Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43^A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[¹⁸F]fluoro-D-glucose [¹⁸F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43^A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43^A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43^A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43^A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43^A315T disease pathogenesis and may prove useful for clinical management of ALS.

目前，对肌萎缩性侧索硬化症（ALS）潜在的TAR DNA结合蛋白43（TDP-43）病理学知之甚少，这阻碍了临床诊断和药物开发的努力。为了更好地理解疾病的病理生理，正电子发射断层扫描（PET）和多参数磁共振成像（mp-MRI）提供了一种非侵入性模式来研究体内分子，结构和神经化学异常。我们首次报告了在TDP-43 ^A315T ALS小鼠模型中进行纵向PET-MR研究的结果，该研究调查了小鼠大脑中与疾病相关的变化。2-脱氧-2- [ ¹⁸ F]氟-D-葡萄糖[ ¹⁸F] FDG PET显示TDP-43 ^A315T小鼠的运动皮层和体感皮层中的葡萄糖代谢显着降低，而在3到7个月大时，双侧黑质，网状和杏仁核的区域中的代谢升高-转基因对照。MR光谱数据显示，与对照组相比，TDP-43 ^A315T小鼠的运动皮层和后^脑中的谷氨酸+谷氨酰胺（Glx）和胆碱水平发生了显着变化。使用动脉旋转标记方法进行的脑血流量（CBF）测量显示，脑灌注没有明显的年龄或组依赖性变化。扩散MRI指数显示TDP-43 ^A315T在大脑不同运动区域的瞬时变化大约14个月大的老鼠。在有症状的18个月大的小鼠的大脑中观察到细胞质TDP-43蛋白质包涵体，但在无症状的转基因或野生型小鼠中未观察到。我们的研究结果表明，与健康人相比，转基因TDP-43 ^A315T小鼠的特定大脑区域会发生与疾病和年龄相关的功能和神经化学变化，以及有限的结构变化。总而言之，这些发现为TDP-43 ^A315T疾病的发病机理提供了新的^线索，并可能被证明可用于ALS的临床管理。