Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics Among Patients With Late-Life Depression.
Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics Among Patients With Late-Life Depression.
复制标题
DOI：
10.1001/jamapsychiatry.2022.0020
复制
发表时间：
2022-03
期刊：
影响因子：
25.8
通讯作者：
J. Wen;C. H. Fu;D. Tosun;Y. Veturi;Zhijian Yang;A. Abdulkadir;E. Mamourian;D. Srinivasan;I. Skampardoni;Ashutosh Kumar Singh;H. Nawani;J. Bao;G. Erus;H. Shou;M. Habes;J. Doshi;E. Varol;R. S. Mackin;Aristeidis Sotiras;Yong Fan;A. Saykin;Y. Sheline;Li Shen;M. Ritchie;D. Wolk;M. Albert;S. Resnick;C. Davatzikos
中科院分区：
文献类型：
--
作者：
J. Wen;C. H. Fu;D. Tosun;Y. Veturi;Zhijian Yang;A. Abdulkadir;E. Mamourian;D. Srinivasan;I. Skampardoni;Ashutosh Kumar Singh;H. Nawani;J. Bao;G. Erus;H. Shou;M. Habes;J. Doshi;E. Varol;R. S. Mackin;Aristeidis Sotiras;Yong Fan;A. Saykin;Y. Sheline;Li Shen;M. Ritchie;D. Wolk;M. Albert;S. Resnick;C. Davatzikos
重要性晚年抑郁(LLD)的特点是临床表现具有相当大的异质性。解开这种异质性可能有助于阐明病因机制，并支持精确和个体化的药物治疗。目的横向和纵向描述LLD与神经解剖学、认知功能、临床症状和遗传特征相关的疾病相关异质性。设计、设置和参与者基于成像的老化和神经退行性疾病坐标系统(ISTAGING)研究是一个国际多中心联盟，通过汇集和协调来自13项研究的数据来调查大脑老化，这些研究有超过35000名参与者，其中包括一组患有严重抑郁障碍的人。这项研究分析了来自多中心样本(N=996)的多模式数据，包括神经成像、神经认知评估和遗传学。将半监督聚类方法(通过判别分析的异质性)应用于区域灰质(GM)脑体积，以获得维度表示。收集了2017年7月至2020年7月的数据，并分析了2020年7月至2021年12月的数据。主要结果和指标确定了两个维度来描述体向GM图中与LLD相关的异质性、白质(WM)部分各向异性、神经认知功能、临床表型和遗传学。结果共纳入501例LLD患者(平均年龄67.39[5.56]岁；女性332例)和495例健康对照组(平均年龄66.53[5.16]岁；女性333例)。与健康对照组相比，维度1的患者显示出相对保存完好的大脑解剖结构，没有出现西医活动中断。相比之下，维度2的患者表现出广泛的脑萎缩和WM完整性中断，以及认知障碍和更高的抑郁严重程度。此外，1个从头开始独立的遗传变异(rs13120336；染色体：4,186387714；次要等位基因G)与维度1(优势比2.35；SE 0.15；P=3.14×10 8)显著相关，但与维度2无关。在普通人群中，这2个维度显示了18%~27%的基于单核苷酸变异的显著遗传力(在UK Biobank中N=12518)。在进行纵向测量的一组个体中，维度2的人在GM和脑年龄方面经历了更快的纵向变化(Cohen f2=0.03；P=0.02)，并且更有可能发展为阿尔茨海默病(Cohen f2=0.03；P=.03)，而维度1的人(N=1431名参与者和7224次扫描来自阿尔茨海默病神经成像倡议[ADNI]、巴尔的摩老龄化纵向研究[BLSA]和老年痴呆风险对照的生物标记物[BIOCARD]数据集)。结论和相关性本研究将LLD的异质性表征为两个维度，具有不同的神经解剖学、认知、临床和遗传学特征。这种维度方法为研究LLD的异质性以及潜在维度与可能的疾病机制、临床结果和干预反应的相关性提供了潜在的机制。
Importance Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35 000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12 518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2 = 0.03; P = .02) and were more likely to progress to Alzheimer disease (Cohen f2 = 0.03; P = .03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions.