Woodworth Davis C, Lou Jerry J, Yong William H, Head Elizabeth, Corrada María M, Nelson Peter T, Sajjadi S Ahmad
Department of Neurology, University of California, Irvine, CA 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
Brain. 2025 May 5. doi: 10.1093/brain/awaf158.
Hippocampal sclerosis of aging (HS-A) -severe cell loss and gliosis in the hippocampal formation- is a neuropathologic change (NC) that affects up to 20% of elderly persons with dementia. The etiology of HS-A is heterogeneous, but HS-A is strongly associated with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC). Other NCs have also been implicated in relation to HS-A, but these associations have been inconsistent across previous studies. Also, because LATE-NC and HS-A are so strongly associated, it is important to adjust for LATE-NC when examining associations between other NCs and HS-A. The goal of this study was to examine associations of other common NCs with HS-A, both before and after adjusting for LATE-NC. We analyzed the National Alzheimer's Coordinating Center (NACC) neuropathology dataset and examined associations of Alzheimer's disease NC (ADNC), Lewy bodies (LB), and cerebrovascular NCs, with HS-A, adjusting for LATE-NC in multiple ways. We used Bayesian multilevel logistic regression models with monotonic modeling for ordinal predictors, and report the odds ratios (OR) or average OR across levels (aOR) along with 95% credibility intervals (CI) as well as expected frequencies of HS-A for selected models and predictor levels. Of n=1933 autopsy participants included (average age at death of 83 years, 51.3% women), HS-A was present in 278 (14.4%). LATE-NC was strongly associated with HS-A (aOR=3.7, 95% CI=[2.8, 5.0]). While ADNC showed a modest association with HS-A in models where LATE-NC was not included as a predictor (aOR=1.4, CI=[1.1, 1.8]), this association was reduced when adjusting for LATE-NC (aOR=1.11, CI=[0.9, 1.5]); results were similar for the ADNC-related A/B/C scores and limbic LBs. However, several cerebrovascular NCs were similarly associated with HS-A both without adjusting for LATE-NC (atherosclerosis aOR=1.4, arteriolosclerosis aOR=1.6, white matter rarefaction (WMR) aOR=1.4) and with adjusting for LATE-NC (atherosclerosis aOR=1.4, arteriolosclerosis aOR=1.5, WMR aOR=1.3). In a combined model, LATE-NC was strongly associated with HS-A, but global cerebrovascular NCs, as well as APOE-ε4 (increased odds), and education (decreased odds), were also associated with HS-A. Predicted HS-A frequency for predictor levels of no LATE-NC or global cerebrovascular NCs was 1.5% (CI=[0.6%, 3.1%]), while it was 94.5% (CI=[84%, 99.5%]) for LATE-NC stage 3 and severe global cerebrovascular NC levels. LATE-NC is likely the most important cause of HS-A. While ADNC seems to be associated with HS-A through its association with LATE-NC, the association of cerebrovascular with HS-A independent of LATE-NC underlines the importance of vascular factors in the etiology of HS-A.
衰老性海马硬化（HS-A）——海马结构中严重的细胞丢失和胶质增生——是一种神经病理改变（NC），在高达20%的老年痴呆患者中出现。HS-A的病因是异质性的，但HS-A与以边缘系统为主的年龄相关TDP-43脑病神经病理改变（LATE-NC）密切相关。其他神经病理改变也与HS-A有关，但这些关联在以往研究中并不一致。此外，由于LATE-NC和HS-A关联如此紧密，在研究其他神经病理改变与HS-A之间的关联时，对LATE-NC进行校正很重要。本研究的目的是在对LATE-NC进行校正之前和之后，检验其他常见神经病理改变与HS-A的关联。我们分析了国家阿尔茨海默病协调中心（NACC）的神经病理学数据集，并检验了阿尔茨海默病神经病理改变（ADNC）、路易小体（LB）和脑血管神经病理改变与HS-A的关联，以多种方式对LATE-NC进行校正。我们使用具有序数预测变量单调建模的贝叶斯多级逻辑回归模型，并报告优势比（OR）或各水平的平均OR（aOR）以及95%可信区间（CI），以及选定模型和预测变量水平的HS-A预期频率。在纳入的n = 1933名尸检参与者中（平均死亡年龄83岁，51.3%为女性），278人（14.4%）存在HS-A。LATE-NC与HS-A密切相关（aOR = 3.7，95% CI = [2.8, 5.0]）。在未将LATE-NC作为预测变量的模型中，ADNC与HS-A呈适度关联（aOR = 1.4，CI = [1.1, 1.8]），但在对LATE-NC进行校正后，这种关联减弱（aOR = 1.11，CI = [0.9, 1.5]）；ADNC相关的A/B/C评分和边缘路易小体的结果类似。然而，几种脑血管神经病理改变在未对LATE-NC进行校正（动脉粥样硬化aOR = 1.4，小动脉硬化aOR = 1.6，白质疏松（WMR）aOR = 1.4）和对LATE-NC进行校正（动脉粥样硬化aOR = 1.4，小动脉硬化aOR = 1.5，WMR aOR = 1.3）时，与HS-A的关联相似。在一个联合模型中，LATE-NC与HS-A密切相关，但总体脑血管神经病理改变以及APOE-ε4（优势增加）和教育程度（优势降低）也与HS-A有关。预测无LATE-NC或总体脑血管神经病理改变的预测变量水平的HS-A频率为1.5%（CI = [0.6%, 3.1%]），而LATE-NC 3期和严重总体脑血管神经病理改变水平时为94.5%（CI = [84%, 99.5%]）。LATE-NC可能是HS-A的最重要原因。虽然ADNC似乎通过与LATE-NC的关联与HS-A相关，但脑血管与HS-A独立于LATE-NC的关联强调了血管因素在HS-A病因中的重要性。
