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Cortical hypometabolism in Parkinson’s disease is linked to cholinergic basal forebrain atrophy 帕金森病的皮质代谢降低与胆碱能性基底前脑萎缩有关
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 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。
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引用次数: 0
Glial cell deficits are a key feature of schizophrenia: implications for neuronal circuit maintenance and histological differentiation from classical neurodegeneration 神经胶质细胞缺陷是精神分裂症的一个关键特征:对神经回路维持和经典神经变性的组织学分化的影响
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 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.

功能失调的神经胶质细胞在精神分裂症病理生理中起着重要作用。死后研究提供了证据,证明精神分裂症患者大脑不同区域的神经胶质细胞数量显著减少。胶质细胞数量减少在少突胶质细胞中最为明显,但星形胶质细胞密度也有减少的报道。这篇综述强调了寡聚和星形胶质细胞缺陷是精神分裂症的一个关键的组织病理学特征,不同于神经退行性疾病的典型变化。精神分裂症患者少突胶质细胞的显著缺陷可能以两种方式出现:(i)成熟功能受损的少突胶质细胞死亡;(ii)由于祖细胞未成熟而缺乏成熟的少突胶质细胞。我们还详细分析了关于星形胶质细胞缺陷的争议。无论其来源如何,神经胶质细胞缺陷有几个病理生理后果。其中,由于少突胶质细胞数量减少而导致的髓鞘形成缺陷可能是最重要的因素,导致精神分裂症中观察到的神经元与大脑不同区域之间的连接断开。当神经胶质细胞死亡时,它似乎是通过退化,这一过程基本上是可逆的。因此,治疗干预(i)帮助拯救神经胶质细胞(ii)或促进其成熟可能是一个可行的选择。由于单靠抗精神病药物治疗似乎并不能预防神经胶质细胞的丧失或成熟缺陷,因此人们正在积极寻找新的治疗方案。目前的建议包括抗抑郁药和其他化学制剂的应用以及体育锻炼,以及将健康的神经胶质细胞植入精神分裂症患者的大脑。
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引用次数: 0
From placenta to the foetus: a systematic review of in vitro models of stress- and inflammation-induced depression in pregnancy 从胎盘到胎儿:妊娠期应激和炎症诱导的抑郁体外模型的系统综述
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 10.1038/s41380-024-02866-1
Madeline Kirkpatrick, Gargi Mandal, Ismail Elhadidy, Nicole Mariani, Kristi Priestley, Carmine M. Pariante, Alessandra Borsini

Background

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.

背景怀孕期间的抑郁可能通过母体皮质醇和细胞因子向子宫内环境的转移而增加后代患精神疾病的脆弱性。然而,精确的细胞和分子机制在很大程度上是不清楚的。动物研究可以在系统水平上代表这种复杂的病理生理,但成本高昂,而且在伦理上具有挑战性。虽然更简单,但体外模型提供了高通量的机会。因此,本系统综述整合了与妊娠期抑郁相关的体外模型的发现,以产生新的假设和干预目标。方法系统分析研究糖皮质激素或细胞因子对胎盘或胎儿神经祖细胞(npc)的影响,并与性激素联合或不联合处理。结果纳入的50项研究中,11项使用胎盘细胞,39项使用npc;令人惊讶的是,只有一项研究将雌激素和皮质醇结合使用,没有一项研究将胎盘细胞和npc结合使用。在胎盘细胞中,皮质醇或细胞因子降低了营养转运蛋白的表达和类固醇生成酶的活性,并增加了细胞因子的产生。npc表现出增殖和分化的减少,通过特定的分子途径,即抑制刺猬信号传导和激活犬尿氨酸途径。在这些细胞中,研究还强调了应激和炎症途径的表观遗传启动。综上所述,应激和炎症不仅会影响胎盘对胎儿的营养和激素的调节,还会通过胎盘炎症的增加激活下游通路,最终对胎儿神经发生产生不利影响。未来的研究应该探究性激素如何调节这些机制,以开发针对妊娠抑郁症的靶向治疗方法。
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引用次数: 0
Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice 锂可以使dyrk1a敲入小鼠的asd相关神经元、突触和行为表型正常化
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-05 DOI: 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.

Dyrk1A缺陷与多种神经发育障碍有关,包括发育迟缓、智力残疾(ID)和自闭症谱系障碍(ASD)。据报道,小鼠中Dyrk1a的单倍性不足会导致asd相关表型。然而,关键的病理机制尚不清楚,人类DYRK1A突变在小鼠中仍未表征。在这里,我们产生并研究了携带人类ASD患者突变(Ile48LysfsX2;Dyrk1a-I48K老鼠)。这些小鼠表现出严重的小头畸形、社交和认知缺陷、树突萎缩、兴奋性突触缺陷,以及富含多种信号通路和突触蛋白的磷酸化蛋白质组学模式改变。早期慢性锂治疗新生突变小鼠在幼年和成年阶段恢复了脑容量、行为、树突、突触和信号/突触磷酸化蛋白质组表型。这些结果表明,信号/突触改变有助于Dyrk1a-I48K小鼠的表型改变,并且通过锂处理对这些改变的早期纠正在预防幼年期和成年期表型方面具有持久的作用。
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引用次数: 0
X‐chromosome-wide association study for Alzheimer’s disease 阿尔茨海默病的X染色体全相关性研究
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-04 DOI: 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 × 108) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 106). 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.

由于方法学上的原因,x染色体在阿尔茨海默病(AD)的主要全基因组关联研究中没有被纳入。为了解决这个问题并更好地描述AD的遗传景观,我们对115,841例AD病例或AD代理病例进行了深入的x染色体全关联研究(XWAS),其中包括52,214例临床诊断的AD病例和613,671例对照。我们考虑了三种方法来解释女性不同的x染色体失活(XCI)状态,即随机XCI,偏态XCI和逃逸XCI。我们没有检测到任何全基因组显著信号(P≤5 × 10−8),但鉴定出7个x染色体显著位点(P≤1.6 × 10−6)。索引变异在Xp22.32、FRMPD4、DMD和Xq25基因座中很常见,而在WNK3、PJA1和DACH2基因座中很少见。总的来说,这个功能强大的XWAS在x染色体的非假常染色体区域没有发现AD的遗传风险因素,但它发现了值得进一步研究的暗示信号。
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引用次数: 0
Deciphering white matter microstructural alterations in catatonia according to ICD-11: replication and machine learning analysis 根据ICD-11解读紧张症的白质微观结构变化:复制和机器学习分析
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 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.

紧张症是一种严重的精神运动障碍,以运动、情感和认知行为异常为特征。尽管先前的磁共振成像(MRI)研究表明,白质(WM)连接障碍在紧张症的发病机制中起着重要作用,但目前尚不清楚连接精神运动区域的白质束的微结构改变是否有助于更好地对紧张症患者进行分类。在这里,根据ICD-11标准,从两个独立的队列(whiteCAT/复制队列)中收集弥散加权MRI数据,这些队列中有(n = 45/n = 13)和没有(n = 56/n = 26)紧张症患者。使用Northoff (NCRS)和Bush-Francis (BFCRS)紧张症评定量表检查紧张症严重程度。我们使用基于束的空间统计(TBSS),束测(tractsig)和机器学习(ML)根据束测值以及新开发的工具RadTract生成的束测特征对紧张症患者进行分类。与非紧张症患者相比,紧张症患者在不同胼胝体节段(CC_1, CC_3, CC_4, CC_5和CC_6)的TractSeg测量显示分数各向异性(FA)改变。我们的分类结果表明,与传统的肌束测量值相比,接受肌束切开术训练的患者表现更高。此外,在CC_6中,我们利用whiteCAT数据中识别的tractomics特征成功训练了两个分类器。这些分类器分别应用于白色ecat和复制队列,显示出与白色ecat队列的接受者工作特征下面积(AUROC)值(0.79)和复制队列的0.76相当的性能。相比之下,FA量测法训练导致白色ecat组的AUROC值较低,为0.66,复制组为0.51。总之,这些发现强调了CC - WM微结构改变在紧张症病理生理中的意义。成功地使用基于ML的分类模型来识别紧张症患者有可能提高诊断精度。
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引用次数: 0
Tempering an interpretation based on quality of data to make causal conclusions about race, inequities, and brain differences 根据数据质量调整解释,得出关于种族、不平等和大脑差异的因果结论
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-30 DOI: 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。
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引用次数: 0
Beyond out-of-sample: robust and generalizable multivariate neuroanatomical patterns of psychiatric problems in youth 超出样本:青少年精神问题的稳健和可推广的多变量神经解剖学模式
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-30 DOI: 10.1038/s41380-024-02855-4
Bing Xu, Hao Wang, Lorenza Dall’Aglio, Mannan Luo, Yingzhe Zhang, Ryan Muetzel, Henning Tiemeier

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.

由于先前的脑-行为关联研究缺乏区域收敛性和较差的可复制性,绘制精神问题的不同脑结构一直具有挑战性。通过利用两个独立的大型神经发育队列,ABCD和Generation R研究(总N = 11271),我们实施了一种无监督的机器学习技术,该技术具有高度严格的概括性测试,以确定跨儿童精神问题不同领域的可靠大脑行为关联。在所有测量的精神症状中,发现了一种多变量脑行为关联,反映了与儿童注意力问题相关的皮质表面积的广泛减少。至关重要的是,这种关联在不同的人群和研究方案中显示出显著的普遍性,显示出潜在的临床实用性。此外,衍生脑维度得分预测了儿童三年后的认知和学业功能,也与多动症的多基因得分有关。我们的研究结果表明,注意力问题可能是一种表型,可以为不同人群的儿童建立有希望的多元神经生物学预测模型。未来的研究可以将这项研究扩展到不同的发展时期,并在临床样本中检验功能评估、诊断和疾病轨迹的预测价值。
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引用次数: 0
Adolescent social isolation decreases colonic goblet cells and impairs spatial cognition through the reduction of cystine 青少年社会隔离减少结肠杯状细胞,并通过减少胱氨酸损害空间认知
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-29 DOI: 10.1038/s41380-024-02826-9
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

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.

青少年时期的负面经历,如社会孤立、欺凌和虐待,会增加成年后患精神疾病的风险。然而,由这些因素引起的精神疾病的发病机制仍然知之甚少。在青少年中,压力会影响肠-脑轴的肠道稳态。本研究确定青少年SI是否通过破坏结肠功能诱发行为异常。暴露于SI的青春期小鼠表现出空间认知缺陷和海马小胶质细胞激活(HIP)。SI降低了产生黏液蛋白的杯状细胞的分化,这伴随着肠道微生物群组成的改变,特别是黏液摄食细菌的消耗。利巴米胺治疗可促进结肠杯状细胞分化,减轻si诱导的空间认知缺陷和髋部小胶质细胞激活,并降低半胱氨酸(同型半胱氨酸的下游代谢物)。胱氨酸治疗可改善si诱导的空间认知缺陷,并增加HIP中小胶质C-C基序趋化因子配体7 (CCL7)水平。CC基序趋化因子受体2 (CCR2)和3 (CCR3)拮抗剂在髋关节中抑制CCL7受体可预防SI诱导的空间认知缺陷。氯膦酸脂质体消融小胶质细胞后向髋部灌注CCL7诱导空间认知缺陷。这些发现表明青少年SI通过破坏结肠杯状细胞降低血清胱氨酸水平,通过触发髋部小胶质细胞激活导致空间认知缺陷。我们的研究结果表明,CCL7在海马小胶质细胞中的表达增加可能通过激活CCR2和CCR3而导致空间认知缺陷。
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引用次数: 0
Structural alterations as a predictor of depression – a 7-Tesla MRI-based multidimensional approach 结构改变作为抑郁症的预测因子——基于7特斯拉核磁共振的多维方法
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-29 DOI: 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.

重度抑郁症(MDD)是一种与默认模式网络(DMN)变化有关的衰弱状态。通常报道的特征包括灰质体积(GMV)、皮质厚度(CoT)和脑回化的改变。使用超高场强MRI和机器学习方法对这些变量进行全面检查可能会对抑郁症的病理生理学产生新的见解,并有助于开发更个性化的治疗方法。使用7-T-MRI获得41例确诊MDD患者和41例年龄和性别匹配的健康对照者的大脑图像。DMN的包装遵循Schaefer 600 Atlas。基于混合模型重复测量分析的结果,支持向量机(SVM)计算和留一交叉验证确定了结构特征对MDD存在的预测能力。连续排列程序确定哪些区域有助于分类结果。将这些区域的变化与BDI-II和AMDP评分相关联,为本研究增加了一个解释性方面。CoT没有描述混合模型的相关变化,因此被排除在进一步的分析之外。该支持向量机在使用回转数据时获得了0.76的良好预测精度。GMV不是疾病存在的可行预测因子,然而,它在左侧海马旁回与BDI-II测量的疾病严重程度相关。因此,DMN的结构数据可能包含预测MDD存在的必要信息。然而,由于高GMV方差和旋转的静态特征,预测病程或治疗反应可能存在固有的挑战。数据获取和分析方面的进一步改进可能有助于克服这些困难。
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引用次数: 0
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Molecular Psychiatry
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