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Association between probable sarcopenia and dementia risk: a prospective cohort study with mediation analysis. 可能的肌肉疏松症与痴呆症风险之间的关系:前瞻性队列研究与中介分析。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-10-01 DOI: 10.1038/s41398-024-03131-3
Yitong Ling, Shiqi Yuan, Xiaxuan Huang, Shanyuan Tan, Hongtao Cheng, Li Li, Shuna Li, Liying Huang, Anding Xu, Jun Lyu

The role of alcohol consumption as a mediator in the risk between sarcopenia and dementia remains inadequately studied. There is currently limited research on whether the association between sarcopenia and the risk of Alzheimer's disease (AD) is influenced by genetic susceptibility. Our study incorporated a total of 483,637 baseline non-dementia participants, who were classified into groups of individuals with no sarcopenia and those with probable sarcopenia based on the definition. We employed Cox proportional hazards models to evaluate the association between probable sarcopenia and the risk of all cause dementia (ACD), AD, and vascular dementia (VD). We conducted mediation analysis to explore the role of alcohol consumption in the association between probable sarcopenia and the risk of ACD, AD, and VD. During the median follow-up period of 13.6 years, we documented 9000 new cases of ACD (including 4061 AD and 2025 VD). Fully adjusted multivariate model revealed a significant correlation between probable sarcopenia and elevated risk for ACD (HR = 1.54, 95% CI: 1.46-1.62, p < 0.001), AD (HR = 1.32, 95% CI: 1.21-1.43, p < 0.001), and VD (HR = 1.69, 95% CI: 1.52-1.89, p < 0.001). Mediation analysis elucidates that alcohol consumption explained 12.8%, 15.2%, and 11.1% of the associations of probable sarcopenia with the risk of ACD, AD, and VD, respectively. An interactive relationship prevails between probable sarcopenia and genetic factors (p for interaction <0.001), and regardless of the degree of genetic risk, probable sarcopenia correlates with an elevated AD risk. Our study reveals a significant association between probable sarcopenia and an increased risk of dementia, with alcohol consumption playing a mediating role in this association. There is an interaction between probable sarcopenia and genetic susceptibility related to the risk of AD.

关于饮酒在肌肉疏松症与痴呆症之间的风险中所起的中介作用,目前研究尚不充分。目前,关于肌肉疏松症与阿尔茨海默病(AD)风险之间的关系是否受遗传易感性影响的研究还很有限。我们的研究共纳入了 483 637 名基线非痴呆症参与者,并根据定义将他们分为无肌肉疏松症和可能患有肌肉疏松症两组。我们采用 Cox 比例危险模型来评估可能的肌肉疏松症与全因痴呆症(ACD)、注意力缺失症(AD)和血管性痴呆症(VD)风险之间的关系。我们还进行了中介分析,以探讨饮酒在可能的肌肉疏松症与全因痴呆症、注意力缺失症和血管性痴呆症风险之间的关联中的作用。在中位 13.6 年的随访期间,我们记录了 9000 例新的 ACD 病例(包括 4061 例 AD 和 2025 例 VD)。经充分调整的多变量模型显示,可能的肌肉疏松症与 ACD 风险升高之间存在显著的相关性(HR = 1.54,95% CI:1.46-1.62,P<0.05)。
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引用次数: 0
Psilocybin increases optimistic engagement over time: computational modelling of behaviour in rats. 随着时间的推移,迷幻药会增加乐观的参与度:对大鼠行为的计算建模。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03103-7
Elizabeth L Fisher, Ryan Smith, Kyna Conn, Andrew W Corcoran, Laura K Milton, Jakob Hohwy, Claire J Foldi

Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.

作为治疗抑郁症的一种新型药理干预措施,迷幻药已显示出良好的前景,迷幻药治疗后的急性效应与积极情绪的增加和悲观情绪的减少有关。尽管在治疗精神疾病的临床试验中证明了迷幻药的有效性,但人们对迷幻药影响的信息处理机制还不甚了解。在这里,我们将主动推理和强化学习计算模型与能够捕捉大鼠参与行为的新型双臂匪徒逆向学习任务相结合。该模型显示,大鼠在接受迷幻药后会通过提高任务参与度获得更多奖励,而任务参与度的提高是由遗忘率的改变和损失厌恶的降低所促成的。这些研究结果表明,迷幻药可能会通过改变信念更新而产生乐观偏差,这对缺乏乐观情绪的临床人群具有转化潜力。
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引用次数: 0
Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects. 在一项针对健康受试者的双盲安慰剂对照研究中,麦司卡林产生了急性剂量依赖性效应。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03116-2
Aaron Klaiber, Yasmin Schmid, Anna M Becker, Isabelle Straumann, Livio Erne, Alen Jelusic, Jan Thomann, Dino Luethi, Matthias E Liechti

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.

经典迷幻剂重新引起了研究和治疗的兴趣。尽管人类使用麦司卡林的传统由来已久,但仍缺乏有关其剂量依赖性急性效应和药代动力学的现代数据。此外,麦司卡林的作用机制也未在人体中进行过研究。我们采用随机、双盲、安慰剂对照、交叉设计的方法,让 16 名健康受试者(8 名女性)分别服用安慰剂、麦司卡林(100、200、400 和 800 毫克)和 800 毫克麦司卡林以及血清素-5-羟色胺-2A(5-HT2A)受体拮抗剂酮赛林(40 毫克),以评估用药后 30 小时内的主观效应、自主神经效应、不良反应和药代动力学。剂量大于 100 毫克的麦司卡林会诱发剂量依赖性急性主观效应。剂量大于 100 毫克时,麦司卡林会增加收缩压和舒张压,剂量在 200-800 毫克之间没有差异。心率的增加与剂量有关。麦司卡林的药代动力学与剂量成正比。随着 100-800 毫克麦司卡林剂量的增加,主观效应的平均持续时间从 6.4 小时增加到 14 小时。服用 800 毫克剂量时,恶心和呕吐是常见的不良反应。同时服用酮塞林可减轻和缩短 800 毫克麦司卡林的急性效应,使其与 100 毫克和 200 毫克的剂量相当。在调查的剂量范围内,主观反应没有上限效应,但最高剂量的耐受性较低。这些结果可能有助于为今后的研究寻找剂量,并表明麦司卡林的急性效应主要由 5-HT2A 受体介导。
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引用次数: 0
Contagion of depression: a double-edged sword. 抑郁症的传染:一把双刃剑。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-30 DOI: 10.1038/s41398-024-03124-2
Chen-Wei Huang, Ting Hu, Hong Zheng, Yi-Lin Wu, Jia-Mei Li, Yi-Ming Wang, Wen-Jun Su, Wei Wang, Yun-Zi Liu, Chun-Lei Jiang

Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders.

抑郁症是一个严重的心理健康问题,对经济有着广泛的影响,最近的研究表明,抑郁症可能会在人与人之间传播。然而,这种传染的机制仍不清楚,社会缓冲效应也未得到充分研究。本研究采用了三种啮齿动物模型,包括压力交叉模型、同居诱导模型和非接触诱导抑郁传染模型,来探索这些机制。在这里,我们报告说,与抑郁小鼠同居的天真小鼠表现出皮质酮水平升高和抑郁行为,而与应激小鼠同居的天真小鼠则不同,它们没有表现出这些变化,甚至减轻了应激小鼠的绝望情绪。非接触式同居不会产生显著的行为差异,但接触抑郁小鼠的垫料会降低天真小鼠的蔗糖偏好。这项研究引入了抑郁传染的可靠模型,表明抑郁传染的运作与应激传递无关。抑郁传染和社会缓冲之间的相互作用可能在不同的环境中有所不同。这些发现为抑郁传染机制和预防抑郁障碍的潜在策略提供了新的见解。
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引用次数: 0
Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission. 受体和新陈代谢对咖啡因防止酒精诱导刺激间叶多巴胺传导能力的影响。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03112-6
Valentina Bassareo, Riccardo Maccioni, Giuseppe Talani, Simone Zuffa, Yasin El Abiead, Irene Lorrai, Tomoya Kawamura, Sofia Pantis, Roberta Puliga, Romina Vargiu, Daniele Lecca, Paolo Enrico, Alessandra Peana, Laura Dazzi, Pieter C Dorrestein, Pietro Paolo Sanna, Enrico Sanna, Elio Acquas

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

酒精和咖啡因的消费影响着全球数十亿人的生活。尽管最近有证据表明咖啡因会削弱酒精的强化作用,但却缺乏咖啡因对酒精刺激的间叶多巴胺(DA)功能的影响特征。酒精作为salsolinol的原药,可兴奋后腹侧被盖区(pVTA)的DA神经元,并增加核团外壳(AcbSh)的DA释放。在这里,我们展示了咖啡因通过对 A2A 腺苷受体(A2AR)的拮抗作用,阻止了酒精对间叶 DA 功能的依赖性激活,这种激活在体内是通过对 AcbSh DA 的脑微量透析评估的,在体外是通过对 pVTA DA 神经元发射的电生理记录评估的。因此,虽然A1R拮抗剂DPCPX不能阻止酒精对DA功能的影响,但咖啡因和A2AR拮抗剂SCH 58261都能阻止酒精依赖性体内pVTA产生salsolinol和AcbSh DA增加,以及酒精依赖性体外pVTA DA神经元兴奋。然而,咖啡因也能阻止直接的鲨烯醇和吗啡刺激的DA功能,这表明咖啡因也能发挥这些抑制作用,而不影响酒精诱导的鲨烯醇的形成或生物利用度。最后,pVTA 的非靶向代谢组学研究表明,咖啡因能拮抗酒精介导的对脂质信号转导和能量代谢相关分子(如磷脂酰胆碱、脂肪酰胺、肉毒碱)的影响,这可能代表咖啡因在损害酒精介导的刺激间叶 DA 传递方面的另一种与香豆素醇无关的机制。总之,这项研究的结果增强了咖啡因和 A2AR 拮抗剂在未来开发酒精使用障碍的预防/治疗策略方面的潜力。
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引用次数: 0
Targeting auditory verbal hallucinations in schizophrenia: effective connectivity changes induced by low-frequency rTMS. 针对精神分裂症患者的听觉言语幻觉:低频经颅磁刺激引起的有效连接变化
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03106-4
Xie Yuanjun, Muzhen Guan, Tian Zhang, Chaozong Ma, Lingling Wang, Xinxin Lin, Chenxi Li, Zhongheng Wang, Ma Zhujing, Huaning Wang, Fang Peng

Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as an effective intervention for alleviating symptoms of psychiatric disorders, particularly schizophrenia characterized by persistent auditory verbal hallucinations (AVH). However, the underlying mechanism of its action remain elusive. This study employed a randomized controlled design to investigate the impact of low-frequency rTMS on the neural connectivity at the stimulate site, specifically left temporoparietal junction (TPJ), in schizophrenia patients with suffering from AVH. Using Dynamic Causal Modeling (DCM), this study assessed changes in directed connectivity patterns and their correlations with clinical symptomatology. The results demonstrated significant improvements in AVH. Notably, significant changes in connectivity were observed, including both abnormal functional connectivity and effective connectivity among multiple brain regions. Particularly, the inhibition effects from the left precentral gyrus and left medial superior frontal gyrus to the left TPJ were closely associated with improvements in AVH. These findings underscore the potential of rTMS to effectively modulate neural pathways implicated in hallucinations in schizophrenia, thereby providing a neurobiological foundation for its therapeutic effects.

低频重复经颅磁刺激(rTMS)已成为一种有效的干预措施,可减轻精神疾病的症状,尤其是以持续性听觉言语幻觉(AVH)为特征的精神分裂症。然而,其潜在的作用机制仍然难以捉摸。本研究采用随机对照设计,研究低频经颅磁刺激对精神分裂症患者刺激部位(尤其是左侧颞顶叶交界处(TPJ))神经连接的影响。本研究采用动态因果模型(DCM)评估了定向连接模式的变化及其与临床症状的相关性。结果表明,AVH 有了明显改善。值得注意的是,研究人员观察到连通性发生了重大变化,包括异常功能连通性和多个脑区之间的有效连通性。特别是,从左侧中央前回和左侧内侧额上回到左侧 TPJ 的抑制作用与 AVH 的改善密切相关。这些发现强调了经颅磁刺激可以有效调节与精神分裂症幻觉有关的神经通路,从而为其治疗效果提供了神经生物学基础。
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引用次数: 0
Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation. 失调的miR-124介导父亲早期社会隔离导致的社会记忆行为受损
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-28 DOI: 10.1038/s41398-024-03109-1
Sijia Chen, Shixin Ding, Yingting Pang, Yuxi Jin, Peng Sun, Yue Li, Min Cao, Yimiao Wang, Ze Wang, Tianqi Wang, Ying Zou, Yanli Zhang, Ming Xiao

Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.

早期社会隔离(SI)会导致成年后情绪和行为的各种异常。然而,社会隔离对后代的负面影响仍不清楚。这项研究发现,父系早期社会隔离会导致 F1 年轻成年小鼠的社会记忆缺陷和焦虑样行为,并改变内侧前额叶皮层(mPFC)的髓鞘和突触。对 F1 后代进行 2 周的 SI 会加剧 mPFC 中的社会记忆障碍和髓鞘化不足。此外,在F1小鼠的mPFC中下调miR-124(一种髓鞘生成的关键抑制因子)或过度表达其靶基因Nr4a1可改善社交互动能力,并促进少突胶质细胞的成熟和髓鞘的形成。从机理上讲,父系 SI 小鼠精子中 miR-124 水平的升高会通过表观遗传传递给子代,从而改变 mPFC 少突胶质细胞中 miR-124/Nr4a1/ 糖皮质激素受体的表达水平。这反过来又阻碍了依赖髓鞘生成的社会行为的建立。这项研究揭示了一种新的机制,通过这种机制,miR-124介导了早期隔离应激的代际效应,最终损害了社会行为和神经发育的建立。
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引用次数: 0
A context-dependent model of resilient functioning after childhood maltreatment-the case for flexible biobehavioral synchrony. 儿童遭受虐待后恢复功能的环境依赖模型--灵活的生物行为同步性案例。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-27 DOI: 10.1038/s41398-024-03092-7
Kerstin Konrad, Vanessa B Puetz

Many children who experience childhood adversity, whether in the form of threat or deprivation, develop adaptive competencies that lead to resilient functioning. Still, research has not succeeded in accurately predicting the level of resilient functioning by any kind of biomarkers, likely because it has sidelined the flexibility inherent in a construct that is situationally and developmentally variable. Whilst recent research acknowledges the importance of redefining resilience in order to reflect its dynamic nature after adversity, evidence for specific behaviors that are developmentally adaptive and dynamic throughout the lifespan is limited. We here propose a model in which resilient functioning is crucially dependent on the individual's capability to flexibly synchronize with and segregate from another's cognitive-affective, behavioral, and physiological states, known as 'biobehavioral synchrony'. Such an adaptive interpersonal skill is rooted in (a) the early caregiving experience and its regulatory effects on an individual's physiological stress reactivity, as well as (b) the development of self-other distinction which can be affected by childhood maltreatment. Bridging the gap between accounts of flexible resilient functioning and the latest thinking in biobehavioral synchrony, we will review behavioral and neurobiological evidence that threat and deprivation in childhood interfere with the development of dynamic, context-sensitive boundaries between self and other, mediated by the (right) tempo-parietal junction (a central neural hub for interpersonal synchronization), which puts the individual at risk for affective fusion or cut-off from others' arousal states. Our proposed model charts a path for investigating the differential effects of maltreatment experiences and mechanisms for intergenerational transmission of non-sensitive caregiving. We conclude with metrics, data analysis methods, and strategies to facilitate flexible biobehavioral synchrony.

许多经历过童年逆境的儿童,无论是受到威胁还是被剥夺,都会发展出适应能力,从而产生复原功能。然而,研究并没有成功地通过任何一种生物标志物来准确预测复原功能的水平,这很可能是因为研究忽略了一个因情况和发展而变化的结构所固有的灵活性。虽然最近的研究承认了重新定义复原力以反映其在逆境后动态性质的重要性,但关于在整个生命周期中具有发展适应性和动态性的特定行为的证据却很有限。我们在此提出了一个模型,在该模型中,抗逆力的发挥关键取决于个体灵活地与他人的认知-情感、行为和生理状态同步或分离的能力,即所谓的 "生物行为同步"。这种适应性人际交往技能的根源在于:(a)早期的照顾经历及其对个体生理压力反应的调节作用;以及(b)自我与他者区分的发展,而这种发展可能会受到童年虐待的影响。我们将通过回顾行为学和神经生物学方面的证据,证明童年时期的威胁和剥夺会干扰自我与他人之间动态的、对情境敏感的界限的发展,而这种界限是由(右侧)节拍-顶叶交界处(人际同步的中心神经枢纽)介导的,它使个体面临情感融合或与他人唤醒状态隔绝的风险。我们提出的模型为研究虐待经历的不同影响以及非敏感性照料的代际传递机制指明了道路。最后,我们将介绍促进灵活的生物行为同步的衡量标准、数据分析方法和策略。
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引用次数: 0
Magnitude and kinetics of a set of neuroanatomic volume and thickness together with white matter hyperintensity is definitive of cognitive status and brain age. 一组神经解剖体积和厚度以及白质高密度的大小和动力学可确定认知状态和脑年龄。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-27 DOI: 10.1038/s41398-024-03097-2
Neha Yadav, Niraj Kumar Gupta, Darshit Thakar, Vivek Tiwari

Even among the subjects classified as cognitively normal, there exists a subset of individuals at a given chronological age (CA) who harbor white matter hyperintensity (WMH) while another subset presents with low or undetectable WMH. Here, we conducted a comprehensive MRI segmentation of neuroanatomic structures along with WMH quantification in groups of cognitively normal (CN), cognitively impaired (CI) individuals, and individuals with an etiological diagnosis of cognitive impairment owing to Alzheimer's Disease (CI-AD) across the early (50-64 years), intermediate (65-79 years), and late (≥80 years) age groups from the NACC cohort. Neuroanatomic volumetry quantification revealed that thinning of the parahippocampal gyrus in the early (p = 0.016) and intermediate age groups (p = 0.0001) along with an increase in CSF (p = 0.0009) delineates between CI and CI-AD subjects. Although, a significant loss of ~5-10% in volume of gray matter (p(CN vs CI) < 0.0001, p(CN vs CI-AD) < 0.0001), white matter (p(CN vs CI) = 0.002, p(CN vs CI-AD) = 0.0003) and hippocampus (p(CN vs CI) = 0.007, p(CN vs CI-AD) < 0.0001) was evident at the early age groups in the CI and CI-AD compared to CN but it was not distinct between CI and CI-AD. Using the neuroanatomic and WMH volume, and the supervised decision tree-based ML modeling, we have established that a minimum set of Three brain quantities; Total brain (GM + WM), CSF, and WMH volume, provide the Optimal quantitative features discriminative of cognitive status as CN, CI, and CI-AD. Furthermore, using the volume/thickness of 178 neuroanatomic structures, periventricular and deep WMH volume quantification for the 819 CN subjects, we have developed a quantitative index as 'Brain Age' (BA) depictive of neuroanatomic health at a given CA. Subjects with elevated WMH load (5-10 ml) had increased BA ( + 0.6 to +4 years) than the CA. Increased BA in the subjects with elevated WMH is suggestive of WMH-induced vascular insult leading to accelerated and early structural loss than expected for a given CA. Henceforth, this study establishes that quantification of WMH together with an optimal number of neuroanatomic features is mandatory to delve into the biological underpinning of aging and aging-associated cognitive disorders.

即使在被归类为认知正常的受试者中,也有一部分人在特定的年龄段(CA)存在白质高密度(WMH),而另一部分人则表现为低WMH或无法检测到WMH。在此,我们对 NACC 队列中认知正常(CN)、认知受损(CI)和因阿尔茨海默病(CI-AD)而被病因学诊断为认知受损的早期(50-64 岁)、中期(65-79 岁)和晚期(≥80 岁)年龄组的人群进行了全面的神经解剖结构 MRI 分段和 WMH 定量。神经解剖容积定量分析显示,早期(p = 0.016)和中间年龄组(p = 0.0001)的海马旁回变薄,CSF 增加(p = 0.0009),是 CI 和 CI-AD 受试者之间的区别。虽然灰质(p(CN vs CI) (CN vs CI-AD) (CN vs CI) = 0.002, p(CN vs CI-AD) = 0.0003)和海马(p(CN vs CI) = 0.007, p(CN vs CI-AD) = 0.0003)的体积损失约为 5-10%,但这并不意味着CI和CI-AD受试者的灰质和海马的体积会发生变化。
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引用次数: 0
Longitudinal changes in DNA methylation associated with clozapine use in treatment-resistant schizophrenia from two international cohorts. 来自两个国际队列的耐药精神分裂症患者使用氯氮平相关的 DNA 甲基化纵向变化。
IF 5.8 1区 医学 Q1 PSYCHIATRY Pub Date : 2024-09-27 DOI: 10.1038/s41398-024-03102-8
Amy L Gillespie, Emma M Walker, Eilis Hannon, Grant A McQueen, Kyra-Verena Sendt, Alessia Avila, John Lally, Cynthia Okhuijsen-Pfeifer, Marte van der Horst, Alkomiet Hasan, Emma L Dempster, Joe Burrage, Jan Bogers, Dan Cohen, Marco P Boks, David A Collier, Alice Egerton, Jurjen J Luykx, Jonathan Mill, James H MacCabe

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p < 5 × 10-5) in a linear model and 90 DMPs in a non-linear quadratic model. We compared these results to data from our previous epigenome-wide association study (EWAS) meta-analysis of psychosis, finding evidence that many previously identified DMPs associated with schizophrenia and treatment-resistant schizophrenia might reflect exposure to clozapine. In conclusion, our results indicate that clozapine exposure is associated with changes in DNA methylation and cellular composition. Our study shows that medication effects might confound many case-control studies of neuropsychiatric disorders performed in blood.

第二代抗精神病药物氯氮平是一种治疗耐药性精神分裂症的药物。在临床前啮齿类动物模型和耐药性精神分裂症的横断面研究中,氯氮平曾与表观遗传学变化有关。然而,横断面研究容易受到混杂因素的影响,而且无法区分诊断和药物治疗的影响。因此,我们对两个独立队列的耐药精神分裂症谱系障碍患者(38 人)的连续血液样本(126 份)中的 DNA 甲基化进行了分析,这些患者在加入研究后开始服用氯氮平,并接受了长达 6 个月的随访。我们发现,从 DNA 甲基化数据中得出的细胞类型比例估计值(特别是 B 细胞)与服用氯氮平的时间有明显的非线性变化。我们使用混合效应回归模型来确定与服用氯氮平时间相关的特定位点的 DNA 甲基化变化,在线性模型中确定了 37 个差异甲基化位点(DMPs)(p -5),在非线性二次模型中确定了 90 个差异甲基化位点。我们将这些结果与之前的表观基因组全关联研究(EWAS)中有关精神病的荟萃分析数据进行了比较,发现有证据表明,之前发现的许多与精神分裂症和耐药精神分裂症相关的 DMPs 可能反映了氯氮平的暴露。总之,我们的研究结果表明,氯氮平暴露与 DNA 甲基化和细胞组成的变化有关。我们的研究表明,药物的影响可能会混淆许多在血液中进行的神经精神疾病病例对照研究。
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引用次数: 0
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Translational Psychiatry
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