Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases

Abstract

Cerebrovascular activity is not only crucial to optimal cerebral perfusion, but also plays an important role in the glymphatic clearance of interstitial waste, including α-synuclein. This highlights a need to evaluate how cerebrovascular activity is altered in Lewy body diseases. This review begins by discussing how vascular risk factors and cardiovascular autonomic dysfunction may serve as upstream or direct influences on cerebrovascular activity. We then discuss how patients with Lewy body disease exhibit reduced and delayed cerebrovascular activity, hypoperfusion, and reductions in measures used to capture cerebrospinal fluid flow, suggestive of a reduced capacity for glymphatic clearance. Given the lack of an existing framework, we propose a model by which these processes may foster α-synuclein aggregation and neuroinflammation. Importantly, this review highlights several avenues for future research that may lead to treatments early in the disease course, prior to neurodegeneration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; cerebrovascular activity; dementia with Lewy bodies; glymphatic system; neurovascular complex.

Figure 1.

Overview of the neurovascular unit. The neurovascular unit is composed of vascular cells (endothelial and smooth muscle cells), glial cells (astrocytes and microglia), and neurons. It is responsible for providing optimal cerebral blood flow, efficient clearance mechanisms via the glymphatic system, and passage of highly selective substances via the blood brain barrier. The structure of the neurovascular unit varies across the neurovascular tree. The capillaries are largely responsible for perfusion, though the upstream arteries and arterioles provide sufficient blood flow in coordination with intrinsic and systemic factors including the autonomic nervous system. The appreciation of the broader influences on the neurovascular unit has led to the use of the term the neurovascular complex. The glymphatic system (lower right) is a fluid flow clearance system that relies on the flow of the cerebrospinal fluid (CSF) from the periarterial spaces into the interstitial space (at which point it is referred to as interstitial fluid; ISF) to the lower pressured perivenous spaces, though other models propose alternate mechanisms. While there is ongoing debate about the nature of the flow (e.g. bulk flow versus diffusion), evidence suggests the flow of ISF across the interstitial space carries solutes towards the perivenous space for clearance by the meningeal and cervical lymphatic vessels. Increasing evidence suggests that the bulk flow is facilitating by cerebrovascular activity (e.g. vasodilation and changes in cerebral blood flow) in addition to the aquaporin-4 (AQP4) water channel’s role.

Figure 2.

Potential interactions between cerebrovascular mechanisms and established Lewy body disease processes. Vascular risk and cardiovascular autonomic dysfunction both influence and challenge cerebrovascular functioning. While the cerebrovascular system is able to compensate for these factors, to a degree, more severe cardiovascular risk and autonomic dysfunction, such as orthostatic hypotension, may lead to episodic hypoperfusion and hypoxia that may initiate a cascade of effects. This may include acidification and an increase in reactive oxygen species (ROS), that lead to or enhance α-synuclein aggregation within neurons (lower pathway). Additionally, as cerebrovascular activity drives CSF flow into the interstitial space, facilitating clearance of α-synuclein, reduced and delayed cerebrovascular activity may contribute to excess α-synuclein, enhancing opportunity for α-synuclein aggregation (upper pathway). These processes may, in turn, exacerbate neuroinflammation and damage the endothelium. The lower left panel illustrates Braak’s original staging demonstrating the substantia nigra pars compacta (SNc) is impacted earlier and more severely. We suggest the SNc is particularly susceptible to these mechanisms due to its high energetic demand and unique interactions between α-synuclein and dopamine synthesis. As cerebrovascular activity is more severely altered, broader regions of the brain are impacted.