From the Institute of Science and Technology for Brain-Inspired Intelligence (C.S., W.C., J.K., G.D., C.X., X.-M.Z., B.S., J.F.), Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education (C.S., G.D., C.X., X.-M.Z., J.F.), Shanghai Center for Mathematical Sciences (J.K.), and MOE Frontiers Center for Brain Science (X.-M.Z., J.F.), Fudan University, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.); Behavioural and Clinical Neuroscience Institute (B.S.) and Department of Psychiatry (B.S.), University of Cambridge, UK; and Zhangjiang Fudan International Innovation Center (J.F.), Shanghai, China.
Neurology. 2022 Jul 11;99(2):e164-e175. doi: 10.1212/WNL.0000000000200583.
To investigate the independent associations of social isolation and loneliness with incident dementia and to explore the potential neurobiological mechanisms.
We utilized the UK Biobank cohort to establish Cox proportional hazard models with social isolation and loneliness as separate exposures. Demographic (sex, age, and ethnicity), socioeconomic (education level, household income, and Townsend deprivation index), biological (body mass index, genotype, diabetes, cancer, cardiovascular disease, and other), cognitive (speed of processing and visual memory), behavioral (current smoker, alcohol intake, and physical activity), and psychological (social isolation or loneliness, depressive symptoms, and neuroticism) factors measured at baseline were adjusted. Then, voxel-wise brainwide association analyses were used to identify gray matter volumes (GMVs) associated with social isolation and with loneliness. Partial least squares regression was performed to test the spatial correlation of GMV differences and gene expression using the Allen Human Brain Atlas.
We included 462,619 participants (mean age at baseline 57.0 years [SD 8.1]). With a mean follow-up of 11.7 years (SD 1.7), 4,998 developed all-cause dementia. Social isolation was associated with a 1.26-fold increased risk of dementia (95% CI, 1.15-1.37) independently of various risk factors including loneliness and depression (i.e., full adjustment). However, the fully adjusted hazard ratio for dementia related to loneliness was 1.04 (95% CI, 0.94-1.16) and 75% of this relationship was attributable to depressive symptoms. Structural MRI data were obtained from 32,263 participants (mean age 63.5 years [SD 7.5]). Socially isolated individuals had lower GMVs in temporal, frontal, and other (e.g., hippocampal) regions. Mediation analysis showed that the identified GMVs partly mediated the association between social isolation at baseline and cognitive function at follow-up. Social isolation-related lower GMVs were related to underexpression of genes that are downregulated in Alzheimer disease and to genes that are involved in mitochondrial dysfunction and oxidative phosphorylation.
Social isolation is a risk factor for dementia that is independent of loneliness and many other covariates. Social isolation-related brain structural differences coupled with different molecular functions also support the associations of social isolation with cognition and dementia. Social isolation may thus be an early indicator of an increased risk of dementia.
探讨社会隔离和孤独感与痴呆症发病的独立相关性，并探讨潜在的神经生物学机制。
我们利用英国生物库队列，建立了以社会隔离和孤独感为单独暴露因素的 Cox 比例风险模型。在基线测量的人口统计学（性别、年龄和种族）、社会经济学（教育水平、家庭收入和汤森剥夺指数）、生物学（体重指数、基因型、糖尿病、癌症、心血管疾病和其他）、认知（处理速度和视觉记忆）、行为（当前吸烟者、饮酒量和体力活动）和心理（社会隔离或孤独感、抑郁症状和神经质）因素进行了调整。然后，我们使用体素全脑关联分析来识别与社会隔离和孤独感相关的灰质体积（GMV）。使用艾伦人类大脑图谱进行偏最小二乘回归，以测试 GMV 差异和基因表达的空间相关性。
我们纳入了 462619 名参与者（基线时的平均年龄为 57.0 岁[SD 8.1]）。平均随访 11.7 年（SD 1.7）后，4998 人发生了全因痴呆。社会隔离与痴呆风险增加 1.26 倍相关（95%CI，1.15-1.37），独立于各种风险因素，包括孤独感和抑郁（即完全调整）。然而，与孤独感相关的痴呆的完全调整后的风险比为 1.04（95%CI，0.94-1.16），其中 75%的关系归因于抑郁症状。32263 名参与者（平均年龄 63.5 岁[SD 7.5]）获得了结构 MRI 数据。与社会隔离相关的个体在颞叶、额叶和其他（如海马）区域的 GMV 较低。中介分析表明，在基线时的社会隔离与随访时的认知功能之间，所确定的 GMV 部分介导了关联。与社会隔离相关的较低 GMV 与阿尔茨海默病中下调的基因和参与线粒体功能障碍和氧化磷酸化的基因的低表达有关。
社会隔离是痴呆症的一个危险因素，独立于孤独感和许多其他协变量。社会隔离相关的脑结构差异以及不同的分子功能也支持社会隔离与认知和痴呆症的关联。因此，社会隔离可能是痴呆症风险增加的早期指标。
