Aksnes Mari, Capogna Elettra, Vidal-Piñeiro Didac, Chaudhry Farrukh Abbas, Myrstad Marius, Idland Ane-Victoria, Halaas Nathalie Bodd, Dakhil Shams, Blennow Kaj, Zetterberg Henrik, Walhovd Kristine Beate, Watne Leiv Otto, Fjell Anders Martin
Department of Geriatric Medicine, University of Oslo, Oslo, Norway.
Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway.
Neurobiol Aging. 2023 Nov;131:11-23. doi: 10.1016/j.neurobiolaging.2023.05.012. Epub 2023 May 29.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β and phosphorylated tau. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging.
基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）与年龄相关的神经退行性变和阿尔茨海默病（AD）有关，但其在正常衰老过程中的作用尚不清楚。我们使用线性混合模型来确定脑脊液（CSF）中MMP-2、MMP-3、MMP-10、TIMP-123（TIMP-1、TIMP-2和TIMP-3的复合物）或TIMP-4的基线水平或每年变化率是否能预测认知未受损个体双侧内嗅皮质厚度、海马体积或侧脑室体积的变化。我们还评估了对CSF AD生物标志物淀粉样β蛋白和磷酸化tau蛋白的影响。MMP-3的低基线水平预示着更大的脑室体积和更多的内嗅皮质变薄。随着时间的推移，CSF中MMP-2水平升高预示着更多的内嗅皮质变薄、海马萎缩和脑室扩张，而随着时间的推移，TIMP-123升高预示着脑室扩张。没有MMP/TIMPs能预测CSF AD生物标志物的变化。值得注意的是，我们首次表明MMP-2和TIMP-123水平的纵向升高可能预示着与年龄相关的脑萎缩。总之，MMPs和TIMPs可能在认知未受损的衰老过程中的脑萎缩中起作用。
