Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一类以运动功能进行性受损为主要特征的神经退行性疾病。然而，相当比例的受累患者会出现严重的认知功能障碍，并伴随广泛的白质（white matter, WM）与灰质（gray matter, GM）微观结构损伤。本研究旨在明确：通过超高场扩散磁共振成像（ultra-high field diffusion MRI, UHFD-MRI）采集的高斯与非高斯扩散模型，是否可作为检测ALS临床前模型脑白质与灰质早期结构变化的合适工具。研究对ALS模型小鼠（G93A-SOD1小鼠）在16.7 T磁场中进行扫描。扩散张量成像（diffusion tensor imaging, DTI）与神经突方向离散度与密度成像（neurite orientation dispersion and density imaging, NODDI）结果显示，症状前阶段，深部白质（胼胝体）、浅表（大脑皮层）及深部（海马体）灰质的轴突组织完整性（以各向异性分数（Fractional Anisotropy, FA）表征）与神经突含量（以细胞内体积分数（Intracellular Volume Fraction, ICVF）表征）均出现下降。额外的扩散峰度成像（diffusion kurtosis imaging, DKI）分析表明，灰质的平均峰度（mean kurtosis, MK）出现范围更广、出现更早的降低，这可能与神经元复杂度下降相关。本研究通过ALS荧光小鼠报告品系（黄色荧光蛋白（YFP）标记的G93A-SOD1小鼠）完成了组织学验证。DTI、NODDI与DKI模型的联合应用已被证实可更全面地评估ALS脑内早期微观结构变化，尤其是在与高级认知功能相关的脑区。该综合成像策略有望成为早期检测神经影像标志物的有效工具。