MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.
MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.
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DOI：
10.1002/acn3.51730
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发表时间：
2023-03
影响因子：
5.3
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中科院分区：
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白质损伤是阿尔茨海默病的一个特征，但人们对阿尔茨海默病过程的各个方面与白质结构的关键特征之间的关系知之甚少。我们检测了阿尔茨海默病（Aß42/40 ratio; pTau181）、神经元损伤（NfL）和反应性星形胶质细胞增生（GFAP）生物标志物与髓磷脂含量和轴突密度的MRI测量的相关性。在BLSA和GESTALT研究中，认知正常的参与者接受髓磷脂含量（由髓磷脂水分数[MWF]定义）和轴突密度（由神经突密度指数[NDI]定义）的MRI测量，我们量化了Aβ42、Aβ40、pTau181、NfL和GFAP的血浆水平。使用调整人口统计学变量的线性回归模型将这些血浆生物标志物水平与MRI测量相关联。共有119名参与者接受MWF成像（年龄：56 [SD 21]），其中43名接受NDI成像（年龄：50 [SD 18]）。我们发现血浆生物标志物与总脑髓磷脂含量之间没有关系。然而，二次分析发现较高的GFAP与较低的颞叶MWF相关（ß = - 0.13; P = 0.049）。此外，较高水平的NfL （ß = - 0.22; P = 0.009）和GFAP （ß = - 0.29; P = 0.002）与较低的脑轴突总密度相关。二级分析发现，较低的Aβ42/40比值和较高的pTau181也与较低的轴突密度相关，但仅在选定的脑区。在额外调整心血管危险因素后，这些结果仍然相似。神经元损伤和星形胶质形成的血浆生物标志物与轴突密度降低和区域特异性髓磷脂含量相关。轴突丧失和脱髓鞘可能与神经退行性变和星形胶质增生同时发生，先于临床意义上的认知能力下降。
White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aβ42, Aβ40, pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = −0.13; P = 0.049). Further, higher levels of NfL (ß = −0.22; P = 0.009) and GFAP (ß = −0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region‐specific myelin content. Axonal loss and demyelination may co‐occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.