Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Magn Reson Med. 2024 Mar;91(3):1087-1098. doi: 10.1002/mrm.29917. Epub 2023 Nov 9.
The clinical diagnosis and classification of Alexander disease (AxD) relies in part on qualitative neuroimaging biomarkers; however, these biomarkers fail to distinguish and discriminate different subtypes of AxD, especially in the presence of overlap in clinical symptoms. To address this gap in knowledge, we applied neurite orientation dispersion and density imaging (NODDI) to an innovative CRISPR-Cas9 rat genetic model of AxD to gain quantitative insights into the neural substrates and brain microstructural changes seen in AxD and to potentially identify novel quantitative NODDI biomarkers of AxD.
Multi-shell DWI of age- and sex-matched AxD and wild-type Sprague Dawley rats (n = 6 per sex per genotype) was performed and DTI and NODDI measures calculated. A 3 × 2 × 2 analysis of variance model was used to determine the effect of genotype, biological sex, and laterality on quantitative measures of DTI and NODDI across regions of interest implicated in AxD.
There is a significant effect of genotype in the amygdala, hippocampus, neocortex, and thalamus in measures of both DTI and NODDI brain microstructure. A genotype by biological sex interaction was identified in DTI and NODDI measures in the corpus callosum, hippocampus, and neocortex.
We present the first application of NODDI to the study of AxD using a rat genetic model of AxD. Our analysis identifies alterations in NODDI and DTI measures to large white matter tracts and subcortical gray nuclei. We further identified genotype by sex interactions, suggesting a possible role for biological sex in the neuropathogenesis of AxD.
亚历山大病（AxD）的临床诊断和分类部分依赖于定性神经影像学生物标志物；然而，这些生物标志物未能区分和辨别不同亚型的 AxD，尤其是在临床症状存在重叠的情况下。为了解决这一知识空白，我们将神经丝取向分散和密度成像（NODDI）应用于 AxD 的创新 CRISPR-Cas9 大鼠遗传模型，以深入了解 AxD 中所见的神经基质和脑微观结构变化，并可能确定 AxD 的新的定量 NODDI 生物标志物。
对年龄和性别匹配的 AxD 和野生型 Sprague Dawley 大鼠（每组 6 只，雌雄各半）进行多壳 DWI，并计算 DTI 和 NODDI 测量值。使用 3×2×2 方差分析模型来确定基因型、生物性别和侧别对涉及 AxD 的感兴趣区域的 DTI 和 NODDI 定量测量值的影响。
在杏仁核、海马体、新皮质和丘脑的 DTI 和 NODDI 脑微结构测量中，基因型有显著影响。在胼胝体、海马体和新皮质的 DTI 和 NODDI 测量中，发现了基因型与生物性别相互作用。
我们首次应用 NODDI 对 AxD 进行了研究，使用了 AxD 的大鼠遗传模型。我们的分析确定了 NODDI 和 DTI 测量值对白质大束和皮质下灰质核的改变。我们进一步确定了基因型与性别的相互作用，这表明生物性别可能在 AxD 的神经发病机制中起作用。
