Pub Date : 2024-12-05DOI: 10.1038/s41380-024-02842-9
Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Niels Okkels, Laura Muñoz-Delgado, Jacob Horsager, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Elena Iglesias-Camacho, Manuela San-Eufrasio, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Fátima Carrillo, Juan Francisco Martín-Rodríguez, Florinda Roldan Lora, David García-Solís, Per Borghammer, Pablo Mir, Michel J. Grothe
Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [18F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [18F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R2 = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R2 = 0.16, p = 0.01). Topographic correspondence analysis with the [18F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.
FDG-PET的皮质代谢低下是帕金森病(PD)认知障碍的一种公认的神经成像生物标志物,但其病理生理起源尚不完全清楚。基底前脑胆碱能变性(cBF)是pd相关认知障碍的一个重要病理特征,可能通过皮质投射区胆碱能失神经支配导致皮质代谢降低。在这里,我们研究了95名患有不同程度认知障碍的PD参与者在3T-MRI上的分区域cBF体积、[18F]FDG-PET上的皮质低代谢和认知缺陷之间的体内关联。我们在第二组队列中通过[18F]FEOBV-PET突触前胆碱能末端密度成像进一步评估了脑血流相关低代谢的皮质模式与PD中胆碱能失神经控制模式的空间对应关系。脑后皮质突出区体积较低与广泛的新皮质低代谢显著相关[p(FDR) < 0.05],这介导了脑后皮质萎缩和认知障碍之间的关联(介导比例:43%,p < 0.001)。在联合模型中,脑皮质后部萎缩比皮质局部萎缩更能解释皮质代谢低下(R2 = 0.26, p < 0.001)的差异(R2 = 0.16, p = 0.01)。与[18F]FEOBV-PET模式的地形对应分析显示,在PD中表现出最明显的cbf相关低代谢的皮质区域与表现出最严重的胆碱能失神经支配的皮质区域相对应(Spearman 's ρ = 0.57, p < 0.001)。综上所述,PD后脑皮质萎缩与失神经皮质靶区代谢降低选择性相关,从而介导脑皮质萎缩对认知功能障碍的影响。这些数据首次提供了体内证据,证明胆碱能变性是帕金森病患者认知障碍基础上皮层代谢低下的主要病理关联。
{"title":"Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy","authors":"Miguel A. Labrador-Espinosa, Jesús Silva-Rodriguez, Niels Okkels, Laura Muñoz-Delgado, Jacob Horsager, Sandra Castro-Labrador, Pablo Franco-Rosado, Ana María Castellano-Guerrero, Elena Iglesias-Camacho, Manuela San-Eufrasio, Daniel Macías-García, Silvia Jesús, Astrid Adarmes-Gómez, Elena Ojeda-Lepe, Fátima Carrillo, Juan Francisco Martín-Rodríguez, Florinda Roldan Lora, David García-Solís, Per Borghammer, Pablo Mir, Michel J. Grothe","doi":"10.1038/s41380-024-02842-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02842-9","url":null,"abstract":"<p>Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [<sup>18</sup>F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [<sup>18</sup>F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [<i>p</i>(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, <i>p</i> < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (<i>R</i><sup>2</sup> = 0.26, <i>p</i> < 0.001) than local atrophy in the cortical areas themselves (<i>R</i><sup>2</sup> = 0.16, <i>p</i> = 0.01). Topographic correspondence analysis with the [<sup>18</sup>F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s <i>ρ</i> = 0.57, <i>p</i> < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"199 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776891","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}
Pub Date : 2024-12-05DOI: 10.1038/s41380-024-02861-6
Hans-Gert Bernstein, Madeleine Nussbaumer, Veronika Vasilevska, Henrik Dobrowolny, Thomas Nickl-Jockschat, Paul C. Guest, Johann Steiner
Dysfunctional glial cells play a pre-eminent role in schizophrenia pathophysiology. Post-mortem studies have provided evidence for significantly decreased glial cell numbers in different brain regions of individuals with schizophrenia. Reduced glial cell numbers are most pronounced in oligodendroglia, but reduced astrocyte cell densities have also been reported. This review highlights that oligo- and astroglial deficits are a key histopathological feature in schizophrenia, distinct from typical changes seen in neurodegenerative disorders. Significant deficits of oligodendrocytes in schizophrenia may arise in two ways: (i) demise of mature functionally compromised oligodendrocytes; and (ii) lack of mature oligodendrocytes due to failed maturation of progenitor cells. We also analyse in detail the controversy regarding deficits of astrocytes. Regardless of their origin, glial cell deficits have several pathophysiological consequences. Among these, myelination deficits due to a reduced number of oligodendrocytes may be the most important factor, resulting in the disconnectivity between neurons and different brain regions observed in schizophrenia. When glial cells die, it appears to be through degeneration, a process which is basically reversible. Thus, therapeutic interventions that (i) help rescue glial cells (ii) or improve their maturation might be a viable option. Since antipsychotic treatment alone does not seem to prevent glial cell loss or maturation deficits, there is intense search for new therapeutic options. Current proposals range from the application of antidepressants and other chemical agents as well as physical exercise to engrafting healthy glial cells into brains of schizophrenia patients.
{"title":"Glial cell deficits are a key feature of schizophrenia: implications for neuronal circuit maintenance and histological differentiation from classical neurodegeneration","authors":"Hans-Gert Bernstein, Madeleine Nussbaumer, Veronika Vasilevska, Henrik Dobrowolny, Thomas Nickl-Jockschat, Paul C. Guest, Johann Steiner","doi":"10.1038/s41380-024-02861-6","DOIUrl":"https://doi.org/10.1038/s41380-024-02861-6","url":null,"abstract":"<p>Dysfunctional glial cells play a pre-eminent role in schizophrenia pathophysiology. Post-mortem studies have provided evidence for significantly decreased glial cell numbers in different brain regions of individuals with schizophrenia. Reduced glial cell numbers are most pronounced in oligodendroglia, but reduced astrocyte cell densities have also been reported. This review highlights that oligo- and astroglial deficits are a key histopathological feature in schizophrenia, distinct from typical changes seen in neurodegenerative disorders. Significant deficits of oligodendrocytes in schizophrenia may arise in two ways: (i) demise of mature functionally compromised oligodendrocytes; and (ii) lack of mature oligodendrocytes due to failed maturation of progenitor cells. We also analyse in detail the controversy regarding deficits of astrocytes. Regardless of their origin, glial cell deficits have several pathophysiological consequences. Among these, myelination deficits due to a reduced number of oligodendrocytes may be the most important factor, resulting in the disconnectivity between neurons and different brain regions observed in schizophrenia. When glial cells die, it appears to be through degeneration, a process which is basically reversible. Thus, therapeutic interventions that (i) help rescue glial cells (ii) or improve their maturation might be a viable option. Since antipsychotic treatment alone does not seem to prevent glial cell loss or maturation deficits, there is intense search for new therapeutic options. Current proposals range from the application of antidepressants and other chemical agents as well as physical exercise to engrafting healthy glial cells into brains of schizophrenia patients.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"27 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782525","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}
Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the in-utero environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.
Methods
The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.
Results
Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.
Conclusions
Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.
{"title":"From placenta to the foetus: a systematic review of in vitro models of stress- and inflammation-induced depression in pregnancy","authors":"Madeline Kirkpatrick, Gargi Mandal, Ismail Elhadidy, Nicole Mariani, Kristi Priestley, Carmine M. Pariante, Alessandra Borsini","doi":"10.1038/s41380-024-02866-1","DOIUrl":"https://doi.org/10.1038/s41380-024-02866-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the <i>in-utero</i> environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"31 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782527","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}
Pub Date : 2024-12-05DOI: 10.1038/s41380-024-02865-2
Junyeop Daniel Roh, Mihyun Bae, Hyosang Kim, Yeji Yang, Yeunkeum Lee, Yisul Cho, Suho Lee, Yan Li, Esther Yang, Hyunjee Jang, Hyeonji Kim, Hyun Kim, Hyojin Kang, Jacob Ellegood, Jason P. Lerch, Yong Chul Bae, Jin Young Kim, Eunjoon Kim
Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.
{"title":"Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice","authors":"Junyeop Daniel Roh, Mihyun Bae, Hyosang Kim, Yeji Yang, Yeunkeum Lee, Yisul Cho, Suho Lee, Yan Li, Esther Yang, Hyunjee Jang, Hyeonji Kim, Hyun Kim, Hyojin Kang, Jacob Ellegood, Jason P. Lerch, Yong Chul Bae, Jin Young Kim, Eunjoon Kim","doi":"10.1038/s41380-024-02865-2","DOIUrl":"https://doi.org/10.1038/s41380-024-02865-2","url":null,"abstract":"<p>Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of <i>Dyrk1a</i> in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human <i>DYRK1A</i> mutations remain uncharacterized in mice. Here, we generated and studied <i>Dyrk1a</i>-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776843","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}
Pub Date : 2024-12-04DOI: 10.1038/s41380-024-02838-5
Julie Le Borgne, Lissette Gomez, Sami Heikkinen, Najaf Amin, Shahzad Ahmad, Seung Hoan Choi, Joshua Bis, Benjamin Grenier-Boley, Omar Garcia Rodriguez, Luca Kleineidam, Juan Young, Kumar Parijat Tripathi, Lily Wang, Achintya Varma, Rafael Campos-Martin, Sven van der Lee, Vincent Damotte, Itziar de Rojas, Sagnik Palmal, Richard Lipton, Eric Reiman, Ann McKee, Philip De Jager, William Bush, Scott Small, Allan Levey, Andrew Saykin, Tatiana Foroud, Marilyn Albert, Bradley Hyman, Ronald Petersen, Steven Younkin, Mary Sano, Thomas Wisniewski, Robert Vassar, Julie Schneider, Victor Henderson, Erik Roberson, Charles DeCarli, Frank LaFerla, James Brewer, Russell Swerdlow, Linda Van Eldik, Kara Hamilton-Nelson, Henry Paulson, Adam Naj, Oscar Lopez, Helena Chui, Paul Crane, Thomas Grabowski, Walter Kukull, Sanjay Asthana, Suzanne Craft, Stephen Strittmatter, Carlos Cruchaga, James Leverenz, Alison Goate, M. Ilyas Kamboh, Peter St George-Hyslop, Otto Valladares, Amanda Kuzma, Laura Cantwell, Matthias Riemenschneider, John Morris, Susan Slifer, Carolina Dalmasso, Atahualpa Castillo, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J. Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M. Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Alexandre de Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Jesper Qvist Thomassen, Yolande A. L. Pijnenburg, Henne Holstege, John van Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Jean-François Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Paola Bossù, Carlo Masullo, Giacomina Rossi, Frank Jessen, Victoria Fernandez, Patrick Gavin Kehoe, Ruth Frikke-Schmidt, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Jonathan Haines, Lindsay Farrer, Richard Mayeux, Li-San Wang, Rebecca Sims, Anita DeStefano, Gerard D. Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Wiesje van der Flier, Alfredo Ramirez, Margaret Pericak-Vance, Ole A. Andreassen, Cornelia Van Duijn, Mikko Hiltunen, Agustín Ruiz, Josée Dupuis, Eden Martin, Jean-Charles Lambert, Brian Kunkle, Céline Bellenguez
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10−8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10−6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
{"title":"X‐chromosome-wide association study for Alzheimer’s disease","authors":"Julie Le Borgne, Lissette Gomez, Sami Heikkinen, Najaf Amin, Shahzad Ahmad, Seung Hoan Choi, Joshua Bis, Benjamin Grenier-Boley, Omar Garcia Rodriguez, Luca Kleineidam, Juan Young, Kumar Parijat Tripathi, Lily Wang, Achintya Varma, Rafael Campos-Martin, Sven van der Lee, Vincent Damotte, Itziar de Rojas, Sagnik Palmal, Richard Lipton, Eric Reiman, Ann McKee, Philip De Jager, William Bush, Scott Small, Allan Levey, Andrew Saykin, Tatiana Foroud, Marilyn Albert, Bradley Hyman, Ronald Petersen, Steven Younkin, Mary Sano, Thomas Wisniewski, Robert Vassar, Julie Schneider, Victor Henderson, Erik Roberson, Charles DeCarli, Frank LaFerla, James Brewer, Russell Swerdlow, Linda Van Eldik, Kara Hamilton-Nelson, Henry Paulson, Adam Naj, Oscar Lopez, Helena Chui, Paul Crane, Thomas Grabowski, Walter Kukull, Sanjay Asthana, Suzanne Craft, Stephen Strittmatter, Carlos Cruchaga, James Leverenz, Alison Goate, M. Ilyas Kamboh, Peter St George-Hyslop, Otto Valladares, Amanda Kuzma, Laura Cantwell, Matthias Riemenschneider, John Morris, Susan Slifer, Carolina Dalmasso, Atahualpa Castillo, Fahri Küçükali, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J. Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Mercè Boada, Pablo García-González, Raquel Puerta, Pablo Mir, Luis M. Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Jose Luís Royo, Eloy Rodriguez-Rodriguez, Hilkka Soininen, Alexandre de Mendonça, Shima Mehrabian, Latchezar Traykov, Jakub Hort, Martin Vyhnalek, Jesper Qvist Thomassen, Yolande A. L. Pijnenburg, Henne Holstege, John van Swieten, Inez Ramakers, Frans Verhey, Philip Scheltens, Caroline Graff, Goran Papenberg, Vilmantas Giedraitis, Anne Boland, Jean-François Deleuze, Gael Nicolas, Carole Dufouil, Florence Pasquier, Olivier Hanon, Stéphanie Debette, Edna Grünblatt, Julius Popp, Roberta Ghidoni, Daniela Galimberti, Beatrice Arosio, Patrizia Mecocci, Vincenzo Solfrizzi, Lucilla Parnetti, Alessio Squassina, Lucio Tremolizzo, Barbara Borroni, Benedetta Nacmias, Marco Spallazzi, Davide Seripa, Innocenzo Rainero, Antonio Daniele, Paola Bossù, Carlo Masullo, Giacomina Rossi, Frank Jessen, Victoria Fernandez, Patrick Gavin Kehoe, Ruth Frikke-Schmidt, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Jonathan Haines, Lindsay Farrer, Richard Mayeux, Li-San Wang, Rebecca Sims, Anita DeStefano, Gerard D. Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Wiesje van der Flier, Alfredo Ramirez, Margaret Pericak-Vance, Ole A. Andreassen, Cornelia Van Duijn, Mikko Hiltunen, Agustín Ruiz, Josée Dupuis, Eden Martin, Jean-Charles Lambert, Brian Kunkle, Céline Bellenguez","doi":"10.1038/s41380-024-02838-5","DOIUrl":"https://doi.org/10.1038/s41380-024-02838-5","url":null,"abstract":"<p>Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10<sup>−</sup><sup>8</sup>) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10<sup>−</sup><sup>6</sup>). The index variants were common for the Xp22.32, <i>FRMPD4, DMD</i> and Xq25 loci, and rare for the <i>WNK3</i>, <i>PJA1</i>, and <i>DACH2</i> loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763297","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}
Pub Date : 2024-12-02DOI: 10.1038/s41380-024-02821-0
Robin Peretzke, Peter F. Neher, Geva A. Brandt, Stefan Fritze, Sebastian Volkmer, Jonas Daub, Georg Northoff, Jonas Bohn, Yannick Kirchhoff, Saikat Roy, Klaus H. Maier-Hein, Andreas Meyer-Lindenberg, Dusan Hirjak
Catatonia is a severe psychomotor disorder characterized by motor, affective and cognitive-behavioral abnormalities. Although previous magnetic resonance imaging (MRI) studies suggested white matter (WM) dysconnectivity in the pathogenesis of catatonia, it is unclear whether microstructural alterations of WM tracts connecting psychomotor regions might contribute to a better classification of catatonia patients. Here, diffusion-weighted MRI data were collected from two independent cohorts (whiteCAT/replication cohort) of patients with (n = 45/n = 13) and without (n = 56/n = 26) catatonia according to ICD-11 criteria. Catatonia severity was examined using the Northoff (NCRS) and Bush-Francis (BFCRS) Catatonia Rating Scales. We used tract-based spatial statistics (TBSS), tractometry (TractSeg) and machine-learning (ML) to classify catatonia patients from tractometry values as well as tractomics features generated by the newly developed tool RadTract. Catatonia patients showed fractional anisotropy (FA) alterations measured via TractSeg in different corpus callosum segments (CC_1, CC_3, CC_4, CC_5 and CC_6) compared to non-catatonia patients across both cohorts. Our classification results indicated a higher level of performance when trained on tractomics as opposed to traditional tractometry values. Moreover, in the CC_6, we successfully trained two classifiers using the tractomics features identified in the whiteCAT data. These classifiers were applied separately to the whiteCAT and replication cohorts, demonstrating comparable performance with Area Under the Receiver Operating Characteristics (AUROC) values of 0.79 for the whiteCAT cohort and 0.76 for the replication cohort. In contrast, training on FA tractometry resulted in lower AUROC values of 0.66 for the whiteCAT cohort and 0.51 for the replication cohort. In conclusion, these findings underscore the significance of CC WM microstructural alterations in the pathophysiology of catatonia. The successful use of an ML based classification model to identify catatonia patients has the potential to improve diagnostic precision.
{"title":"Deciphering white matter microstructural alterations in catatonia according to ICD-11: replication and machine learning analysis","authors":"Robin Peretzke, Peter F. Neher, Geva A. Brandt, Stefan Fritze, Sebastian Volkmer, Jonas Daub, Georg Northoff, Jonas Bohn, Yannick Kirchhoff, Saikat Roy, Klaus H. Maier-Hein, Andreas Meyer-Lindenberg, Dusan Hirjak","doi":"10.1038/s41380-024-02821-0","DOIUrl":"https://doi.org/10.1038/s41380-024-02821-0","url":null,"abstract":"<p>Catatonia is a severe psychomotor disorder characterized by motor, affective and cognitive-behavioral abnormalities. Although previous magnetic resonance imaging (MRI) studies suggested white matter (WM) dysconnectivity in the pathogenesis of catatonia, it is unclear whether microstructural alterations of WM tracts connecting psychomotor regions might contribute to a better classification of catatonia patients. Here, diffusion-weighted MRI data were collected from two independent cohorts (whiteCAT/replication cohort) of patients with (n = 45/n = 13) and without (n = 56/n = 26) catatonia according to ICD-11 criteria. Catatonia severity was examined using the Northoff (NCRS) and Bush-Francis (BFCRS) Catatonia Rating Scales. We used tract-based spatial statistics (TBSS), tractometry (TractSeg) and machine-learning (ML) to classify catatonia patients from tractometry values as well as tractomics features generated by the newly developed tool RadTract. Catatonia patients showed fractional anisotropy (FA) alterations measured via TractSeg in different corpus callosum segments (CC_1, CC_3, CC_4, CC_5 and CC_6) compared to non-catatonia patients across both cohorts. Our classification results indicated a higher level of performance when trained on tractomics as opposed to traditional tractometry values. Moreover, in the CC_6, we successfully trained two classifiers using the tractomics features identified in the whiteCAT data. These classifiers were applied separately to the whiteCAT and replication cohorts, demonstrating comparable performance with Area Under the Receiver Operating Characteristics (AUROC) values of 0.79 for the whiteCAT cohort and 0.76 for the replication cohort. In contrast, training on FA tractometry resulted in lower AUROC values of 0.66 for the whiteCAT cohort and 0.51 for the replication cohort. In conclusion, these findings underscore the significance of CC WM microstructural alterations in the pathophysiology of catatonia. The successful use of an ML based classification model to identify catatonia patients has the potential to improve diagnostic precision.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"79 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758498","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}
Pub Date : 2024-11-30DOI: 10.1038/s41380-024-02859-0
Michael S. Scheeringa
In volume 28 of this journal, Harnett et al. [1] reported their effort to understand how structural inequities partially explain differences between racial groups on neurophysiology and brain connectivity [1]. The authors’ interpretation was that inequities are a form of chronic stress of structural racism which acts on human development to cause enduring brain differences. Given the strong interest in unequal treatment of races and government’s history of intervening with a strong hand when justified by science, I believe this paper merits additional comment on how the findings were interpreted.
在该杂志的第28卷中,Harnett et al. b[1]报道了他们为理解结构不平等如何部分解释种族群体在神经生理学和大脑连通性方面的差异所做的努力b[1]。作者的解释是,不平等是结构性种族主义的一种慢性压力形式,它对人类的发展起作用,导致持久的大脑差异。考虑到人们对种族不平等待遇的强烈兴趣,以及政府在有科学依据的情况下以强硬手段进行干预的历史,我认为这篇论文值得对这些发现的解释进行额外的评论。
{"title":"Tempering an interpretation based on quality of data to make causal conclusions about race, inequities, and brain differences","authors":"Michael S. Scheeringa","doi":"10.1038/s41380-024-02859-0","DOIUrl":"https://doi.org/10.1038/s41380-024-02859-0","url":null,"abstract":"In volume 28 of this journal, Harnett et al. [1] reported their effort to understand how structural inequities partially explain differences between racial groups on neurophysiology and brain connectivity [1]. The authors’ interpretation was that inequities are a form of chronic stress of structural racism which acts on human development to cause enduring brain differences. Given the strong interest in unequal treatment of races and government’s history of intervening with a strong hand when justified by science, I believe this paper merits additional comment on how the findings were interpreted.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"203 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756299","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}
Mapping differential brain structures for psychiatric problems has been challenging due to a lack of regional convergence and poor replicability in previous brain-behavior association studies. By leveraging two independent large cohorts of neurodevelopment, the ABCD and Generation R Studies (total N = 11271), we implemented an unsupervised machine learning technique with a highly stringent generalizability test to identify reliable brain-behavior associations across diverse domains of child psychiatric problems. Across all psychiatric symptoms measured, one multivariate brain-behavior association was found, reflecting a widespread reduction of cortical surface area correlated with higher child attention problems. Crucially, this association showed marked generalizability across different populations and study protocols, demonstrating potential clinical utility. Moreover, the derived brain dimension score predicted child cognitive and academic functioning three years later and was also associated with polygenic scores for ADHD. Our results indicated that attention problems could be a phenotype for establishing promising multivariate neurobiological prediction models for children across populations. Future studies could extend this investigation into different development periods and examine the predictive values for assessment of functioning, diagnosis, and disease trajectory in clinical samples.
{"title":"Beyond out-of-sample: robust and generalizable multivariate neuroanatomical patterns of psychiatric problems in youth","authors":"Bing Xu, Hao Wang, Lorenza Dall’Aglio, Mannan Luo, Yingzhe Zhang, Ryan Muetzel, Henning Tiemeier","doi":"10.1038/s41380-024-02855-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02855-4","url":null,"abstract":"<p>Mapping differential brain structures for psychiatric problems has been challenging due to a lack of regional convergence and poor replicability in previous brain-behavior association studies. By leveraging two independent large cohorts of neurodevelopment, the ABCD and Generation R Studies (total <i>N</i> = 11271), we implemented an unsupervised machine learning technique with a highly stringent generalizability test to identify reliable brain-behavior associations across diverse domains of child psychiatric problems. Across all psychiatric symptoms measured, one multivariate brain-behavior association was found, reflecting a widespread reduction of cortical surface area correlated with higher child attention problems. Crucially, this association showed marked generalizability across different populations and study protocols, demonstrating potential clinical utility. Moreover, the derived brain dimension score predicted child cognitive and academic functioning three years later and was also associated with polygenic scores for ADHD. Our results indicated that attention problems could be a phenotype for establishing promising multivariate neurobiological prediction models for children across populations. Future studies could extend this investigation into different development periods and examine the predictive values for assessment of functioning, diagnosis, and disease trajectory in clinical samples.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756303","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}
Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.
{"title":"Adolescent social isolation decreases colonic goblet cells and impairs spatial cognition through the reduction of cystine","authors":"Moeka Tanabe, Kazuo Kunisawa, Imari Saito, Aika Kosuge, Hiroyuki Tezuka, Tomoki Kawai, Yuki Kon, Koyo Yoshidomi, Akari Kagami, Masaya Hasegawa, Hisayoshi Kubota, Haruto Ojika, Tadashi Fujii, Takumi Tochio, Yoshiki Hirooka, Kuniaki Saito, Toshitaka Nabeshima, Akihiro Mouri","doi":"10.1038/s41380-024-02826-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02826-9","url":null,"abstract":"<p>Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"84 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753762","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}
Pub Date : 2024-11-29DOI: 10.1038/s41380-024-02854-5
Gereon J. Schnellbächer, Ravichandran Rajkumar, Tanja Veselinović, Shukti Ramkiran, Jana Hagen, Maria Collee, N. Jon Shah, Irene Neuner
Major depressive disorder (MDD) is a debilitating condition that is associated with changes in the default-mode network (DMN). Commonly reported features include alterations in gray matter volume (GMV), cortical thickness (CoT), and gyrification. A comprehensive examination of these variables using ultra-high field strength MRI and machine learning methods may lead to novel insights into the pathophysiology of depression and help develop a more personalized therapy. Cerebral images were obtained from 41 patients with confirmed MDD and 41 healthy controls, matched for age and gender, using a 7-T-MRI. DMN parcellation followed the Schaefer 600 Atlas. Based on the results of a mixed-model repeated measures analysis, a support vector machine (SVM) calculation followed by leave-one-out cross-validation determined the predictive ability of structural features for the presence of MDD. A consecutive permutation procedure identified which areas contributed to the classification results. Correlating changes in those areas with BDI-II and AMDP scores added an explanatory aspect to this study. CoT did not delineate relevant changes in the mixed model and was excluded from further analysis. The SVM achieved a good prediction accuracy of 0.76 using gyrification data. GMV was not a viable predictor for disease presence, however, it correlated in the left parahippocampal gyrus with disease severity as measured by the BDI-II. Structural data of the DMN may therefore contain the necessary information to predict the presence of MDD. However, there may be inherent challenges with predicting disease course or treatment response due to high GMV variance and the static character of gyrification. Further improvements in data acquisition and analysis may help to overcome these difficulties.
{"title":"Structural alterations as a predictor of depression – a 7-Tesla MRI-based multidimensional approach","authors":"Gereon J. Schnellbächer, Ravichandran Rajkumar, Tanja Veselinović, Shukti Ramkiran, Jana Hagen, Maria Collee, N. Jon Shah, Irene Neuner","doi":"10.1038/s41380-024-02854-5","DOIUrl":"https://doi.org/10.1038/s41380-024-02854-5","url":null,"abstract":"<p>Major depressive disorder (MDD) is a debilitating condition that is associated with changes in the default-mode network (DMN). Commonly reported features include alterations in gray matter volume (GMV), cortical thickness (CoT), and gyrification. A comprehensive examination of these variables using ultra-high field strength MRI and machine learning methods may lead to novel insights into the pathophysiology of depression and help develop a more personalized therapy. Cerebral images were obtained from 41 patients with confirmed MDD and 41 healthy controls, matched for age and gender, using a 7-T-MRI. DMN parcellation followed the Schaefer 600 Atlas. Based on the results of a mixed-model repeated measures analysis, a support vector machine (SVM) calculation followed by leave-one-out cross-validation determined the predictive ability of structural features for the presence of MDD. A consecutive permutation procedure identified which areas contributed to the classification results. Correlating changes in those areas with BDI-II and AMDP scores added an explanatory aspect to this study. CoT did not delineate relevant changes in the mixed model and was excluded from further analysis. The SVM achieved a good prediction accuracy of 0.76 using gyrification data. GMV was not a viable predictor for disease presence, however, it correlated in the left parahippocampal gyrus with disease severity as measured by the BDI-II. Structural data of the DMN may therefore contain the necessary information to predict the presence of MDD. However, there may be inherent challenges with predicting disease course or treatment response due to high GMV variance and the static character of gyrification. Further improvements in data acquisition and analysis may help to overcome these difficulties.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"65 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753742","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}