The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal H3A 2B4, Canada.
Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal H4J 1C5, Canada.
Brain. 2022 Sep 14;145(9):3162-3178. doi: 10.1093/brain/awac187.
Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.
孤立性快速眼动睡眠行为障碍（iRBD）是一种以 REM 睡眠期间异常行为和发声为特征的突触核蛋白病。大多数 iRBD 患者随着时间的推移会发展为路易体痴呆、帕金森病或多系统萎缩。iRBD 患者表现出类似于明显突触核蛋白病的脑萎缩模式。然而，将脑萎缩与潜在的α-突触核蛋白病理生理学联系起来的机制尚不清楚。我们的目标是研究α-突触核蛋白的类朊病毒和区域性易感性假说如何解释 iRBD 中的脑萎缩。我们使用多中心队列的 182 名经多导睡眠图证实的 iRBD 患者进行了 T1 加权 MRI，我们对患者（67.8 岁，84%为男性）和 261 名健康对照者（66.2 岁，75%）进行了基于顶点的皮质表面和基于变形的形态计量学分析，以定量分析脑萎缩，并研究 iRBD 中运动和认知功能的形态学相关性。接下来，我们应用基于代理的易感-感染-清除模型（即一种基于结构连接和基因表达模拟病理性α-突触核蛋白传播的计算模型），并通过统计比较模拟的区域脑萎缩与患者观察到的萎缩来测试它是否通过模拟再现 iRBD 中的萎缩。然后，我们通过比较模型拟合与在基因表达或连接性随机化的空模型中获得的模型拟合，评估 SNCA 和 GBA 基因表达和脑连接的影响。结果表明，iRBD 患者存在皮质变薄和组织变形，这与运动和认知功能相关。接下来，我们发现计算模型再现了患者的皮质变薄（r=0.51，P=0.0007）和组织变形（r=0.52，P=0.0005），并且连接组的结构以及 SNCA 和 GBA 基因表达有助于塑造 iRBD 中的萎缩。我们进一步证明，与网络测量或基因表达单独使用相比，基于代理的完整模型在再现 iRBD 中的萎缩模式方面表现更好。总之，iRBD 中的萎缩广泛存在，与运动和认知功能相关，并且可以使用基于代理的建模、结构连接和基因表达的动力学来再现。这些发现支持这样的概念，即类朊病毒样传播和区域性易感性都可以解释前驱性突触核蛋白病中观察到的萎缩。因此，基于代理的易感-感染-清除模型可能是测试神经退行性疾病假说和旨在减缓或阻止α-突触核蛋白病理学传播的新疗法的有用工具。
