Molecular Psychiatry最新文献

{"title":"Neuroimaging-derived biological brain age and its associations with glial reactivity and synaptic dysfunction cerebrospinal fluid biomarkers","authors":"Irene Cumplido-Mayoral, Gonzalo Sánchez-Benavides, Natalia Vilor-Tejedor, David López-Martos, Anna Brugulat-Serrat, Marta Milà-Alomà, Carles Falcon, Raffaele Cacciaglia, Carolina Minguillón, Karine Fauria, Gwendlyn Kollmorgen, Clara Quijano-Rubio, José Luis Molinuevo, Oriol Grau-Rivera, Marc Suárez-Calvet, Verónica Vilaplana, Juan Domingo Gispert","doi":"10.1038/s41380-025-02961-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02961-x","url":null,"abstract":"<p>Magnetic resonance Imaging (MRI)-derived brain-age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial reactivity and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer’s <i>continuum</i>, and if these mechanisms are differently associated with AD-related cortical atrophy. We further evaluated their effects on cognitive decline. We included 380 cognitively unimpaired individuals from the ALFA+ study, for which we computed their brain-age deltas by subtracting chronological age from their brain age predicted by machine learning algorithms. We studied the cross-sectional linear associations between brain-age delta and cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction (neurogranin, GAP43, synaptotagmin-1, SNAP25, and α-synuclein), glial reactivity (sTREM2, YKL-40, GFAP, and S100b) and inflammation (interleukin-6). We also studied the cross-sectional linear associations between AD signature and these CSF biomarkers, We further evaluated the mechanisms linking baseline brain-age delta and longitudinal cognitive decline by performing mediation analyses. To reproduce our findings on an independent cohort, we included 152 cognitively unimpaired and 310 mild cognitive impaired (MCI) individuals from the ADNI study. We found that higher CSF sTREM2 was associated with a younger brain-age after adjusting for AD pathology, both in ALFA+ cognitively unimpaired and in ADNI MCI individuals. Furthermore, we found that CSF sTREM2 fully mediated the link between older brain-age and cognitive decline in ALFA+. In summary, we showed that the protective microglial state reflected by higher CSF sTREM2 has a beneficial impact on biological brain aging that may partly explains the variability in cognitive decline in early AD stages, independently of AD pathology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"108 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transdiagnostic types of formal thought disorder and their association with gray matter brain structure: a model-based cluster analytic approach","authors":"Frederike Stein, Anna Merle Gudjons, Katharina Brosch, Luca Mira Keunecke, Julia-Katharina Pfarr, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Hanna Wersching, Adrian Wroblewski, Kira Flinkenflügel, Janik Goltermann, Dominik Grotegerd, Susanne Meinert, Katharina Thiel, Alexandra Winter, Nina Alexander, Tim Hahn, Hamidreza Jamalabadi, Andreas Jansen, Axel Krug, Igor Nenadić, Benjamin Straube, Udo Dannlowski, Tilo Kircher","doi":"10.1038/s41380-025-03009-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03009-w","url":null,"abstract":"<p>Formal thought disorder (FTD) is a complex syndrome affecting language and thought processes in psychotic and affective disorders. Clustering (i.e., identification of data-driven clinical subtypes) establishes latent (sub-) structures into psychopathological syndromes. A latent profile analysis (LPA) of FTD symptoms was conducted in 1 032 patients diagnosed with Schizophrenia-Spectrum-Disorders (n = 107), Major Depressive (n = 800), and Bipolar Disorder (n = 125). Clusters were compared for cognition and psychopathology. Associations with gray matter volume (GMV) and cortical surface (gyrification, cortical complexity, sucal depth) were explored using T1-weighted MRI data, analyzed with CAT12. Robustness-analyses in an age- and sex-matched subsample (n = 321) with the same n for each diagnosis (n = 107) were applied. LPA revealed 4 transdiagnostic clusters: <i>minimal</i> FTD, <i>poverty</i>, <i>inhibition</i>, <i>severe</i> FTD that remained stable in an age- and sex-matched subsample and in each diagnosis separately. Patients exhibiting <i>severe</i> FTD compared to <i>minimal</i> FTD showed GMV reductions in the right superior and middle frontal gyri. <i>Inhibition</i> showed a GMV reduction in the right inferior and middle temporal gyri, and fusiform gyrus compared with <i>minimal</i> and <i>severe</i> FTD. Sulcal depth was reduced around the left insula, superior temporal sulcus and temporal pole in the <i>poverty</i> cluster, and in the bilateral insula in the <i>severe</i> cluster, both compared to the <i>inhibition</i> cluster. No results for cortical thickness, gyrification, and complexity were found. Results from the total sample could be replicated in the matched subsample. Our results unravel the clinical heterogeneity of FTD psychopathology across affective and psychotic disorders. Associations of FTD clusters with neuroanatomical substrates imply language-related brain structures being involved in thought and language impairment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"34 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erasing “bad memories”: reversing aberrant synaptic plasticity as therapy for neurological and psychiatric disorders","authors":"Zhuoyue Shi, Kailong Wen, Nabilah H. Sammudin, Nicholas LoRocco, Xiaoxi Zhuang","doi":"10.1038/s41380-025-03013-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03013-0","url":null,"abstract":"<p>Dopamine modulates corticostriatal plasticity in both the direct and indirect pathways of the cortico-striato-thalamo-cortical (CSTC) loops. These gradual changes in corticostriatal synaptic strengths produce long-lasting changes in behavioral responses. Under normal conditions, these mechanisms enable the selection of the most appropriate responses while inhibiting others. However, under dysregulated dopamine conditions, including a lack of dopamine release or dopamine signaling, these mechanisms could lead to the selection of maladaptive responses and/or the inhibition of appropriate responses in an experience-dependent and task-specific manner. In this review, we propose that preventing or reversing such maladaptive synaptic strengths and erasing such aberrant “memories” could be a disease-modifying therapeutic strategy for many neurological and psychiatric disorders. We review evidence from Parkinson’s disease, drug-induced parkinsonism, L-DOPA-induced dyskinesia, obsessive-compulsive disorder, substance use disorders, and depression as well as research findings on animal disease models. Altogether, these studies allude to an emerging theme in translational neuroscience and promising new directions for therapy development. Specifically, we propose that combining pharmacotherapy with behavioral therapy or with deep brain stimulation (DBS) could potentially cause desired changes in specific neural circuits. If successful, one important advantage of correcting aberrant synaptic plasticity is long-lasting therapeutic effects even after treatment has ended. We will also discuss the potential molecular targets for these therapeutic approaches, including the cAMP pathway, proteins involved in synaptic plasticity as well as pathways involved in new protein synthesis. We place special emphasis on RNA binding proteins and epitranscriptomic mechanisms, as they represent a new frontier with the distinct advantage of rapidly and simultaneously altering the synthesis of many proteins locally.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"69 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant personal space is associated with paranoia, altered stress regulation, and unfavourable outcomes at 6 months’ follow-up in schizophrenia","authors":"Adamantini Hatzipanayioti, Sebastian Walther, Nicole Gangl, Frauke Conring, Florian Wüthrich, Katharina Stegmayer","doi":"10.1038/s41380-025-02999-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02999-x","url":null,"abstract":"<p>Paranoia is a central feature of schizophrenia and linked with poor outcomes. Paranoid experience is sometimes hard to identify in the clinical interview. In contrast, personal space (PS) measures detected patients with paranoia with excellent sensitivity and specificity. Here we test whether we can substantiate aberrant PS regulation in paranoia and whether PS was associated with stress markers and longitudinal outcomes. We included 144 participants (92 patients with schizophrenia spectrum disorders and 52 age and sex-matched healthy controls). We measured PS and stress markers during two behavioural tasks on interpersonal distance. In addition, we assessed social outcomes at baseline and after 6 months. Data corroborated that paranoia increased PS. Moreover, we confirmed that PS detected paranoia with excellent sensitivity (92%) at 1.1 m, and severe paranoia with 87% sensitivity and 81% specificity at 1.6 m. In addition, stress (Electrodermal activity) during the PS task was associated with paranoia and PS. Furthermore, higher stress at baseline predicted less improvement of social outcome after 6 months. Finally, improvement of PS over 6 months was associated with improvement of social functioning. PS may indeed serve as a simple bedside test for paranoia. Furthermore, results have direct implications in clinical practice as they suggest that it is advisable to maintain increased PS with paranoid patients. In addition, altered stress regulation and persistently increased PS may indicate unfavourable outcomes in the short-term follow-up. Thus, patients with persistently increased PS may benefit from special therapeutic attention.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linked emergence of racial disparities in mental health and epigenetic biological aging across childhood and adolescence","authors":"Muna Aikins, Yayouk Willems, Deniz Fraemke, Colter Mitchell, Bridget Goosby, Laurel Raffington","doi":"10.1038/s41380-025-03010-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03010-3","url":null,"abstract":"<p>Marginalization due to structural racism may confer an increased risk for aging-related diseases – in part – via effects on people’s mental health. Here we leverage a prospective birth cohort study to examine whether the emergence of racial disparities in mental health and DNA-methylation measures of biological aging (<i>i.e</i>., DunedinPACE, GrimAge Acceleration, PhenoAge Acceleration) are linked across childhood and adolescence. We further consider to what extent racial disparities are statistically accounted for by perinatal and postnatal factors in preregistered analyses of 4898 participants from the Future of Families &amp; Child Wellbeing Study, of which 2039 had repeated saliva DNA methylation at ages 9 and 15 years. We find that racially marginalized children had higher levels of externalizing and internalizing behaviors and diverging longitudinal internalizing slopes. Black compared to White identifying children, children living in more racially segregated neighborhoods, and racially marginalized children more affected by colorism tended to have higher age-9 levels of biological aging and more biological age acceleration over adolescence. Notably, longitudinal increases in internalizing and externalizing behavior were correlated with increases in biological aging. While racial and ethnic disparities in mental health were largely statistically accounted for by socioeconomic variables, differences in biological aging were often still visible after including potential mediating variables. These findings underscore the urgency for future research to consider biological aging processes from early life and collect more comprehensive measures of structural racism in developmental cohorts. Programs dedicated to advancing racial health equity must address the psychological and physical effects of structural racism on children and adolescents.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal microstructural changes following electroconvulsive therapy in severe depression","authors":"A. Le Berre, D. Attali, I. Uszynski, C. Debacker, M. Lui, S. Charron, M. Moyal, F. Ramon, A. Henensal, J. Benzakoun, L. Mekaoui, P. Gorwood, C. Poupon, A. Cachia, C. Oppenheim, M. Plaze","doi":"10.1038/s41380-025-03016-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03016-x","url":null,"abstract":"<p>Electroconvulsive therapy (ECT) induces hippocampal volume increases in depressed patients, potentially reflecting neuroplasticity. We hypothesized that Neurite Orientation Dispersion and Density Imaging (NODDI) could provide in vivo evidence of hippocampal neuroplasticity following ECT. This longitudinal study evaluated 43 depressed patients undergoing ECT and 24 controls. MRI and clinical assessments were performed at baseline (V1), after 5 sessions (V2), and post-treatment (V3). Evaluations included a 3 T MR-scan with 3DT1-weighted and multi-shell diffusion (b = 200/1500/2500 s/mm², 30/45/60directions) sequences. Q-ball, Diffusion Tensor, and NODDI models provided: axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), generalized FA (GFA), neurite density index (NDI), isotropic fraction (Fiso), and orientation dispersion index (ODI). FreeSurfer extracted whole hippocampal and subfield volumes from T1-weighted images. Longitudinal changes were assessed with linear mixed-effect models. 107 MRIs from patients and 24 MRIs from controls were analyzed. ECT induced significant bilateral hippocampal volume increases (<i>p</i> &lt; 0.001). Group comparisons showed consistently higher FA, lower GFA and ODI in patients compared to controls at all time-points. Following ECT, significant diffusion changes included decreased hippocampal GFA, FA, AD, MD and Fiso, along with increased ODI and NDI. NDI and Fiso changes were localized to the dentate gyrus but not the hippocampal tail. ECT responders showed a significant right hippocampal volume increase at V2 compared to non-responders. After ECT, hippocampal volume increases are accompanied by bilateral changes in NODDI parameters, particularly in the dentate gyrus, consistent with hippocampal neuroplasticity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype","authors":"Emily M. Teichman, Jianping Hu, Hsiao-yun Lin, Rachel L. Fisher-Foye, Anthony Blando, Xiaoping Hu, H. Ümit Kaniskan, Sarah E. Montgomery, Min Cai, Lyonna F. Parise, Jun Wang, Scott J. Russo, Ming-Hu Han, Jian Jin, Carole Morel","doi":"10.1038/s41380-025-02972-8","DOIUrl":"https://doi.org/10.1038/s41380-025-02972-8","url":null,"abstract":"<p>Major Depressive Disorder (MDD) is a devastating, multifactorial disease with limited pharmacological treatment options. Patients with MDD exhibit alterations in their dopamine (DA) signaling pathways through the midbrain ventral tegmental area (VTA). A similar observation is also detected in preclinical models of stress - mice exhibit behavioral and physiological impairments following chronic social defeat stress (CSDS). Prior studies demonstrate that CSDS-susceptible mice have increased VTA DA neuronal excitability, in part driven by an upregulation in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Inhibiting HCN channels with known inhibitors such as Cilobradine alleviates the negative behavioral effects of CSDS. Here, we aimed to identify Cilobradine analogs with improved neural tropism and inhibitory efficacy. Two compounds, <b>MS7710</b> and <b>MS7712</b>, differing by their left-hand side moieties, have a similar, potent inhibitory effect on VTA DA <i>I</i>_h currents as compared to Cilobradine, and a greater inhibitory effect than Cilobradine on VTA DA firing rate. We demonstrate that <b>MS7710</b> and <b>MS7712</b> have superior brain/plasma concentration ratios as compared to Cilobradine. They were efficacious at inhibiting VTA DA neuron firing rate and bursting activity in CSDS-susceptible male mice at lower doses than Cilobradine, which was recapitulated in female CSDS-susceptible mice with <b>MS7710</b>. Finally, we define that a single intraperitoneal injection of <b>MS7710</b> ameliorates CSDS-induced social interaction deficits and reward-associated cognitive inflexibility for at least two weeks in male and female mice. These findings yield a novel HCN channel inhibitor with improved neural tropism and stress-alleviating effects that could provide a basis for future antidepressant drug discovery.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"13 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor: Comments on 'Striking long-term beneficial effects of single-dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming' by Brownstien et al. (2024).","authors":"James J Gattuso, Carey Wilson, Anthony J Hannan, Thibault Renoir","doi":"10.1038/s41380-025-03005-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03005-0","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPRi-based screen of autism spectrum disorder risk genes in microglia uncovers roles of ADNP in microglia endocytosis and synaptic pruning","authors":"Olivia M. Teter, Amanda McQuade, Venus Hagan, Weiwei Liang, Nina M. Dräger, Sydney M. Sattler, Brandon B. Holmes, Vincent Cele Castillo, Vasileios Papakis, Kun Leng, Steven Boggess, Tomasz J. Nowakowski, James Wells, Martin Kampmann","doi":"10.1038/s41380-025-02997-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02997-z","url":null,"abstract":"<p>Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification of ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk genes alter development. Most functional genomics studies have focused on the role of these genes in neurons and neural progenitor cells. However, roles for ASD risk genes in other cell types are largely uncharacterized. There is evidence from postmortem tissue that microglia, the resident immune cells of the brain, appear activated in ASD. Here, we used CRISPRi-based functional genomics to systematically assess the impact of ASD risk gene knockdown on microglia activation and phagocytosis. We developed an iPSC-derived microglia-neuron coculture system and high-throughput flow cytometry readout for synaptic pruning to enable parallel CRISPRi-based screening of phagocytosis of beads, synaptosomes, and synaptic pruning. Our screen identified <i>ADNP</i>, a high-confidence ASD risk genes, as a modifier of microglial synaptic pruning. We found that microglia with ADNP loss have altered endocytic trafficking, remodeled proteomes, and increased motility in coculture.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"25 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Striatal dopamine tone is positively associated with adiposity in humans as determined by PET using dual dopamine type-2 receptor antagonist tracers","authors":"Valerie L. Darcey, Juen Guo, Meible Chi, Stephanie T. Chung, Amber B. Courville, Isabelle Gallagher, Peter Herscovitch, Rebecca Howard, Melissa La Noire, Lauren Milley, Alex Schick, Michael Stagliano, Sara Turner, Nicholas Urbanski, Shanna Yang, Eunha Yim, Nan Zhai, Megan S. Zhou, Kevin D. Hall","doi":"10.1038/s41380-025-02960-y","DOIUrl":"https://doi.org/10.1038/s41380-025-02960-y","url":null,"abstract":"<p>The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for &gt;20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [¹⁸F]fallypride and [¹¹C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20–44 kg/m²). Within-subject D2BP measurements using the two tracers were moderately correlated (r = 0.47, <i>p</i> &lt; 0.001). D2BP was negatively correlated with BMI as measured by [¹¹C]raclopride (r = −0.51; <i>p</i> &lt; 0.0001) but not [¹⁸F]fallypride (r = −0.01; <i>p</i> = 0.92) and these correlation coefficients were significantly different from each other (<i>p</i> &lt; 0.001). Given that [¹⁸F]fallypride has greater binding affinity to dopamine type-2 receptors than [¹¹C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.ClinicalTrials.gov Identifier: NCT03648892</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"59 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}