Manivannan Ashwinee, Foley Lesley M, Hitchens T Kevin, Rattray Ivan, Bates Gillian P, Modo Michel
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Animal Imaging Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Neuroprotection. 2023 Sep;1(1):66-83. doi: 10.1002/nep3.14. Epub 2022 Dec 20.
Huntington's disease is a progressive neurodegenerative disorder. Brain atrophy, as measured by volumetric magnetic resonance imaging (MRI), is a downstream consequence of neurodegeneration, but microstructural changes within brain tissue are expected to precede this volumetric decline. The tissue microstructure can be assayed non-invasively using diffusion MRI, which also allows a tractographic analysis of brain connectivity.
We here used ex vivo diffusion MRI (11.7 T) to measure microstructural changes in different brain regions of end-stage (14 weeks of age) wild type and R6/2 mice (male and female) modeling Huntington's disease. To probe the microstructure of different brain regions, reduce partial volume effects and measure connectivity between different regions, a 100 μm isotropic voxel resolution was acquired.
Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice, mean, axial, and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice. Whole brain streamlines were only reduced in male R6/2 mice, but streamline density was increased. Region-to-region tractography indicated reductions in connectivity between the cortex, hippocampus, and thalamus with the striatum, as well as within the basal ganglia (striatum-globus pallidus-subthalamic nucleus-substantia nigra-thalamus).
Biological sex and left/right hemisphere affected tractographic results, potentially reflecting different stages of disease progression. This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions. In a translation setting, these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models, as well as patients with Huntington's disease.
亨廷顿舞蹈症是一种进行性神经退行性疾病。通过容积磁共振成像（MRI）测量的脑萎缩是神经退行性变的下游后果，但脑组织内的微观结构变化预计会先于这种容积下降。可以使用扩散MRI对组织微观结构进行无创检测，扩散MRI还可对脑连接性进行纤维束成像分析。
我们在此使用离体扩散MRI（11.7 T）来测量野生型和模拟亨廷顿舞蹈症的R6/2小鼠（14周龄，雌雄均有）终末期不同脑区的微观结构变化。为了探测不同脑区的微观结构、减少部分容积效应并测量不同区域之间的连接性，采集了100μm各向同性体素分辨率的数据。
虽然各向异性分数未显示野生型对照组和R6/2小鼠之间存在任何差异，但雌性R6/2小鼠的平均扩散率、轴向扩散率和径向扩散率增加，而雄性R6/2小鼠则降低。全脑纤维束仅在雄性R6/2小鼠中减少，但纤维束密度增加。区域间纤维束成像显示，皮层、海马体和丘脑与纹状体之间以及基底神经节（纹状体 - 苍白球 - 底丘脑核 - 黑质 - 丘脑）内部的连接性降低。
生物性别和左右半球影响纤维束成像结果，这可能反映了疾病进展的不同阶段。这项原理验证研究表明，扩散MRI和纤维束成像可能提供新的生物标志物，将不同脑区的容积变化联系起来。在转化研究中，这些测量构成了一种新工具，可用于评估神经保护剂等干预措施对转基因模型以及亨廷顿舞蹈症患者的治疗效果。
