Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, 21224.
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, 21224.
Ann Clin Transl Neurol. 2023 Mar;10(3):397-407. doi: 10.1002/acn3.51730. Epub 2023 Feb 10.
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 (Aß 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 Aβ , Aβ , 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 Aβ 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.
白质损伤是阿尔茨海默病的特征之一，但人们对阿尔茨海默病进程的各个方面如何与白质结构的关键特征相关知之甚少。我们研究了阿尔茨海默病（Aβ比值；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 MRI 测量的髓鞘含量和轴突密度之间的关联。
在接受 MRI 测量髓鞘含量（由髓鞘水分数[MWF]定义）和轴突密度（由神经丝密度指数[NDI]定义）的 BLSA 和 GESTALT 研究中的认知正常参与者中，我们量化了血浆中 Aβ、Aβ、pTau181、NfL 和 GFAP 的水平。使用调整了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 测量值相关联。
共有 119 名参与者接受了 MWF 成像（年龄：56[SD 21]），其中 43 名接受了 NDI 成像（年龄：50[SD 18]）。我们没有发现血浆生物标志物与总脑髓鞘含量之间存在关系。然而，二次分析发现，较高的 GFAP 与颞叶的 MWF 较低相关（β=-0.13；P=0.049）。此外，较高的 NfL（β=-0.22；P=0.009）和 GFAP（β=-0.29；P=0.002）水平与总脑轴突密度降低相关。二次分析发现，较低的 Aβ比值和较高的 pTau181也与轴突密度降低相关，但仅在特定脑区。这些结果在进一步调整心血管危险因素后仍然相似。
神经元损伤和星形胶质细胞增生的血浆生物标志物与轴突密度降低和特定区域的髓鞘含量降低相关。轴突丢失和脱髓鞘可能与神经退行性变和星形胶质细胞增生同时发生，早于有意义的认知能力下降。
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