Buongiorno Mariateresa, Marzal Clara, Fernandez Manel, Cullell Natalia, de Mena Lorena, Sánchez-Benavides Gonzalo, de la Sierra Alejandro, Krupinski Jerzy, Compta Yaroslau
Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Terrassa, Spain.
Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Institut de Neurociències (UBNeuro), Universitat de Barcelona, Barcelona, Spain.
Front Aging Neurosci. 2023 Aug 24;15:1251755. doi: 10.3389/fnagi.2023.1251755. eCollection 2023.
Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.
α-突触核蛋白病的临床和认知进展具有高度异质性。虽然一些患者在很长一段时间内保持稳定，但另一些患者则会早期出现痴呆或快速的运动功能衰退。睡眠障碍和夜间血压异常已被确定为临床进展的独立危险因素，但缺乏将这两个方面联系起来的机理解释。我们假设，类淋巴系统受损可能在临床进展中起关键作用。类淋巴系统在特定睡眠阶段清除脑内废物，血压是推动间质液通过脑组织以清除蛋白质废物的动力。因此，严重的睡眠改变（如快速眼动睡眠行为障碍）与严重自主神经功能障碍导致的夜间血压生理性下降缺乏相结合，可能构成类淋巴系统功能衰竭的完美风暴，导致异常蛋白质聚集和扩散增加。在路易体疾病（帕金森病和路易体痴呆）中，神经元内α-突触核蛋白和细胞外淀粉样β蛋白的增加会导致认知衰退，而在多系统萎缩中，少突胶质细胞病理变化增加与更快的恶性运动进展有关。我们提出了一个研究模型，可能有助于开展旨在阐明类淋巴功能及相关因素作用的研究，主要针对α-突触核蛋白病，但也可能与其他与蛋白质聚集相关的神经退行性疾病相关。如果该模型被证明是有用的，可能会开辟新的治疗途径，以类淋巴功能为靶点（例如通过控制夜间血压），目的是改善α-突触核蛋白病的认知和运动进展。
