In vivo 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.

SIGNIFICANCE STATEMENT 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.

人体中突触核蛋白病的体内功能和结构性脑成像已为整个皮层和皮层下的受影响网络提供了丰富的新知识。尽管取得了这一进展，人们对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知之甚少。在这里，我们通过纵向进行旋转脚架，扩散磁共振成像（MRI），静止状态功能性MRI（fMRI）和感觉诱发性fMRI来检查运动能力，脑微结构，功能性脑活动和α-syn病理之间的时间关系。在三个时间点（每组10只雄性和10只雌性）对20只注射α-syn原纤维的小鼠和20只PBS注射的小鼠进行了研究。肌内注射M83 ^+/–后肢中的α-syn原纤维注射后16周，小鼠会沿着脊髓，脑干和中脑导致进行性α-syn病理。我们的研究结果表明，外周注射α-syn对中枢神经系统具有急性全身作用，因此在α-syn病理到达大脑之前，注射后四周，大脑中的结构和静止状态功能活动会发生变化。注射后12周，观察到结构和感觉诱发的功能性大脑活动变化的单独模式与以前报道的α-syn病理学和免疫激活区域共定位。发现注射后12周pons的微结构变化可预测存活时间，并在可测量的运动功能障碍之前发生。

重要性声明α-突触核蛋白（α-syn）病理在神经退行性疾病（例如帕金森氏病，路易体痴呆和多系统萎缩症）中起关键作用。α-syn病理学对运动，脑微结构和功能性脑活动的纵向影响尚不清楚。使用高场成像，我们显示了初步证据，即外周注射α-syn原纤维会诱导在α-syn病理进展的不同时间阶段发生的功能和结构变化的独特模式。我们的结果挑战了现有假设，即α-syn病理学必须先于大脑结构和功能的改变。另外，