The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association

Abstract

Background: Preservation of brain health has emerged as a leading public health priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among brain cells, meninges, and the hematic and lymphatic vasculature (the neurovasculome) that is highly relevant to the maintenance of cognitive function. In this scientific statement, a multidisciplinary team of experts examines these advances, assesses their relevance to brain health and disease, identifies knowledge gaps, and provides future directions.

Methods: Authors with relevant expertise were selected in accordance with the American Heart Association conflict-of-interest management policy. They were assigned topics pertaining to their areas of expertise, reviewed the literature, and summarized the available data.

Results: The neurovasculome, composed of extracranial, intracranial, and meningeal vessels, as well as lymphatics and associated cells, subserves critical homeostatic functions vital for brain health. These include delivering O₂ and nutrients through blood flow and regulating immune trafficking, as well as clearing pathogenic proteins through perivascular spaces and dural lymphatics. Single-cell omics technologies have unveiled an unprecedented molecular heterogeneity in the cellular components of the neurovasculome and have identified novel reciprocal interactions with brain cells. The evidence suggests a previously unappreciated diversity of the pathogenic mechanisms by which disruption of the neurovasculome contributes to cognitive dysfunction in neurovascular and neurodegenerative diseases, providing new opportunities for the prevention, recognition, and treatment of these conditions.

Conclusions: These advances shed new light on the symbiotic relationship between the brain and its vessels and promise to provide new diagnostic and therapeutic approaches for brain disorders associated with cognitive dysfunction.

Keywords: AHA Scientific Statements; Alzheimer disease; aging; cerebrovascular circulation; cognition; dementia; leukoaraiosis; vascular.

Figure 1.. Vascular architecture and zonation from pial arteriole and penetrating branches diving into the brain parenchyma to ascending venule and pial venule emerging from the brain.

Schematic representation of the cerebral microvasculature and associated cells in neocortex. In the well-studied cerebral cortex, a 2-dimensional plexus of arterioles on the pial surface dives into the cortical parenchyma to form penetrating arterioles. Small offshoots emerge from penetrating arterioles to supply the capillary bed. The first few branches of these offshoots are distinct from both the penetrating arteriole and true capillaries and are called the arteriole-capillary transition. In mice, capillaries make up >90% of the total vascular length and form a dense 3-dimensional network throughout the parenchyma. Capillaries then coalesce into a larger capillary-venous transition vessel, which drains into ascending venules and eventually back into venules of the pial surface. Cell types identified by single-cell transcriptomics (Supplemental Table 1) remain to be precisely mapped onto the cerebrovascular architecture and complemented by proteomic studies. However, knowledge derived from in situ RNA hybridization, immunohistochemistry, and transgenic mouse lines begins to build the picture of where the cell types reside within the arteriole-capillary-venous circuit and their positions within the vascular wall. Available murine Cre drivers still target principal vascular and vascular-associated cell types, but mouse lines that target cell type subclusters are emerging (Supplemental Table 2). aaSMC indicates arteriolar smooth muscle cell; aEC, arterial endothelial cell; aSMC, arterial smooth muscle cell; capEC, capillary endothelial cell; PC, pericyte; vEC, venous endothelial cell; and vSMC, venous smooth muscle cell.

Figure 2.. Schematic representation of neurovascular clearance pathways from the brain.

Simplified depiction of the major clearance pathways operating through the neurovasculature. These include intramural periarterial drainage, mixing between cerebrospinal fluid (CSF) and interstitial fluid (ISF) and glymphatic flow. See text for details and references.