Ford Andria L, Fellah Slim, Wang Yan, Unger-Levinson Kira, Hagan Maria, Reis Martin N, Mirro Amy, Lewis Josiah B, Ying Chunwei, Guilliams Kristin P, Fields Melanie E, An Hongyu, King Allison A, Chen Yasheng
Department of Neurology, Washington University in St Louis School of Medicine, St Louis, Missouri.
Mallinckrodt Institute of Radiology, Washington University in St Louis School of Medicine, St Louis, Missouri.
JAMA Netw Open. 2025 Jan 2;8(1):e2453669. doi: 10.1001/jamanetworkopen.2024.53669.
Both sickle cell anemia (SCA) and socioeconomic status have been associated with altered brain structure and cognitive disability, yet precise mechanisms underlying these associations are unclear.
To determine whether brains of individuals with and without SCA appear older than chronological age and if brain age modeling using brain age gap (BAG) can estimate cognitive outcomes and mediate the association of socioeconomic status and disease with these outcomes.
DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study of 230 adults with and without SCA, individuals underwent brain magnetic resonance imaging (MRI) and cognitive assessment. Brain age was estimated using DeepBrainNet, a model trained to estimate chronological age from 14 468 structural MRIs from healthy individuals across the lifespan. BAG was defined as estimated brain age minus chronological age. Linear regression examined clinical factors associated with BAG and the ability of BAG to estimate cognitive performance compared to neuroimaging metrics of brain health and ischemic brain injury, such as normalized whole brain volume, white matter mean diffusivity (MD), and infarct volume. BAG and white matter MD were tested further as mediators of the association of socioeconomic status and SCA with cognitive performance. Data were analyzed from October 15, 2023, to July 1, 2024.
SCA disease status and economic deprivation as measured using the area deprivation index (ADI).
Executive function, crystallized function, processing speed, and full-scale intelligence quotient (FSIQ) were derived from the National Institutes of Health (NIH) Toolbox and Wechsler Abbreviated Scale of Intelligence, Second Edition.
Among 230 included adults, 123 individuals had SCA (median [IQR] age, 26.4 [21.8-34.3] years; 77 female [63%]) and 107 individuals did not (control cohort; median [IQR] age, 30.1 [26.3-34.8] years; 77 female [72%]). Participants with SCA had a larger median (IQR) BAG compared to individuals in the control cohort (14.2 [8.0-19.2] vs 7.3 [3.2-11.1] years; median difference, 6.13 years; 95% CI, 4.29-8.05 years; P < .001). Individuals in the control cohort demonstrated a larger BAG relative to the reference population (mean difference, 7.52 years; 95% CI, 6.32-8.72 years; P < .001). Higher economic deprivation was associated with BAG in the control cohort (β [SE] per 1% ADI increase, 0.079 [0.028]; 95% CI, 0.023 to 0.135; P = .006), while intracranial vasculopathy (β [SE], 6.562 [1.883]; 95% CI, 2.828 to 10.296; P < .001) and hemoglobin S percentage (β [SE] per 1% increase, 0.089 [0.032]; 95% CI, 0.026 to 0.151; P = .006) were associated with BAG in participants with SCA. Across neuroimaging metrics of brain health, BAG demonstrated the largest effect size for cognitive outcomes in the control cohort (eg, executive function: r = -0.430; P = .001), while white matter MD demonstrated the largest effect size for cognitive outcomes (eg, executive function: r = -0.365; P = .001) in the SCA cohort. Across the study population, BAG mediated the association of ADI with cognitive performance (eg, executive function: β [SE] per 1-unit decrease in ADI, -0.031 [0.014]; 95% CI, -0.061 to -0.006), while BAG (eg, FSIQ: β [SE], -3.79 [1.42]; 95% CI, -6.87 to -1.40) and white matter MD (eg, FSIQ: β [SE], -4.55 [1.82]; 95% CI, -8.14 to -0.94) mediated the association of SCA with cognitive performance.
Adults with SCA and a healthy control cohort with greater economic deprivation demonstrated older brain age, suggestive of insufficient brain development, premature brain aging, or both. Brain estimates of chronological age may inform mechanisms of the association between chronic disease and socioeconomic status with cognitive outcomes in healthy and SCA populations, yet will require confirmation in larger and longitudinal studies.
镰状细胞贫血（SCA）和社会经济地位均与大脑结构改变和认知障碍有关，但这些关联背后的确切机制尚不清楚。
确定患有和未患有SCA的个体的大脑是否比实际年龄显得更老，以及使用脑龄差距（BAG）进行脑龄建模是否能够估计认知结果，并介导社会经济地位和疾病与这些结果之间的关联。
设计、设置和参与者：在这项对230名患有和未患有SCA的成年人的横断面研究中，个体接受了脑磁共振成像（MRI）和认知评估。使用DeepBrainNet估计脑龄，该模型经过训练，可根据来自不同年龄段健康个体的14468份结构MRI来估计实际年龄。BAG定义为估计脑龄减去实际年龄。线性回归分析了与BAG相关的临床因素，以及与脑健康和缺血性脑损伤的神经影像学指标（如全脑标准化体积、白质平均扩散率（MD）和梗死体积）相比，BAG估计认知表现的能力。进一步测试BAG和白质MD作为社会经济地位和SCA与认知表现之间关联的中介因素。数据于2023年10月15日至2024年7月1日进行分析。
使用地区贫困指数（ADI）衡量的SCA疾病状态和经济剥夺情况。
执行功能、晶体智力、处理速度和全量表智商（FSIQ）来自美国国立卫生研究院（NIH）工具箱和韦氏智力量表简式第二版。
在纳入的230名成年人中，123名个体患有SCA（年龄中位数[四分位间距]，26.4[21.8 - 34.3]岁；77名女性[63%]），107名个体未患SCA（对照组；年龄中位数[四分位间距]，30.1[26.3 - 34.8]岁；77名女性[72%]）。与对照组个体相比，患有SCA的参与者的BAG中位数（四分位间距）更大（14.2[8.0 - 19.2]岁对7.3[3.2 - 11.1]岁；中位数差异，6.13岁；95%置信区间，4.29 - 8.05岁；P <.001）。对照组个体相对于参考人群表现出更大的BAG（平均差异，7.52岁；95%置信区间，6.32 - 8.72岁；P <.001）。在对照组中，更高的经济剥夺与BAG相关（每增加1% ADI，β[标准误]为0.079[0.028]；95%置信区间，0.023至0.135；P = 0.006），而在患有SCA的参与者中，颅内血管病变（β[标准误]，6.562[1.883]；95%置信区间，2.828至10.296；P <.001）和血红蛋白S百分比（每增加1%，β[标准误]为0.089[0.032]；95%置信区间，0.026至0.151；P = 0.006）与BAG相关。在脑健康的神经影像学指标中，BAG在对照组中对认知结果的效应量最大（例如，执行功能：r = -0.430；P = 0.001），而白质MD在SCA组中对认知结果的效应量最大（例如，执行功能：r = -0.365；P = 0.001）。在整个研究人群中，BAG介导了ADI与认知表现之间的关联（例如，执行功能：每降低1个单位ADI，β[标准误]为 -0.031[0.014]；95%置信区间，-0.061至 -0.006），而BAG（例如，FSIQ：β[标准误]，-3.79[1.42]；95%置信区间，-6.87至 -1.40）和白质MD（例如，FSIQ：β[标准误]，-4.55[1.82]；95%置信区间，-8.14至 -0.94）介导了SCA与认知表现之间的关联。
患有SCA的成年人以及经济剥夺程度更高的健康对照组表现出脑龄更大，提示大脑发育不足、过早脑老化或两者皆有。根据实际年龄对大脑进行的估计可能有助于揭示慢性病和社会经济地位与健康人群和SCA人群认知结果之间关联的机制，但仍需要在更大规模的纵向研究中加以证实。
