Stotesbury Hanne, Kawadler Jamie M, Hales Patrick W, Saunders Dawn E, Clark Christopher A, Kirkham Fenella J
Developmental Neurosciences, UCL Great Ormond Institute of Child Health, London, United Kingdom.
Department of Radiology, Great Ormond Hospital, London, United Kingdom.
Front Neurol. 2019 Aug 13;10:871. doi: 10.3389/fneur.2019.00871. eCollection 2019.
It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose that macro-circulatory hyper-perfusion, regions of relative micro-circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies.
众所周知，镰状细胞病（SCD）患者存在发生神经并发症的重大风险，包括显性和隐匿性中风、微观结构损伤及认知障碍。然而，其潜在机制仍知之甚少，部分原因在于相关研究结果大多被孤立看待。在此，我们回顾了有越来越多证据支持的机制途径，并提出一个综合的系统生物学框架来理解神经风险。借鉴SCD其他血管床的研究工作以及更广泛的中风文献，我们提出，大循环过度灌注、相对微循环灌注不足区域以及脑储备机制耗竭，共同导致脑血管不稳定状态。我们认为，在这种状态下，组织氧供应脆弱，易受临床状况变化的干扰，如果代谢需求超过组织氧合，就有可能发生中风和/或微观结构损伤。该框架整合了该领域的最新进展，突出了悬而未决的问题，并朝着对神经风险进行病理生理联系解释迈出了第一步，这可能有助于为未来的筛查和治疗策略提供信息。
