Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK.
Sleep Disorders Center, Department of General and Specialized Medicine, University Hospital of Parma, 43125, Parma, Italy.
Curr Neurol Neurosci Rep. 2024 Sep;24(9):389-412. doi: 10.1007/s11910-024-01359-6. Epub 2024 Jul 20.
Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances".
17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.
睡眠障碍是帕金森病（PD）最常见的非运动症状之一，在其他α-突触核蛋白病中也同样频繁地被报道，如路易体痴呆（DLB）和多系统萎缩（MSA）。最近，食欲素系统被认为在基于显著环境设定点的觉醒控制中起作用，并且其在 α-突触核蛋白病中的睡眠问题中的失调也被转化动物模型的研究结果所证实。然而，其在 α-突触核蛋白病患者中的作用尚不清楚。因此，我们系统地回顾和批判性评估了当代关于食欲素系统与 α-突触核蛋白病睡眠障碍之间关联的证据。在这个系统综述中，我们通过使用 MeSH 术语、关键词和标题词（如“α-突触核蛋白病”和“食欲素”和“睡眠障碍”），在 PubMed、Web of Science 和 PsychINFO 等电子数据库中搜索，确定了研究α-突触核蛋白病（快速眼动睡眠行为障碍（RBD）、帕金森病（PD）、路易体痴呆（DLB）、多系统萎缩（MSA））中食欲素和睡眠的研究。
这项系统性综述共纳入了 17 项研究，其中 2 项研究涉及 RBD，10 项研究涉及 PD，4 项研究涉及 DLB，1 项研究涉及 MSA 患者。总的来说，RBD 和 PD 研究表明，在神经退行性过程的早期阶段，食欲素水平可能会出现潜在的适应性增加，而在疾病的后期、更晚期阶段，报告的水平往往更低。迄今为止，MSA 患者与健康对照组之间的食欲素水平没有差异。目前关于 α-突触核蛋白病中食欲素水平的研究很少。此外，目前研究工作中存在显著的方法学局限性，包括使用非标准化的研究方案和缺乏前瞻性、多中心研究，这使得我们无法就潜在的发病机制得出任何明确的结论。然而，在 α-突触核蛋白病中，食欲素能途径的失调与睡眠障碍之间存在着复杂的、多方面的关系。因此，迫切需要进一步的研究来阐明 α-突触核蛋白病中食欲素能途径的发病机制，以更全面地了解食欲素能途径在 α-突触核蛋白病中的作用。食欲素的药理学干预可能在治疗策略、疾病诊断方面具有多种治疗应用，并且可能对治疗运动和非运动症状都有效。
