J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida 32611.
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida 32611.
J Neurosci. 2020 Aug 19;40(34):6649-6659. doi: 10.1523/JNEUROSCI.0189-20.2020. Epub 2020 Jul 15.
functional and structural brain imaging of synucleinopathies in humans have provided a rich new understanding of the affected networks across the cortex and subcortex. Despite this progress, the temporal relationship between α-synuclein (α-syn) pathology and the functional and structural changes occurring in the brain is not well understood. Here, we examine the temporal relationship between locomotor ability, brain microstructure, functional brain activity, and α-syn pathology by longitudinally conducting rotarod, diffusion magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), and sensory-evoked fMRI on 20 mice injected with α-syn fibrils and 20 PBS-injected mice at three timepoints (10 males and 10 females per group). Intramuscular injection of α-syn fibrils in the hindlimb of M83 mice leads to progressive α-syn pathology along the spinal cord, brainstem, and midbrain by 16 weeks post-injection. Our results suggest that peripheral injection of α-syn has acute systemic effects on the central nervous system such that structural and resting-state functional activity changes occur in the brain by four weeks post-injection, well before α-syn pathology reaches the brain. At 12 weeks post-injection, a separate and distinct pattern of structural and sensory-evoked functional brain activity changes was observed that are co-localized with previously reported regions of α-syn pathology and immune activation. Microstructural changes in the pons at 12 weeks post-injection were found to predict survival time and preceded measurable locomotor deficits. This study provides preliminary evidence for diffusion and fMRI markers linked to the progression of synuclein pathology and has translational importance for understanding synucleinopathies in humans. α-Synuclein (α-syn) pathology plays a critical role in neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The longitudinal effects of α-syn pathology on locomotion, brain microstructure, and functional brain activity are not well understood. Using high field imaging, we show preliminary evidence that peripheral injection of α-syn fibrils induces unique patterns of functional and structural changes that occur at different temporal stages of α-syn pathology progression. Our results challenge existing assumptions that α-syn pathology must precede changes in brain structure and function. Additionally, we show preliminary evidence that diffusion and functional magnetic resonance imaging (fMRI) are capable of resolving such changes and thus should be explored further as markers of disease progression.
在人类中，对突触核蛋白病的功能和结构脑成像提供了对大脑皮层和皮层下受影响网络的丰富新认识。尽管取得了这一进展，但α-突触核蛋白（α-syn）病理学与大脑中发生的功能和结构变化之间的时间关系仍未得到很好的理解。在这里，我们通过在三个时间点（每组 10 只雄性和 10 只雌性）对 20 只注射α-突触核蛋白原纤维的小鼠和 20 只 PBS 注射小鼠进行旋转棒、弥散磁共振成像（MRI）、静息状态功能磁共振成像（fMRI）和感觉诱发 fMRI 的纵向研究，检查运动能力、脑微观结构、功能脑活动和α-syn 病理学之间的时间关系。M83 小鼠后腿肌肉内注射α-突触核蛋白原纤维导致注射后 16 周时沿脊髓、脑干和中脑进行性α-syn 病理学。我们的结果表明，α-突触核蛋白的外周注射对中枢神经系统有急性全身作用，以至于大脑中的结构和静息状态功能活动变化在注射后四周内发生，远早于α-syn 病理学到达大脑。在注射后 12 周时，观察到与先前报道的α-syn 病理学和免疫激活部位相吻合的结构和感觉诱发功能脑活动变化的另一种截然不同的模式。在 12 周时的桥脑的微观结构变化被发现可预测生存时间，并早于可测量的运动缺陷。这项研究为与突触核蛋白病进展相关的扩散和 fMRI 标志物提供了初步证据，对理解人类中的突触核蛋白病具有转化意义。α-突触核蛋白（α-syn）病理学在神经退行性疾病中起着关键作用，例如帕金森氏病、路易体痴呆和多系统萎缩。α-syn 病理学对运动、脑微观结构和功能脑活动的纵向影响尚不清楚。使用高场成像，我们初步证明了外周注射α-突触核蛋白原纤维会诱导在不同的α-syn 病理学进展时间阶段发生的独特的功能和结构变化模式。我们的结果挑战了α-syn 病理学必须先于大脑结构和功能变化的现有假设。此外，我们初步证明扩散和功能磁共振成像（fMRI）能够分辨出这些变化，因此应该进一步探索作为疾病进展的标志物。
