β-amyloid (Aβ) pathology is not always coupled with Alzheimer’s disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aβ(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aβ and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer’s Disease Neuroimaging Initiative dataset. The participants were dichotomously grouped based on either clinical conversion (i.e., change of diagnosis) or cognitive deterioration (fast (FDs) vs. slow decliners (SDs)) using data-driven clustering of the individual annual rates of cognitive decline. To assess cognitive decline in individuals with isolated Aβ(+) or absence of both Aβ and tau (T) pathologies, we investigated the prevalence of non-AD comorbidities and FDG PET hypometabolism patterns suggestive of AD. Baseline tau PET uptake was higher in Aβ(+)FDs than in Aβ(-)FD/SDs and Aβ(+)SDs, independently of baseline cognitive status. Baseline tau PET uptake identified MCI Aβ(+) Converters and Aβ(+)FDs with an area under the curve of 0.85 and 0.87 (composite temporal region of interest) respectively, and was linearly related to the annual rate of cognitive decline in Aβ(+) individuals. The T(+) individuals constituted largely a subgroup of those being Aβ(+) and those clustered as FDs. The most common biomarker profiles in FDs (n = 70) were Aβ(+)T(+) (n = 34, 49%) and Aβ(+)T(-) (n = 19, 27%). Baseline Aβ load was higher in Aβ(+)T(+)FDs (M = 83.03 ± 31.42CL) than in Aβ(+)T(-)FDs (M = 63.67 ± 26.75CL) (p-value = 0.038). Depression diagnosis was more prevalent in Aβ(+)T(-)FDs compared to Aβ(+)T(+)FDs (47% vs. 15%, p-value = 0.021), as were FDG PET hypometabolism pattern not suggestive of AD (86% vs. 50%, p-value = 0.039). Our findings suggest that high tau PET uptake is coupled with both Aβ pathology and accelerated cognitive decline. In cases of isolated Aβ(+), cognitive decline may be associated with changes within the AD spectrum in a multi-morbidity context, i.e., mixed AD.
β-淀粉样蛋白(Aβ)病理学并不总是与阿尔茨海默病(AD)相关的认知能力下降同时发生。我们评估了 tau PET 识别 Aβ(+)个体的准确性,这些个体显示出前瞻性的疾病进展。我们从阿尔茨海默病神经影像学倡议数据集中选取了 396 名认知功能未受损和受损的患者,他们的基线 Aβ 和 tau PET 随访时间≥ 2 年。根据临床转换(即诊断改变)或认知退化(快速(FDs)与慢速(SDs)),利用数据驱动的个人年度认知衰退率聚类对参与者进行二分法分组。为了评估孤立Aβ(+)或同时缺乏Aβ和tau(T)病理的个体的认知能力下降情况,我们调查了非AD合并症的患病率以及提示AD的FDG PET代谢减低模式。基线tau PET摄取量在Aβ(+)FD中高于Aβ(-)FD/SD和Aβ(+)SD,与基线认知状态无关。基线tau PET摄取量可识别MCI Aβ(+)转换者和Aβ(+)FD,曲线下面积分别为0.85和0.87(综合颞部感兴趣区),并与Aβ(+)个体的认知能力年下降率呈线性关系。T(+)个体主要是 Aβ(+)个体和 FDs 聚类个体的一个亚群。在 FDs(n = 70)中,最常见的生物标志物特征是 Aβ(+)T(+)(n = 34,49%)和 Aβ(+)T(-)(n = 19,27%)。Aβ(+)T(+)FDs 的基线 Aβ 负荷(M = 83.03 ± 31.42CL)高于 Aβ(+)T(-)FDs 的基线 Aβ 负荷(M = 63.67 ± 26.75CL)(P 值 = 0.038)。与Aβ(+)T(+)FDs相比,抑郁症诊断在Aβ(+)T(-)FDs中更为普遍(47% vs. 15%,p值=0.021),FDG PET低代谢模式未提示AD(86% vs. 50%,p值=0.039)。我们的研究结果表明,tau PET高摄取与Aβ病理学和认知能力加速衰退有关。在孤立的Aβ(+)病例中,认知能力下降可能与多病情况下的AD谱系变化有关,即混合型AD。
{"title":"Tau PET positivity predicts clinically relevant cognitive decline driven by Alzheimer’s disease compared to comorbid cases; proof of concept in the ADNI study","authors":"Konstantinos Ioannou, Marco Bucci, Antonios Tzortzakakis, Irina Savitcheva, Agneta Nordberg, Konstantinos Chiotis","doi":"10.1038/s41380-024-02672-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02672-9","url":null,"abstract":"<p>β-amyloid (Aβ) pathology is not always coupled with Alzheimer’s disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aβ(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aβ and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer’s Disease Neuroimaging Initiative dataset. The participants were dichotomously grouped based on either clinical conversion (i.e., change of diagnosis) or cognitive deterioration (fast (FDs) vs. slow decliners (SDs)) using data-driven clustering of the individual annual rates of cognitive decline. To assess cognitive decline in individuals with isolated Aβ(+) or absence of both Aβ and tau (T) pathologies, we investigated the prevalence of non-AD comorbidities and FDG PET hypometabolism patterns suggestive of AD. Baseline tau PET uptake was higher in Aβ(+)FDs than in Aβ(-)FD/SDs and Aβ(+)SDs, independently of baseline cognitive status. Baseline tau PET uptake identified MCI Aβ(+) Converters and Aβ(+)FDs with an area under the curve of 0.85 and 0.87 (composite temporal region of interest) respectively, and was linearly related to the annual rate of cognitive decline in Aβ(+) individuals. The T(+) individuals constituted largely a subgroup of those being Aβ(+) and those clustered as FDs. The most common biomarker profiles in FDs (<i>n</i> = 70) were Aβ(+)T(+) (<i>n</i> = 34, 49%) and Aβ(+)T(-) (<i>n</i> = 19, 27%). Baseline Aβ load was higher in Aβ(+)T(+)FDs (M = 83.03 ± 31.42CL) than in Aβ(+)T(-)FDs (M = 63.67 ± 26.75CL) (<i>p</i>-value = 0.038). Depression diagnosis was more prevalent in Aβ(+)T(-)FDs compared to Aβ(+)T(+)FDs (47% vs. 15%, <i>p</i>-value = 0.021), as were FDG PET hypometabolism pattern not suggestive of AD (86% vs. 50%, <i>p</i>-value = 0.039). Our findings suggest that high tau PET uptake is coupled with both Aβ pathology and accelerated cognitive decline. In cases of isolated Aβ(+), cognitive decline may be associated with changes within the AD spectrum in a multi-morbidity context, i.e., mixed AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045508","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 : 2024-08-23DOI: 10.1038/s41380-024-02696-1
Andreas Hahn, Murray B. Reed, Matej Murgaš, Chrysoula Vraka, Sebastian Klug, Clemens Schmidt, Godber M. Godbersen, Benjamin Eggerstorfer, David Gomola, Leo R. Silberbauer, Lukas Nics, Cécile Philippe, Marcus Hacker, Rupert Lanzenberger
Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [11C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = −0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = −0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing.
{"title":"Dynamics of human serotonin synthesis differentially link to reward anticipation and feedback","authors":"Andreas Hahn, Murray B. Reed, Matej Murgaš, Chrysoula Vraka, Sebastian Klug, Clemens Schmidt, Godber M. Godbersen, Benjamin Eggerstorfer, David Gomola, Leo R. Silberbauer, Lukas Nics, Cécile Philippe, Marcus Hacker, Rupert Lanzenberger","doi":"10.1038/s41380-024-02696-1","DOIUrl":"https://doi.org/10.1038/s41380-024-02696-1","url":null,"abstract":"<p>Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [<sup>11</sup>C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = −0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = −0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045501","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 : 2024-08-22DOI: 10.1038/s41380-024-02694-3
Claudia Aymerich, Gonzalo Salazar de Pablo, Malein Pacho, Violeta Pérez-Rodríguez, Amaia Bilbao, Lucía Andrés, Borja Pedruzo, Idoia Castillo-Sintes, Nerea Aranguren, Paolo Fusar-Poli, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres, Ana Catalán
Patients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear. To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics. Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95). Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44). Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia compared to oral antipsychotics. Better adherence to the medication and health services may explain this difference. Whenever possible, the use of LAIs should be considered from the FEP.
{"title":"All-cause mortality risk in long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis","authors":"Claudia Aymerich, Gonzalo Salazar de Pablo, Malein Pacho, Violeta Pérez-Rodríguez, Amaia Bilbao, Lucía Andrés, Borja Pedruzo, Idoia Castillo-Sintes, Nerea Aranguren, Paolo Fusar-Poli, Iñaki Zorrilla, Ana González-Pinto, Miguel Ángel González-Torres, Ana Catalán","doi":"10.1038/s41380-024-02694-3","DOIUrl":"https://doi.org/10.1038/s41380-024-02694-3","url":null,"abstract":"<p>Patients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear. To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics. Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95). Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44). Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia compared to oral antipsychotics. Better adherence to the medication and health services may explain this difference. Whenever possible, the use of LAIs should be considered from the FEP.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021967","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 : 2024-08-22DOI: 10.1038/s41380-024-02695-2
Soumyabrata Munshi, Ahlam M Alarbi, Haixia Zheng, Rayus Kuplicki, Kaiping Burrows, Leandra K Figueroa-Hall, Teresa A Victor, Robin L Aupperle, Sahib S Khalsa, Martin P Paulus, T Kent Teague, Jonathan Savitz
A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. Sensitivity analyses excluding covariates yielded similar results. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) remained significant and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. NLRC4 and MFN2 were positively correlated with serum C-reactive protein concentrations, while ASC trended significant. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.
{"title":"Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder.","authors":"Soumyabrata Munshi, Ahlam M Alarbi, Haixia Zheng, Rayus Kuplicki, Kaiping Burrows, Leandra K Figueroa-Hall, Teresa A Victor, Robin L Aupperle, Sahib S Khalsa, Martin P Paulus, T Kent Teague, Jonathan Savitz","doi":"10.1038/s41380-024-02695-2","DOIUrl":"10.1038/s41380-024-02695-2","url":null,"abstract":"<p><p>A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative C<sub>T</sub> (2<sup>-ΔΔCT</sup>) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. Sensitivity analyses excluding covariates yielded similar results. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) remained significant and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. NLRC4 and MFN2 were positively correlated with serum C-reactive protein concentrations, while ASC trended significant. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036356","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 : 2024-08-22DOI: 10.1038/s41380-024-02700-8
Julian Konzok, Mathias Gorski, Thomas W Winkler, Sebastian E Baumeister, Varun Warrier, Michael F Leitzmann, Hansjörg Baurecht
Observational studies suggest that child maltreatment increases the risk of externalizing spectrum disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD). Yet, only few of such associations have been investigated by approaches that provide strong evidence for causation, such as Mendelian Randomization (MR). Establishing causal inference is essential given the growing recognition of gene-environment correlations, which can confound observational research in the context of childhood maltreatment. Evaluating causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases; 256,859 controls), ASPD (381 cases; 252,877 controls), alcohol use disorder (AUD; 13,422 cases; 244,533 controls), opioid use disorder (OUD; 775 cases; 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases; 343,726 controls). We also generated a latent variable 'common externalizing factor' (EXT) using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76-21.40; P = 1.63 × 10-09), AUD (OR, 3.72; 95%-CI, 1.85-7.52; P = 2.42 × 10-04), and the EXT (OR, 2.64; 95%-CI, 1.52-4.60; P = 5.80 × 10-04) across the different analyses and pleiotropy-robust methods. A subsequent GWAS on childhood maltreatment and the externalizing dimension from Externalizing Consortium (EXT-CON) confirmed these results. Two of the top five genes with the strongest associations in EXT GWAS, CADM2 and SEMA6D, are also ranked among the top 10 in the EXT-CON. The present results confirm the existence of a common externalizing factor and an increasing vulnerability caused by child maltreatment, with crucial implications for prevention. However, the partly diverging results also indicate that specific influences impact individual phenotypes separately.
{"title":"Child maltreatment as a transdiagnostic risk factor for the externalizing dimension: a Mendelian randomization study.","authors":"Julian Konzok, Mathias Gorski, Thomas W Winkler, Sebastian E Baumeister, Varun Warrier, Michael F Leitzmann, Hansjörg Baurecht","doi":"10.1038/s41380-024-02700-8","DOIUrl":"https://doi.org/10.1038/s41380-024-02700-8","url":null,"abstract":"<p><p>Observational studies suggest that child maltreatment increases the risk of externalizing spectrum disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD). Yet, only few of such associations have been investigated by approaches that provide strong evidence for causation, such as Mendelian Randomization (MR). Establishing causal inference is essential given the growing recognition of gene-environment correlations, which can confound observational research in the context of childhood maltreatment. Evaluating causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases; 256,859 controls), ASPD (381 cases; 252,877 controls), alcohol use disorder (AUD; 13,422 cases; 244,533 controls), opioid use disorder (OUD; 775 cases; 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases; 343,726 controls). We also generated a latent variable 'common externalizing factor' (EXT) using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76-21.40; P = 1.63 × 10<sup>-09</sup>), AUD (OR, 3.72; 95%-CI, 1.85-7.52; P = 2.42 × 10<sup>-04</sup>), and the EXT (OR, 2.64; 95%-CI, 1.52-4.60; P = 5.80 × 10<sup>-04</sup>) across the different analyses and pleiotropy-robust methods. A subsequent GWAS on childhood maltreatment and the externalizing dimension from Externalizing Consortium (EXT-CON) confirmed these results. Two of the top five genes with the strongest associations in EXT GWAS, CADM2 and SEMA6D, are also ranked among the top 10 in the EXT-CON. The present results confirm the existence of a common externalizing factor and an increasing vulnerability caused by child maltreatment, with crucial implications for prevention. However, the partly diverging results also indicate that specific influences impact individual phenotypes separately.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036355","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 : 2024-08-20DOI: 10.1038/s41380-024-02666-7
Marie H. Sabec, Quentin R. Savage, John L. Wood, Uwe Maskos
The accumulation of β-amyloid oligomers is a hallmark of Alzheimer’s disease, inducing neural and network dysfunction in the early stages of pathology. The hippocampus is affected early in the pathogenesis of AD, however the impact of soluble β-amyloid on the dentate gyrus (DG) subregion of the hippocampus and its interaction with nicotinic acetylcholine receptors (nAChRs) within this region are not known. Using a localized model of over-expression, we show that β-amyloid induces early-onset neuronal hyperactivity and hippocampal-dependent memory deficits in mice. Further, we find the DG region to be under potent and sub-type specific nicotinic control in both healthy and pathophysiological conditions, with targeted receptor inhibition leading to a mnemonic rescue against localized amyloidosis. We show that while neurogenesis and synaptic functions are not severely affected in our model, reducing β2-containing nAChR function is associated with the promotion of young adult-born neurons within the pathological network, suggesting a possible protective mechanism. Our data thus reveal the DG network level changes which occur in the early-stages of β-amyloid accumulation and highlight the downstream consequences of targeted nicotinic neuromodulation.
{"title":"Targeting high-affinity nicotinic receptors protects against the functional consequences of β-amyloid in mouse hippocampus","authors":"Marie H. Sabec, Quentin R. Savage, John L. Wood, Uwe Maskos","doi":"10.1038/s41380-024-02666-7","DOIUrl":"https://doi.org/10.1038/s41380-024-02666-7","url":null,"abstract":"<p>The accumulation of β-amyloid oligomers is a hallmark of Alzheimer’s disease, inducing neural and network dysfunction in the early stages of pathology. The hippocampus is affected early in the pathogenesis of AD, however the impact of soluble β-amyloid on the dentate gyrus (DG) subregion of the hippocampus and its interaction with nicotinic acetylcholine receptors (nAChRs) within this region are not known. Using a localized model of over-expression, we show that β-amyloid induces early-onset neuronal hyperactivity and hippocampal-dependent memory deficits in mice. Further, we find the DG region to be under potent and sub-type specific nicotinic control in both healthy and pathophysiological conditions, with targeted receptor inhibition leading to a mnemonic rescue against localized amyloidosis. We show that while neurogenesis and synaptic functions are not severely affected in our model, reducing β2-containing nAChR function is associated with the promotion of young adult-born neurons within the pathological network, suggesting a possible protective mechanism. Our data thus reveal the DG network level changes which occur in the early-stages of β-amyloid accumulation and highlight the downstream consequences of targeted nicotinic neuromodulation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007518","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 : 2024-08-16DOI: 10.1038/s41380-024-02618-1
Julia R. Clarke, Thiago Sa Bacelar, Gabriel Gripp Fernandes, Raquel Costa da Silva, Leticia S. Antonio, Mariana Queiroz, Renata V. de Souza, Leticia F. Valadão, Gabriel S. Ribeiro, Emanuelle V. De Lima, Lilian C. Colodeti, Luana C. Mangeth, Adalgisa Wiecikowski, Talita N. da Silva, Heitor A. Paula-Neto, Robson da Costa, Yraima Cordeiro, Giselle F. Passos, Claudia P. Figueiredo
Parkinson’s disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.
{"title":"Abatacept inhibits Th17 differentiation and mitigates α-synuclein-induced dopaminergic dysfunction in mice","authors":"Julia R. Clarke, Thiago Sa Bacelar, Gabriel Gripp Fernandes, Raquel Costa da Silva, Leticia S. Antonio, Mariana Queiroz, Renata V. de Souza, Leticia F. Valadão, Gabriel S. Ribeiro, Emanuelle V. De Lima, Lilian C. Colodeti, Luana C. Mangeth, Adalgisa Wiecikowski, Talita N. da Silva, Heitor A. Paula-Neto, Robson da Costa, Yraima Cordeiro, Giselle F. Passos, Claudia P. Figueiredo","doi":"10.1038/s41380-024-02618-1","DOIUrl":"https://doi.org/10.1038/s41380-024-02618-1","url":null,"abstract":"<p>Parkinson’s disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNƔ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991831","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 : 2024-08-15DOI: 10.1038/s41380-024-02693-4
Jessica R Peters, Katja M Schmalenberger, Ashley G Eng, Allison Stumper, Michelle M Martel, Tory A Eisenlohr-Moul
Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that atypical neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions, which include (1) luteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; (2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and (3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders.
{"title":"Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC): A transdiagnostic framework for ovarian steroid influences on psychopathology.","authors":"Jessica R Peters, Katja M Schmalenberger, Ashley G Eng, Allison Stumper, Michelle M Martel, Tory A Eisenlohr-Moul","doi":"10.1038/s41380-024-02693-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02693-4","url":null,"abstract":"<p><p>Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that atypical neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions, which include (1) luteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; (2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and (3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982801","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 : 2024-08-14DOI: 10.1038/s41380-024-02664-9
Samantha R. Pierson, Kimberly L. Fiock, Ruixiang Wang, Nagalakshmi Balasubramanian, Jessica Reinhardt, Kanza M. Khan, Thomas D. James, Mikayla L. Hunter, Benjamin J. Cooper, Hannah R. Williamsen, Ryan Betters, Kaancan Deniz, Gloria Lee, Georgina Aldridge, Marco M. Hefti, Catherine A. Marcinkiewcz
Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer’s disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25–80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, β-amyloid, and TDP-43. To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tauDRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. A significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.
脑干核团中的蛋白质聚集被认为发生在阿尔茨海默病(AD)的早期阶段,但其在推动前驱症状和疾病进展方面的具体作用在很大程度上还不为人所知。背侧剑突核(DRN)含有大量5-羟色胺(5-hydroxytryptamine;5-HT)神经元,它们能调节情绪、与奖赏相关的行为和睡眠,而这些在阿尔茨海默病中都会受到干扰。我们在此报告,25-80 岁无痴呆病史的人的 DRN 中存在 tau 病理学,其发病率与脑室(LC)相当。相比之下,其他病理蛋白(包括α-突触核蛋白、β-淀粉样蛋白和TDP-43)呈阳性的病例较少。为了评估早期tau病理学对行为的影响,我们在小鼠的DRN中过表达了人P301L-tau,观察到了类似抑郁的行为和多动,但没有空间记忆缺陷。相对于神经胶质细胞,Tau病理学主要存在于神经元中,并与DRN中相当比例的Tph2-表达神经元共定位。P301L-tauDRN小鼠的5-HT神经元也过度兴奋,兴奋性突触后电流(EPSC)的振幅增大。此外,DRN中的星形胶质细胞密度升高,并伴随着IL-1α和Frk表达的增加,这表明炎症信号传导增加。此外,在丘脑、下丘脑、杏仁核和尾状核的轴突过程中也检测到了tau病理学。这种tau病理变化的很大一部分与5-羟色胺再摄取转运体(SERT)共聚焦,表明tau可能以前向方式扩散到DRN以外的区域。这些结果表明,在50岁以上的人群中,tau病理结构会在DRN中积累,并可能导致行为失调、5-羟色胺神经元功能障碍和局部星形胶质细胞的激活,而这些可能是AD的前兆指标。
{"title":"Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease","authors":"Samantha R. Pierson, Kimberly L. Fiock, Ruixiang Wang, Nagalakshmi Balasubramanian, Jessica Reinhardt, Kanza M. Khan, Thomas D. James, Mikayla L. Hunter, Benjamin J. Cooper, Hannah R. Williamsen, Ryan Betters, Kaancan Deniz, Gloria Lee, Georgina Aldridge, Marco M. Hefti, Catherine A. Marcinkiewcz","doi":"10.1038/s41380-024-02664-9","DOIUrl":"https://doi.org/10.1038/s41380-024-02664-9","url":null,"abstract":"<p>Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer’s disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25–80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, β-amyloid, and TDP-43. To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tau<sup>DRN</sup> mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. A significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980861","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 : 2024-08-13DOI: 10.1038/s41380-024-02676-5
Grace M. Power, Naomi Warne, Helen Bould, Francesco Casanova, Samuel E. Jones, Tom G. Richardson, Jessica Tyrrell, George Davey Smith, Jon Heron
Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence.
{"title":"The role of body image dissatisfaction in the relationship between body size and disordered eating and self-harm: complimentary Mendelian randomization and mediation analyses","authors":"Grace M. Power, Naomi Warne, Helen Bould, Francesco Casanova, Samuel E. Jones, Tom G. Richardson, Jessica Tyrrell, George Davey Smith, Jon Heron","doi":"10.1038/s41380-024-02676-5","DOIUrl":"https://doi.org/10.1038/s41380-024-02676-5","url":null,"abstract":"<p>Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973881","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}