Brown Thomas M, James Sarah-Naomi, Nicholas Jennifer M, Keuss Sarah, Keshavan Ashvini, Malone Ian B, Coath William, Murray-Smith Heidi, Cash David M, Barkhof Frederik, Richards Marcus, Schott Jonathan M, Sudre Carole H, Barnes Josephine
Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom.
Unit for Lifelong Health and Ageing at UCL, Department of Population Science and Experimental Medicine, University College London, United Kingdom.
Neurology. 2025 Sep 9;105(5):e213975. doi: 10.1212/WNL.0000000000213975. Epub 2025 Aug 19.
Higher white matter hyperintensity volume (WMHV) is associated with hippocampal atrophy, cognitive decline, and dementia; however, it is unknown whether continually increasing WMHV is related to hippocampal atrophy. The aim of this study was to determine whether higher WMHV change rate (WMHVR) is related to higher hippocampal atrophy rate (HAR); this relationship is dependent on cardiovascular risk factors (CVRFs), Alzheimer disease (AD) pathology, and genetic risk; and this relationship is mediated by neuroaxonal degradation.
Participants from Insight46, a substudy of the 1946 British Birth Cohort, underwent combined [F]florbetapir PET/MRI scans at University College London approximately 2.5 years apart. WMHVR was quantified from T2/fluid-attenuated inversion recovery and HAR from T1 sequences. Life-course blood pressure and CVRF data were measured at 6 and 3 time points, respectively. genotype and neurofilament light chain (NfL) quantification were derived from blood samples. Participants with neurologic conditions were excluded from primary analyses. Linear regression was used to test the relationships between WMHVR and HAR, adjusting for sex, age, and total intracranial volume (TIV) and CVRF, -ε4 status, and β-amyloid (Aβ) in separate models. Semipartial was calculated from these models. In a post hoc analysis, structural equation modeling aimed to determine whether NfL mediated the relationship between WMHVR and HAR.
A total of 317 individuals without neurologic conditions (48% female, 100% White British, mean baseline age [SD] = 70.5 [0.6] years) were included. The mean HAR was 0.04 [0.04] mL/y. Each 1 mL/y increase in WMHVR was associated with a 0.014 mL/y (95% CI 0.005-0.022) increase in HAR, adjusted for TIV, age, and sex ( = 0.002). Adjustment for additional variables did not meaningfully attenuate this association (≥0.012 mL/y, ≤ 0.005, all models), and there was no indirect effect through NfL (0.0004 mL/y [95% CI -0.0006 to 0.0012], < 0.1).
Higher WMHVR was associated with HAR between approximately 70 and 73 years, independent of CVRF levels, -ε4 status, and Aβ load, and not mediated by markers of neuroaxonal degradation. Although AD-specific pathology is typically considered the main cause of accelerated HAR, we demonstrated that HAR is also linked to deteriorating WM health. These results will need to be replicated in more diverse cohorts with longer follow-up periods to confirm the findings.
较高的脑白质高信号体积（WMHV）与海马萎缩、认知衰退及痴呆相关；然而，WMHV持续增加是否与海马萎缩有关尚不清楚。本研究的目的是确定较高的WMHV变化率（WMHVR）是否与较高的海马萎缩率（HAR）相关；这种关系是否依赖于心血管危险因素（CVRF）、阿尔茨海默病（AD）病理及遗传风险；以及这种关系是否由神经轴突降解介导。
来自1946年英国出生队列的子研究Insight46的参与者，在伦敦大学学院相隔约2.5年接受了联合的[F]氟比他派PET/MRI扫描。从T2/液体衰减反转恢复序列中量化WMHVR，从T1序列中量化HAR。分别在6个和3个时间点测量生命历程血压和CVRF数据。从血液样本中获取基因型和神经丝轻链（NfL）定量数据。患有神经系统疾病的参与者被排除在主要分析之外。使用线性回归来检验WMHVR与HAR之间的关系，并在单独的模型中对性别、年龄、总颅内体积（TIV）以及CVRF、ε4状态和β-淀粉样蛋白（Aβ）进行调整。从这些模型中计算半偏相关系数。在一项事后分析中，结构方程模型旨在确定NfL是否介导了WMHVR与HAR之间的关系。
总共纳入了317名无神经系统疾病的个体（48%为女性，100%为英国白人，平均基线年龄[标准差]=70.5[0.6]岁）。平均HAR为0.04[0.04]mL/年。在调整了TIV、年龄和性别后，WMHVR每增加1 mL/年与HAR增加0.014 mL/年（95%置信区间0.005 - 0.022）相关（P = 0.002）。对其他变量进行调整并没有显著减弱这种关联（≥0.012 mL/年，P≤0.005，所有模型），并且通过NfL没有间接效应（0.0004 mL/年[95%置信区间 - 0.0006至0.0012]，P<0.1）。
在大约70至73岁之间，较高的WMHVR与HAR相关，独立于CVRF水平、ε4状态和Aβ负荷，且不由神经轴突降解标志物介导。尽管AD特异性病理通常被认为是HAR加速的主要原因，但我们证明HAR也与脑白质健康恶化有关。这些结果需要在更多样化的队列中进行更长时间的随访以证实这些发现。
