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White matter microstructure in obesity and bipolar disorders: an ENIGMA bipolar disorder working group study in 2186 individuals 肥胖与躁狂症的白质微结构:ENIGMA 躁狂症工作组对 2186 人进行的研究
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-05 DOI: 10.1038/s41380-024-02784-2
Lorielle M. F. Dietze, Sean R. McWhinney, Pauline Favre, Christoph Abé, Nina Alexander, Carlotta Barkhau, Francesco Benedetti, Michael Berk, Erlend Bøen, Birgitte Boye, Katharina Brosch, Erick J. Canales-Rodríguez, Dara M. Cannon, Sean P. Carruthers, Emily L. V. Corkum, Udo Dannlowski, Ana M. Díaz-Zuluaga, Katharina Dohm, Torbjørn Elvsåshagen, Kira Flinkenflügel, Lydia Fortea, Lisa S. Furlong, Benjamin I. Goldstein, Dominik Grotegerd, Marius Gruber, Bartholomeus C. M. Haarman, Fleur M. Howells, Neda Jahanshad, Hamidreza Jamalabadi, Andreas Jansen, James A. Karantonis, Kody G. Kennedy, Tilo T. J. Kircher, Anna Luisa Klahn, Peter Kochunov, Anna Kraus, Mikael Landén, Carlos López-Jaramillo, Bradley J. MacIntosh, Elena Mazza, Colm McDonald, Andrew M. McIntosh, Hannah Meinert, Susanne Meinert, Elisa M. T. Melloni, Philip B. Mitchell, Igor Nenadić, Nils Opel, Mary Phillips, Camille Piguet, Mircea Polosan, Edith Pomarol-Clotet, Arnaud Pouchon, Joaquim Radua, Gloria Roberts, Alex J. Ross, Susan L. Rossell, Raymond Salvador, Kang Sim, Jair C. Soares, Giovana B. Zunta-Soares, Frederike Stein, Benjamin Straube, Chao Suo, Lea Teutenberg, Florian Thomas-Odenthal, Sophia I. Thomopoulos, Paula Usemann, Tamsyn E. Van Rheenen, Amelia Versace, Eduard Vieta, Enric Vilajosana, Benson Mwangi, Wei Wen, Heather C. Whalley, Mon-Ju Wu, Ole A. Andreassen, Christopher R. K. Ching, Paul M. Thompson, Josselin Houenou, Tomas Hajek

Although specific risk factors for brain alterations in bipolar disorders (BD) are currently unknown, obesity impacts the brain and is highly prevalent in BD. Gray matter correlates of obesity in BD have been well documented, but we know much less about brain white matter abnormalities in people who have both obesity and BD. We obtained body mass index (BMI) and diffusion tensor imaging derived fractional anisotropy (FA) from 22 white matter tracts in 899 individuals with BD, and 1287 control individuals from 20 cohorts in the ENIGMA-BD working group. In a mega-analysis, we investigated the associations between BMI, diagnosis or medication and FA. Lower FA was associated with both BD and BMI in six white matter tracts, including the corpus callosum and thalamic radiation. Higher BMI or BD were uniquely associated with lower FA in three and six white matter tracts, respectively. People not receiving lithium treatment had a greater negative association between FA and BMI than people treated with lithium in the posterior thalamic radiation and sagittal stratum. In three tracts BMI accounted for 10.5 to 17% of the negative association between the number of medication classes other than lithium and FA. Both overweight/obesity and BD demonstrated lower FA in some of the same regions. People prescribed lithium had a weaker association between BMI and FA than people not on lithium. In contrast, greater weight contributed to the negative associations between medications and FA. Obesity may add to brain alterations in BD and may play a role in effects of medications on the brain.

尽管双相情感障碍(BD)脑部改变的具体风险因素目前尚不清楚,但肥胖会影响大脑,而且在 BD 中非常普遍。肥胖与躁狂症的灰质相关性已有大量文献记载,但我们对同时患有肥胖症和躁狂症的患者脑白质异常的了解要少得多。我们从 ENIGMA-BD 工作组 20 个队列中的 899 名 BD 患者和 1287 名对照组患者的 22 个白质束中获得了体重指数(BMI)和弥散张量成像得出的分数各向异性(FA)。在一项大型分析中,我们研究了体重指数、诊断或药物治疗与 FA 之间的关系。在包括胼胝体和丘脑辐射在内的六个白质束中,较低的 FA 值与 BD 和 BMI 都有关联。较高的体重指数或BD分别在三个和六个白质束中与较低的FA独特相关。在丘脑后部辐射和矢状层,未接受锂治疗者的FA与BMI之间的负相关比接受锂治疗者更大。在三个道中,锂以外的药物种类数量与FA之间的负相关中,BMI占10.5%至17%。超重/肥胖和BD在一些相同的区域都表现出较低的FA。与未服用锂类药物的患者相比,服用锂类药物的患者的体重指数与FA之间的关联较弱。相反,体重越重,药物与FA之间的负相关越明显。肥胖可能会加重BD患者大脑的改变,并可能在药物对大脑的影响中发挥作用。
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引用次数: 0
Attention and executive delays in early childhood: a meta-analysis of neurodevelopmental conditions 幼儿期的注意力和执行力延迟:神经发育状况荟萃分析
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-03 DOI: 10.1038/s41380-024-02802-3
Dabin Lee, Kelsie A. Boulton, Carter Sun, Natalie L. Phillips, Martha Munro, Fiona Kumfor, Eleni A. Demetriou, Adam J. Guastella

The objective of this review was to evaluate attention and executive function performance in children with neurodevelopmental conditions across the first 5 years of life, compared to neurotypical peers. MEDLINE, EMBASE, and PsycINFO databases were searched until June 30, 2023, and studies comparing attention or executive function between children with (or at risk for) neurodevelopmental conditions and neurotypical (or low risk) peers, 0 to 5 years old, were included. Of the 4338 studies identified, 111 studies with 12292 participants were included in the meta-analysis. The qualitative analysis of brain development included 5 studies. Primary outcomes were the standardised mean difference (Hedges’ g) in attention and executive function between groups. Meta-regressions examined moderating effects of age, biological sex, diagnosis, and measure type. Children with neurodevelopmental conditions showed small delays in attention (n = 49 studies, k = 251 outcomes, g = 0.36, 95% CI 0.23-0.48, p < 0.001) and moderate delays in executive function (n = 64 studies, k = 368 outcomes, g = 0.64,95% CI 0.53–0.76, p < 0.001). Attention and executive function delays could not be identified in the first year (equivalence tests, p < 0.001), small to moderate delays were found in toddlerhood and moderate delays by preschool. Delays identified were largely transdiagnostic, although there was some evidence of diagnosis-specific delays for attention and moderation by measure type (informant rating vs performance-based vs physiological). Qualitative analysis described how delays were underpinned by a divergence of brain development in medial prefrontal regions. These findings highlight the potential of using attention and executive measures to detect delay and to intervene in neurodevelopmental conditions early in life.

本综述旨在评估患有神经发育疾病的儿童与神经正常的同龄人相比,在生命最初 5 年中的注意力和执行功能表现。在 2023 年 6 月 30 日之前,我们检索了 MEDLINE、EMBASE 和 PsycINFO 数据库,并纳入了比较神经发育障碍儿童(或高危儿童)和神经正常(或低危)儿童(0-5 岁)的注意力或执行功能的研究。在确定的 4338 项研究中,有 111 项研究、12292 名参与者被纳入荟萃分析。大脑发育的定性分析包括 5 项研究。主要结果是各组间注意力和执行功能的标准化平均差异(Hedges'g)。元回归研究了年龄、生理性别、诊断和测量类型的调节作用。患有神经发育疾病的儿童在注意力方面表现出轻度延迟(n = 49 项研究,k = 251 项结果,g = 0.36,95% CI 0.23-0.48, p <0.001),在执行功能方面表现出中度延迟(n = 64 项研究,k = 368 项结果,g = 0.64,95% CI 0.53-0.76, p <0.001)。注意力和执行功能延迟在一岁内无法确定(等效测试,p <0.001),在幼儿期发现小到中度延迟,学龄前发现中度延迟。尽管有一些证据表明注意力和调节能力方面的延迟存在特定的诊断延迟,但所发现的延迟在很大程度上是跨诊断的(信息评定与基于表现的评定相比,生理评定与基于表现的评定相比)。定性分析描述了大脑内侧前额叶区域的发育差异是如何导致延迟的。这些发现凸显了使用注意力和执行力测量来检测延迟和干预生命早期神经发育状况的潜力。
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引用次数: 0
Causal and common risk pathways linking childhood maltreatment to later intimate partner violence victimization 童年遭受虐待与日后遭受亲密伴侣暴力侵害之间的因果关系和共同风险途径
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-02 DOI: 10.1038/s41380-024-02813-0
Patrizia Pezzoli, Jean-Baptiste Pingault, Thalia C. Eley, Eamon McCrory, Essi Viding

Childhood maltreatment and intimate partner violence (IPV) victimization are major psychiatric risk factors. Maltreatment substantially increases the likelihood of subsequent IPV victimization, but what drives this association is poorly understood. We analyzed retrospective self-reports of maltreatment and IPV victimization in 12,794 participants (58% women, 42% men) from the Twins Early Development Study at ages 21 and 26 using quantitative genetic methods. We estimated the etiological influences common to maltreatment and IPV, and the effect of maltreatment on IPV beyond such common influences. Participants who reported childhood maltreatment ( ~ 7% of the sample) were 3 times more likely than their peers to also report IPV victimization at age 21, 4 times more likely at 26. The association between maltreatment and IPV was mostly due to environmental influences shared by co-twins (42–43%) and genetic influences (30–33%), as well as nonshared environmental influences (25–27%). The association between maltreatment and IPV was similar for women and men, but its etiology partly differed by sex. Maltreatment had a moderate effect on IPV in phenotypic models (β = 0.25–0.30), decreasing to a small-to-moderate range in causally informative models accounting for their common etiology (β = 0.15–0.21). Risk factors common to maltreatment and IPV victimization are largely familial in origin, environmental and genetic. Even considering common risk factors, experiencing maltreatment may be causally related to subsequent IPV victimization. Interventions promoting safe intimate relationships among young adults exposed to maltreatment are warranted and should address family-level environmental risk and individual-level risk shaped by genetics.

童年虐待和亲密伴侣暴力(IPV)受害是主要的精神疾病风险因素。虐待会大大增加随后成为 IPV 受害者的可能性,但这种关联的驱动因素却鲜为人知。我们采用定量遗传学方法分析了双胞胎早期发育研究(Twins Early Development Study)中 12,794 名参与者(58% 为女性,42% 为男性)在 21 岁和 26 岁时对虐待和 IPV 受害情况的回顾性自我报告。我们估计了虐待和 IPV 的共同病因影响,以及虐待对 IPV 的影响超出了这些共同影响。报告童年遭受虐待的参与者(约占样本的 7%)在 21 岁时报告遭受 IPV 的可能性是同龄人的 3 倍,在 26 岁时是同龄人的 4 倍。虐待与 IPV 之间的关联主要是由于同卵双胞胎共享的环境影响(42%-43%)和遗传影响(30%-33%)以及非共享的环境影响(25%-27%)造成的。虐待与 IPV 之间的关系在女性和男性中相似,但其病因在一定程度上因性别而异。在表型模型(β = 0.25-0.30)中,虐待对 IPV 有中等程度的影响,而在考虑到二者共同病因的因果信息模型(β = 0.15-0.21)中,虐待对 IPV 的影响降至小到中等程度。虐待和 IPV 受害的共同风险因素主要来自家庭、环境和遗传。即使考虑到常见的风险因素,遭受虐待也可能与随后的 IPV 受害有因果关系。有必要采取干预措施,促进遭受虐待的年轻成年人建立安全的亲密关系,并应解决家庭层面的环境风险和由遗传形成的个人层面的风险。
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引用次数: 0
Investigating the impact of severe maternal SARS-CoV-2 infection on infant DNA methylation and neurodevelopment. 研究母体严重感染 SARS-CoV-2 对婴儿 DNA 甲基化和神经发育的影响
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1038/s41380-024-02808-x
Rachel A Hill, Andrew Gibbons, Wittaya Suwakulsiri, Angela Taseska, Hayley Darke, Atul Malhotra, Hnin Yee, Michael Fahey, Rod W Hunt, Izaak Lim, Kirsten Palmer, Suresh Sundram

Maternal infections during pregnancy can increase the risk to offspring of developing a neurodevelopmental disorder. Given the global prevalence and severity of infection with Severe Acute Respiratory Syndrome related Coronavirus 2 (SARS-CoV-2), the objective of this study was to determine if in utero exposure to severe maternal SARS-CoV-2 infection alters infant neurodevelopmental outcomes at 12 months and to identify potential biological markers of adverse infant outcomes. Mother-infant dyads exposed to severe SARS-CoV-2 infection (requiring hospitalization) during pregnancy and age and sociodemographic matched control dyads were recruited from Monash Medical Centre, Australia in 2021/22 and prospectively assessed over 12 months. Maternal serum cytokine levels and Edinburgh Postnatal Depression Scale (EPDS) scores were assessed at birth. DNA methylation was assessed from infant buccal swabs at birth (Illumina EPIC BeadChip). Infant neurodevelopmental outcomes at 12 months were assessed using the Ages and Stages Questionnaire (ASQ-3). Mothers exposed to severe SARS-CoV-2 exhibited elevated serum IL-6 and IL-17A and higher EPDS scores than controls at birth. Infants exposed to severe SARS-CoV-2 in utero demonstrated over 3000 significant differentially methylated sites within their genomes compared to non-exposed (adjusted p-value < 0.05), including genes highly relevant to ASD and synaptic pathways. At 12 months, severe SARS-CoV-2 exposed infants scored lower on the ASQ-3 than non-exposed infants, and communication and problem-solving scores negatively correlated with maternal IL-6 levels at birth. DNA methylation changes therefore unveil potential mechanisms linking infection exposure to delayed neurodevelopment and maternal serum IL-6 levels may be a potential biomarker of child developmental delay. Mothers exposed to severe SARS-CoV-2 infections show elevated pro-inflammatory cytokines. Infants exposed in utero to severe SARS-CoV-2 infection show altered DNA methylation at birth and delayed development at 12 months of age. Created in Biorender.com.

孕期母体感染会增加后代患神经发育障碍的风险。鉴于与严重急性呼吸系统综合征相关的冠状病毒 2(SARS-CoV-2)感染在全球的流行程度和严重性,本研究的目的是确定子宫内暴露于严重的母体 SARS-CoV-2 感染是否会改变婴儿 12 个月时的神经发育结果,并确定婴儿不良结果的潜在生物学标志物。研究人员于 2021/22 年从澳大利亚莫纳什医疗中心招募了在怀孕期间受到严重 SARS-CoV-2 感染(需要住院治疗)的母婴二人组以及年龄和社会人口匹配的对照二人组,并对其进行了为期 12 个月的前瞻性评估。出生时对母体血清细胞因子水平和爱丁堡产后抑郁量表(EPDS)评分进行评估。通过婴儿出生时的口腔拭子(Illumina EPIC BeadChip)对DNA甲基化进行评估。使用年龄与阶段问卷(ASQ-3)评估婴儿 12 个月时的神经发育结果。与对照组相比,暴露于严重SARS-CoV-2的母亲在出生时血清IL-6和IL-17A升高,EPDS评分升高。与未暴露于严重 SARS-CoV-2 的婴儿相比,在子宫内暴露于严重 SARS-CoV-2 的婴儿的基因组中有超过 3000 个显著不同的甲基化位点(调整后的 p-value
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引用次数: 0
Serum anti-NMDA receptor antibodies are linked to memory impairment 12 months after stroke 血清抗 NMDA 受体抗体与中风 12 个月后的记忆障碍有关
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1038/s41380-024-02744-w
Friederike A. Arlt, Pia S. Sperber, Regina von Rennenberg, Pimrapat Gebert, Bianca Teegen, Marios K. Georgakis, Rong Fang, Anna Dewenter, Michael Görtler, Gabor C. Petzold, Silke Wunderlich, Inga Zerr, Martin Dichgans, Harald Prüss, Matthias Endres

Patients suffering from strokes are at increased risk of developing post-stroke dementia. Serum anti-NMDA receptor autoantibodies (NMDAR1-abs) have been associated with unfavorable post-stroke outcomes. However, their effect on specific cognitive domains remains unclear. We used data from the prospective multicenter DZNE—mechanisms after stroke (DEMDAS) cohort, and measured NMDAR1-abs in serum at baseline. Cognitive function was assessed with a comprehensive neuropsychological test battery at 6- and 12-months follow-up. We employed crude and stepwise confounder adjusted linear and logistic regression models as well as generalized estimating equation models (GEE) to determine the relevance of NMDAR1-abs seropositivity on cognitive function after stroke. 10.2% (58/569) DEMDAS patients were NMDAR1-abs seropositive (IgM:n = 44/IgA:n = 21/IgG:n = 2). Seropositivity was not associated with global cognitive impairment after stroke. However, NMDAR1-abs seropositive patients performed lower in the memory domain (βadjusted = −0.11; 95%CI = −0.57 to −0.03) and were at increased risk for memory impairment (ORadjusted = 3.8; 95%CI = 1.33–10.82) compared to seronegative patients, 12 months after stroke. Further, NMDAR1-abs were linked to memory impairment over time in GEE from 6- to 12-months follow-up (ORadjusted = 2.41; 95%CI = 1.05–5.49). Our data suggests that NMDAR1-abs contribute to memory dysfunction 1 year after stroke while not affecting other cognitive subdomains. Hence, antineuronal autoimmunity may be involved in distinct mechanisms of post-stroke memory impairment. Clinical trial name and registration number: The Determinants of Dementia After Stroke (DEMDAS; study identifier on clinical trials.gov: NCT01334749)

中风患者罹患中风后痴呆症的风险增加。血清抗 NMDA 受体自身抗体(NMDAR1-abs)与中风后的不良预后有关。然而,它们对特定认知领域的影响仍不清楚。我们使用了前瞻性多中心中风后机制(DZNE-mechanisms after stroke,DEMDAS)队列的数据,并在基线时测量了血清中的 NMDAR1-abs。在 6 个月和 12 个月的随访中,我们使用全面的神经心理学测试对认知功能进行了评估。我们采用了粗略和逐步混杂因素调整线性和逻辑回归模型以及广义估计方程模型(GEE)来确定 NMDAR1-abs 血清阳性与中风后认知功能的相关性。10.2%(58/569)的 DEMDAS 患者 NMDAR1-abs 血清阳性(IgM:n = 44/IgA:n = 21/IgG:n = 2)。血清阳性与中风后的整体认知障碍无关。然而,与血清阴性患者相比,NMDAR1-abs 血清阳性患者在中风 12 个月后的记忆领域表现较差(β 调整后 = -0.11;95%CI = -0.57 至 -0.03),且记忆损伤风险增加(OR 调整后 = 3.8;95%CI = 1.33-10.82)。此外,在随访 6 至 12 个月的 GEE 中,NMDAR1-abs 与记忆力受损的时间相关(OR 调整 = 2.41;95%CI = 1.05-5.49)。我们的数据表明,NMDAR1-abs 会导致中风 1 年后的记忆功能障碍,但不会影响其他认知子域。因此,抗神经元自身免疫可能与中风后记忆障碍的不同机制有关。临床试验名称和注册编号:中风后痴呆的决定因素(DEMDAS;临床试验网站上的研究标识符:NCT01334749)
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引用次数: 0
Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival 神经退行性疾病中的外周先天性免疫表型:基于血液的特征以及与存活的联系
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41380-024-02809-w
Alexandra Strauss, Peter Swann, Stacey L. Kigar, Rafailia Christou, Natalia Savinykh Yarkoni, Lorinda Turner, Alexander G. Murley, Leonidas Chouliaras, Noah Shapiro, Nicholas J. Ashton, George Savulich, W. Richard Bevan-Jones, Ajenthan Surendranthan, Kaj Blennow, Henrik Zetterberg, John T. O’Brien, James B. Rowe, Maura Malpetti

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells in n = 148 people with Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), Lewy body dementia (LBD) as compared to n = 37 healthy controls. To compare groups, we used multivariate dissimilarity analysis and principal component analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between patient groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals’ immune profile weighting, positively to TREM2+ and non-classical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches in dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.

先天性免疫系统在许多神经退行性疾病的发展过程中扮演着不可或缺的角色。除了中枢先天性免疫细胞(如小胶质细胞)外,外周先天性免疫细胞(如血单核细胞、自然杀伤细胞和树突状细胞)在这些疾病中也可能有所不同。然而,不同神经退行性疾病的外周先天性免疫细胞类型的特征描述仍不完整。本研究旨在使用流式细胞仪对148名阿尔茨海默病(AD)、额颞叶痴呆(FTD)、皮质基底综合征(CBS)、进行性核上性麻痹(PSP)和路易体痴呆(LBD)患者的外周血单核细胞进行免疫分型,并与37名健康对照者进行比较,以确定外周先天性免疫特征。为了对各组进行比较,我们对 19 种先天性免疫细胞类型进行了多变量差异分析和主成分分析。我们确定了全因痴呆症患者与健康对照组之间存在显著差异的促炎特征,患者组之间也存在一些显著差异。回归分析证实,血液检测后的死亡时间与个人的免疫特征权重相关,与 TREM2+ 和非典型单核细胞呈正相关,与典型单核细胞呈负相关。总之,这些结果描述了跨诊断的外周免疫特征,并强调了预后与单核细胞细分和功能(通过表面蛋白表达衡量)之间的联系。这些结果表明,血液中的先天性免疫特征可以为与特定神经退行性疾病相关的细胞亚群提供信息,这些亚群与疾病的加速进展和不同诊断的较差生存结果有着显著的联系。基于血液的先天性免疫图谱可能有助于增强痴呆症的精准医疗方法,帮助确定和监测治疗靶点,并对候选免疫疗法的患者进行分层。
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引用次数: 0
Whole exome sequencing identified six novel genes for depressive symptoms 全外显子组测序确定了抑郁症状的六个新基因
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41380-024-02804-1
Ze-Yu Li, Chen-Jie Fei, Rui-Ying Yin, Ju-Jiao Kang, Qing Ma, Xiao-Yu He, Xin-Rui Wu, Yu-Jie Zhao, Wei Zhang, Wei-Shi Liu, Bang-Sheng Wu, Liu Yang, Ying Zhu, Jian-Feng Feng, Jin-Tai Yu, Wei Cheng

Previous genome-wide association studies of depression have primarily focused on common variants, limiting our comprehensive understanding of the genetic architecture. In contrast, whole–exome sequencing can capture rare coding variants, helping to explore the phenotypic consequences of altering protein-coding genes. Here, we conducted a large-scale exome-wide association study on 296,199 participants from the UK Biobank, assessing their depressive symptom scores through the Patient Health Questionnaire-4. We identified 22 genes associated with depressive symptoms, including 6 newly discovered genes (TRIM27, UBD, SVOP, ADGRB2, IRF2BPL, and ANKRD12). Both ontology enrichment analysis and plasma proteomics association analysis consistently revealed that the identified genes were associated with immune responses. Furthermore, we identified associations between these genes and brain regions related to depression, such as anterior cingulate cortex and orbitofrontal cortex. Additionally, phenome-wide association analysis demonstrated that TRIM27 and UBD were associated with neuropsychiatric, cognitive, biochemistry, and inflammatory traits. Our findings offer new insights into the potential mechanisms and genetic architecture of depressive symptoms.

以往的抑郁症全基因组关联研究主要关注常见变异,限制了我们对遗传结构的全面了解。相比之下,全外显子组测序可以捕获罕见的编码变异,有助于探索改变蛋白编码基因的表型后果。我们发现了22个与抑郁症状相关的基因,其中包括6个新发现的基因(TRIM27、UBD、SVOP、ADGRB2、IRF2BPL和ANKRD12)。本体富集分析和血浆蛋白质组学关联分析一致显示,所发现的基因与免疫反应有关。此外,我们还发现了这些基因与抑郁症相关脑区(如前扣带回皮层和眶额皮层)之间的关联。此外,全表型关联分析表明,TRIM27 和 UBD 与神经精神、认知、生物化学和炎症特征相关。我们的研究结果为抑郁症状的潜在机制和遗传结构提供了新的见解。
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引用次数: 0
Integrity of the circadian clock determines regularity of high-frequency and diurnal LFP rhythms within and between brain areas 昼夜节律钟的完整性决定了脑区内部和脑区之间高频和昼夜 LFP 节律的规律性
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41380-024-02795-z
Paul Volkmann, Annika E. I. Geiger, Anisja Hühne-Landgraf, Nina Miljanovic, Jessica Bly, Tobias Engl, Heidrun Potschka, Moritz J. Rossner, Dominic Landgraf

Circadian clocks control most physiological processes of many species. We specifically wanted to investigate the influence of environmental and endogenous rhythms and their interplay on electrophysiological dynamics of neuronal populations. Therefore, we measured local field potential (LFP) time series in wild-type and Cryptochrome 1 and 2 deficient (Cry1/2−/−) mice in the suprachiasmatic nucleus and the nucleus accumbens under regular light conditions and constant darkness. Using refined descriptive and statistical analyses, we systematically profiled LFP time series activity. We show that both environmental and endogenous rhythms strongly influence the rhythmicity of LFP signals and their frequency components, but also shape neuronal patterns on much smaller time scales, as neuronal activity in Cry1/2−/− mice is significantly less regular but at each time more synchronous within and between brain areas than in wild-type mice. These results show that functional circadian rhythms are integral for both circadian and non-circadian coordination of neuronal ensemble dynamics.

昼夜节律控制着许多物种的大部分生理过程。我们特别想研究环境和内源性节律及其相互作用对神经元群电生理动态的影响。因此,我们测量了野生型小鼠和隐色素 1 和 2 缺乏(Cry1/2-/-)型小鼠在常规光照条件和恒定黑暗条件下丘脑上核和伏隔核的局部场电位(LFP)时间序列。通过精细的描述和统计分析,我们对 LFP 时间序列活动进行了系统分析。我们发现,环境节律和内源性节律对 LFP 信号及其频率成分的节律性有很大影响,而且还能在更小的时间尺度上塑造神经元模式,因为 Cry1/2-/- 小鼠的神经元活动明显没有野生型小鼠那么规律,但每次在脑区内部和脑区之间的同步性都比野生型小鼠强。这些结果表明,功能性昼夜节律对于神经元集合动态的昼夜和非昼夜协调都是不可或缺的。
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引用次数: 0
Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay GSK3B 单倍功能缺失变异导致自闭症和发育迟缓
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41380-024-02806-z
Senwei Tan, Qiumeng Zhang, Rui Zhan, Si Luo, Yaoling Han, Bin Yu, Candace Muss, Veronique Pingault, Sandrine Marlin, Andrée Delahaye, Sophia Peters, Claudia Perne, Martina Kreiß, Nino Spataro, Juan Pablo Trujillo-Quintero, Caroline Racine, Frederic Tran-Mau-Them, Chanika Phornphutkul, Aaron D. Besterman, Julian Martinez, Xiuxia Wang, Xiaoyu Tian, Siddharth Srivastava, David K. Urion, Jill A. Madden, Hind Al Saif, Michelle M. Morrow, Amber Begtrup, Xing Li, Sarah Jurgensmeyer, Peter Leahy, Shimin Zhou, Faxiang Li, Zhengmao Hu, Jieqiong Tan, Kun Xia, Hui Guo

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

邻近规范剪接位点或明确剪接相关区域的从头变异更有可能损害剪接,但在自闭症谱系障碍(ASD)中,对这些变异的研究仍然不足。通过分析最近的大型 ASD 基因组测序队列,我们发现,与 4090 个未受影响的兄弟姐妹相比,5048 个疑似患者中存在大量从头产生的潜在剪接干扰变异(PSDVs)。我们发现 55 个基因反复出现新的 PSDV,这些基因对变异的耐受性很差。其中 46 个基因以前与 ASD 或其他神经发育障碍没有密切联系,包括 GSK3B。通过国际多中心合作,我们收集了 15 个 GSK3B 变异个体的基因型和表型数据,并确定了包括发育迟缓、ASD、睡眠障碍和攻击行为在内的常见表型。利用现有的单细胞转录组数据,我们发现 GSK3B 在发育中的大脑背侧祖细胞和中间形式的兴奋神经元中富集。我们发现,在小鼠兴奋性神经元中敲除 Gsk3b 会干扰树突分枝和棘突成熟,而从受影响个体中发现的从头错义变体无法挽救这一点。总之,我们的研究结果表明,PSDVs 可能在 ASD 的遗传病因学中扮演重要角色,并允许优先选择新的 ASD 候选基因。重要的是,我们发现导致 GSK3B 功能缺失的遗传变异可导致具有 ASD 核心特征和发育迟缓的神经发育障碍。
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引用次数: 0
Long-term clinical outcome of a novel bilateral capsulotomy with focused ultrasound in refractory obsessive-compulsive disorder treatment. 在难治性强迫症治疗中使用聚焦超声波的新型双侧囊肿切开术的长期临床效果。
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s41380-024-02799-9
Kyung Won Chang, Jhin Goo Chang, Hyun Ho Jung, Chan-Hyung Kim, Jin Woo Chang, Se Joo Kim

Magnetic resonance-guided focused ultrasound (MRgFUS) capsulotomy is a promising treatment for refractory obsessive-compulsive disorder (OCD); however, long-term clinical outcome studies are lacking. We aimed to investigate the long-term efficacy and safety of MRgFUS capsulotomy in patients with refractory OCD. Ten of the eleven patients who underwent MRgFUS capsulotomy for treatment-resistant OCD between 2013 and 2014 were included in this study. Clinical outcomes were assessed after 10 years of follow-up post-MRgFUS capsulotomy using tools such as neuropsychological test, the Frontal Systems Behavior Scale (FrSBe), and a locally developed MRgFUS-patient-centered outcomes questionnaire. After 10 years of follow-up, there was a mean improvement of 52.3% in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score. Seven out of the ten participants responded fully (Y-BOCS reduction ≥35% + CGI-I 1 or 2) to the procedure, two of whom achieved remission (Y-BOCS score ≤12 and CGI-S 1 or 2). Obsessive-compulsive symptoms and overall functioning significantly reduced and improved, respectively (Y-BOCS = 20.7 after 2 years vs. 16.4 after 10 years, p = 0.012; Global Assessment of Functioning = 57.4 after 2 years vs. 69.0 after 10 years, p = 0.011). The patients experienced significantly improved frontal lobe-related functions (FrSBe Sum before 91.0 ± 17.6 vs. after 78.6 ± 17.7, p < 0.05). No adverse effects, including cases of suicide and neurological deficits, were reported. The majority of the respondents were generally satisfied with MRgFUS capsulotomy. MRgFUS capsulotomy is an effective and safe treatment option for the treatment of severe refractory OCD with sustained efficacy even after 10 years.

磁共振引导下聚焦超声(MRgFUS)囊膜切开术是治疗难治性强迫症(OCD)的一种很有前景的方法;然而,目前还缺乏长期临床效果研究。我们旨在研究 MRgFUS 胶囊切开术对难治性强迫症患者的长期疗效和安全性。本研究纳入了 2013 年至 2014 年期间接受 MRgFUS 胶囊切开术治疗难治性强迫症的 11 例患者中的 10 例。研究人员使用神经心理学测试、额叶系统行为量表(FrSBe)和当地开发的以患者为中心的 MRgFUS 结果问卷等工具,对 MRgFUS 胶囊切除术后随访 10 年的临床结果进行了评估。经过10年的随访,耶鲁-布朗强迫症量表(Y-BOCS)得分平均提高了52.3%。十名参与者中有七人对手术完全满意(Y-BOCS 降低≥35% + CGI-I 1 或 2),其中两人达到缓解(Y-BOCS 评分≤12 和 CGI-S 1 或 2)。强迫症状和总体功能分别明显减轻和改善(2 年后 Y-BOCS = 20.7 vs. 10 年后 16.4,p = 0.012;2 年后总体功能评估 = 57.4 vs. 10 年后 69.0,p = 0.011)。患者的额叶相关功能有了明显改善(FrSBe Sum 前为 91.0 ± 17.6,后为 78.6 ± 17.7,p = 0.012)。
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引用次数: 0
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Molecular Psychiatry
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