Just like a storm brewing in the sky, the combination of altered sleep and neurovascular dysfunction may lead to a perfect storm in the brain. Scientists have observed that patients with alpha-synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies, experience highly variable clinical and cognitive progression. However, the factors linking sleep disturbances and blood pressure abnormalities to this progression have remained unclear. Enter the glymphatic system, a waste clearance mechanism in the brain that operates during specific sleep stages. Imagine blood pressure acting as a force, driving interstitial fluid through brain tissue to remove toxic protein waste. When severe sleep disruptions like REM sleep behavioral disorder occur alongside dysautonomia-induced nocturnal blood pressure abnormalities, it sets the stage for glymphatic failure and increased protein aggregation. In various alpha-synucleinopathies, such as Parkinson’s disease, cognitive decline may result from elevated levels of intraneuronal alpha-synuclein and extracellular amyloid-beta. Alternatively, multisystemic atrophy may exhibit a faster motor deterioration due to increased pathology in oligodendroglia. Researchers propose a model to study the role of glymphatic function in alpha-synucleinopathies and potentially other neurodegenerative diseases linked to abnormal protein accumulation. By controlling nocturnal blood pressure or targeting glymphatic function directly, future treatments could potentially improve cognitive and motor symptoms in these disorders.

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.

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