Florida Alzheimer's Disease Research Center, University of Florida, Gainesville, United States; Department of Psychiatry, University of Florida, Gainesville, United States.
Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, United States; Department of Neuroscience, University of Florida, Gainesville, United States.
Neuroimage. 2019 Nov 15;202:116138. doi: 10.1016/j.neuroimage.2019.116138. Epub 2019 Aug 28.
Extracellular β-amyloid (Aβ) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimer's disease and related neurodegenerative dementias could serve to monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to investigate the effects of Aβ and inflammatory interleukin-6 (IL6), alone or in combination, on in vivo tissue microstructure in the TgCRND8 mouse model of Alzheimer's-type Aβ deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1 T. Images were processed using the diffusion tensor imaging (DTI) model or the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern in white matter (WM) and hippocampus consistent with radial and longitudinal diffusivity deficits along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean, axial and radial diffusivity, and increased orientation dispersion (ODI) and intracellular volume fraction (ICVF) measured in WM and hippocampus. IL6 produced a 'protective-like' effect on WM FA in TgCRND8 mice, observed as an increased FA that counteracted a reduction in FA observed with endogenous Aβ production and accumulation. In addition, we found that ICVF and ODI had an inverse relationship with the functional connectome clustering coefficient. The relationship between NODDI and graph theory metrics suggests that currently unknown microstructure alterations in WM and hippocampus are associated with diminished functional network organization in the brain.
细胞外β-淀粉样蛋白（Aβ）斑块沉积和炎症免疫激活被认为会改变组织微观结构的各个方面，如细胞外游离水、分数各向异性和弥散度，以及轴突过程的密度和几何排列。在阿尔茨海默病和相关神经退行性痴呆中量化这些微观结构变化，可以用于监测或预测疾病进程。在本研究中，我们使用高场弥散磁共振成像（dMRI）来研究 Aβ 和炎症性白细胞介素 6（IL6）单独或联合作用对阿尔茨海默病型 Aβ 沉积的 TgCRND8 小鼠模型体内组织微观结构的影响。TgCRND8 和非转基因（nTg）小鼠表达脑靶向 IL6 或增强的神经胶质纤维酸性蛋白（EGFP 对照），在 11.1 T 下使用 2 壳 54 梯度方向 dMRI 序列进行扫描。使用弥散张量成像（DTI）模型或神经丝取向分散和密度成像（NODDI）模型处理图像。在 TgCRND8 小鼠中，DTI 和 NODDI 处理结果显示，白质（WM）和海马中的微观结构模式与沿轴突和树突过程的径向和纵向弥散度缺陷以及轴突和树突过程的密度和几何复杂性增加一致。这包括 WM 和海马中 FA、均值、轴向和径向弥散度降低，以及取向分散度（ODI）和细胞内体积分数（ICVF）增加。IL6 在 TgCRND8 小鼠的 WM FA 上产生了一种“保护样”作用，表现为 FA 增加，抵消了内源性 Aβ 产生和积累导致的 FA 降低。此外，我们发现 ICVF 和 ODI 与功能连接体聚类系数呈反比关系。NODDI 与图论指标之间的关系表明，目前未知的 WM 和海马微观结构改变与大脑功能网络组织的减弱有关。
