Lungu Ruxanda, Fernandes Francisca F, Pires Monteiro Sara, Outeiro Tiago F, Shemesh Noam
Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.
Institute for Systems and Robotics - Lisboa and Department of Bioengineering, Instituto Superior Técnico - Universidade de Lisboa, Lisbon, Portugal.
J Cereb Blood Flow Metab. 2025 May 7:271678X251338952. doi: 10.1177/0271678X251338952.
Parkinson's disease (PD) is a complex progressive neurodegenerative disorder involving hallmarks such as -Synuclein (Syn) aggregation and dopaminergic dysfunction that affect brain-wide neural activity. Although movement disorders are prominent in PD, sensory impairments also occur relatively early on, mainly in olfactory and, to a lesser extent visual systems. While these deficits have been described mainly at the behavioral and molecular levels, the underlying network-level activity remains poorly understood. Here, we harnessed a human Syn transgenic mouse model of PD with functional MRI (fMRI) to map evoked activity in the visual and olfactory pathways, along with pseudo-Continuous Arterial Spin Labeling (pCASL) and c-FOS measurements to disentangle vascular from neuronal effects. Upon stimulation with either odors or flickering lights, we found significant decreases in fMRI responses along both olfactory and visual pathways, in multiple cortical and subcortical sensory areas. Average Cerebral Blood Flow rates were decreased by ∼10% in the Syn group, while c-FOS levels were reduced by over 50%, suggesting a strong neural driver for the dysfunction, along with more modest vascular contributions. Our study provides insight into brain-level activity in an Syn-based model, and suggests a novel target for biomarking via quantification of simple sensory evoked responses.
帕金森病（PD）是一种复杂的进行性神经退行性疾病，具有诸如α-突触核蛋白（Syn）聚集和多巴胺能功能障碍等特征，这些特征会影响全脑的神经活动。虽然运动障碍在帕金森病中很突出，但感觉障碍也相对较早出现，主要表现在嗅觉方面，在视觉系统中程度较轻。虽然这些缺陷主要在行为和分子水平上被描述，但潜在的网络水平活动仍知之甚少。在这里，我们利用帕金森病的人类Syn转基因小鼠模型，结合功能磁共振成像（fMRI）来绘制视觉和嗅觉通路中的诱发活动，同时利用伪连续动脉自旋标记（pCASL）和c-FOS测量来区分血管和神经元的影响。在用气味或闪烁光刺激后，我们发现在多个皮质和皮质下感觉区域，嗅觉和视觉通路的fMRI反应均显著降低。Syn组的平均脑血流量降低了约10%，而c-FOS水平降低了超过50%，这表明功能障碍有强大的神经驱动因素，同时血管的作用相对较小。我们的研究深入了解了基于Syn的模型中的脑水平活动，并通过量化简单的感觉诱发反应为生物标志物研究提出了一个新的靶点。
