with brain structure and function driving cognition. The United Kingdom Biobank (UKBB) is a large cohort study with extensive assessments, including high-sensitivity serum CRP levels, brain imaging, and various cognitive tasks. With data from 39,200 UKBB participants, we aimed first to determine the relationship between CRP and cognitive performance, and second, to assess metrics of brain morphology as potential mediators in this relationship. Participants were aged 40 to 70 at initial assessment and were mostly Caucasian. After accounting for potential covariates (e.g., age, sex, medical diagnoses, use of selective-serotonin reuptake inhibitors), we found CRP levels to have small, negative associations with fluid intelligence ( = -0.03, 95%CI[-0.05,-0.02], (14381) = -3.62,  = .004), and numeric memory ( = -0.03, 95%CI[-0.05,-0.01], (14366) = -3.31,  = .007). We found no evidence of brain morphology mediating these relationships (all || < 0.001, all  > .55). Our findings from this large sample suggest that serum-assessed CRP is of marginal importance for cognitive performance in mid-to-late aged Caucasians; the small effect sizes of statistically significant associations provide context to previous inconsistent results. The seeming lack of involvement of brain morphology suggests that other brain metrics (e.g., connectivity, functional activation) may be more pertinent to this relationship. Future work should also consider CRP levels measured in the central nervous system and/or other cytokines that may better predict cognitive performance in this population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37414359,

title = {Differential Expression of Anomalous Self-Experiences in Spontaneous Speech in Clinical High-Risk and Early-Course Psychosis Quantified by Natural Language Processing},

author = {Agrima Srivastava and Alexandria Selloni and Zarina R Bilgrami and Cansu Sarac and Alessia McGowan and Matthew Cotter and Johanna Bayer and Jessica Spark and Marija Krcmar and Melanie Formica and Kate Gwyther and Jessica Hartmann and Ezra Ellenberg and Andrea Polari and Patrick McGorry and Jai L Shah and Alison R Yung and Romina Mizrahi and Cheryl M Corcoran and Guillermo A Cecchi and Barnaby Nelson},

doi = {10.1016/j.bpsc.2023.06.007},

issn = {2451-9030},

year  = {2023},

date = {2023-07-01},

journal = {Biol Psychiatry Cogn Neurosci Neuroimaging},

abstract = {BACKGROUND: Basic self-disturbance, or anomalous self-experiences (ASEs), is a core feature of the schizophrenia spectrum. We propose a novel method of natural language processing to quantify ASEs in spoken language by direct comparison to an inventory of self-disturbance, the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). We hypothesized that there would be increased similarity in open-ended speech to the IPASE items in individuals with early-course psychosis (PSY) compared with healthy individuals, with clinical high-risk (CHR) individuals intermediate in similarity.nnMETHODS: Open-ended interviews were obtained from 170 healthy control participants, 167 CHR participants, and 89 PSY participants. We calculated the semantic similarity between IPASE items and "I" sentences from transcribed speech samples using S-BERT (Sentence Bidirectional Encoder Representation from Text). Kolmogorov-Smirnov tests were used to compare distributions across groups. A nonnegative matrix factorization of cosine similarity was performed to rank IPASE items.nnRESULTS: Spoken language of CHR individuals had the greatest semantic similarity to IPASE items when compared to both healthy control (s = 0.44, p < 10) and PSY (s = 0.36, p < 10) individuals, while IPASE scores were higher among PSY than CHR group participants. In addition, the nonnegative matrix factorization approach produced a data-driven domain that differentiated the CHR group from the others.nnCONCLUSIONS: We found that open-ended interviews elicited language with increased semantic similarity to the IPASE by participants in the CHR group compared with patients with psychosis. This demonstrates the utility of these methods for differentiating patients from healthy control participants. This complementary approach has the capacity to scale to large studies investigating phenomenological features of schizophrenia and potentially other clinical populations.},

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{pmid36815595,

title = {Does tobacco dependence worsen cannabis withdrawal in people with and without schizophrenia-spectrum disorders?},

author = {Zac J S Yeap and Justine Marsault and Tony P George and Romina Mizrahi and Rachel A Rabin},

doi = {10.1111/ajad.13394},

issn = {1521-0391},

year  = {2023},

date = {2023-07-01},

journal = {Am J Addict},

volume = {32},

number = {4},

pages = {367--375},

abstract = {BACKGROUND AND OBJECTIVES: Rates of cannabis use disorder (CUD) are higher in people with schizophrenia than in the general population. Irrespective of psychiatric diagnosis, tobacco co-use is prevalent in those with CUD and leads to poor cannabis cessation outcomes. The cannabis withdrawal syndrome is well-established and increases cannabis relapse risk. We investigated whether cannabis withdrawal severity differed as a function of high versus no/low tobacco dependence and psychiatric diagnosis in individuals with CUD.nnMETHOD: Men with CUD (N = 55) were parsed into four groups according to schizophrenia diagnosis and tobacco dependence severity using the Fagerstrom Test for Nicotine Dependence (FTND): men with schizophrenia with high tobacco dependence (SCT+, n = 13; FTND ≥ 5) and no/low tobacco dependence (SCT-, n = 22; FTND ≤ 4), and nonpsychiatric controls with high (CCT+, n = 7; FTND ≥ 5) and no/low (CCT-, n = 13; FTND ≤ 4) tobacco dependence. Participants completed the Marijuana Withdrawal Checklist following 12-h of cannabis abstinence.nnRESULTS: There was a significant main effect of tobacco dependence on cannabis withdrawal severity (p < .001). Individuals with high tobacco dependence had significantly greater cannabis withdrawal severity (M = 13.85 [6.8]) compared to individuals with no/low tobacco dependence (M = 6.49, [4.9]). Psychiatric diagnosis and the interaction effects were not significant. Lastly, cannabis withdrawal severity positively correlated with FTND (r = .41, p = .002).nnCONCLUSION AND SCIENTIFIC SIGNIFICANCE: Among individuals with CUD and high tobacco dependence, cannabis withdrawal severity was elevated twofold, irrespective of diagnosis, relative to individuals with CUD and no/low tobacco dependence. Findings from this study emphasize the importance of addressing tobacco co-use when treating CUD.},

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}

}