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

In the past year how is your doctor using this knowledge to recover any cognitive impairment you had as a result of your stroke? NOTHING? 

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

Costantino Iadecola,

Eric E. Smith,

Josef Anrather,

Chenghua Gu,

Anusha Mishra,

Sanjay Misra,

Miguel A. Perez-Pinzon,

Andy Y. Shih,

Farzaneh A. Sorond,

Susanne J. van Veluw,

… See all authors

Originally published3 Apr 2023https://doi.org/10.1161/STR.0000000000000431Stroke. 2023;54:e251–e271

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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.

Dementia is one of the world’s largest public health problems. In the United States, >500 000 individuals are diagnosed with dementia each year.¹ More than 1.5% of the US population is currently living with dementia.¹ The costs for providing care for individuals with dementia are enormous, exceeding those for cardiovascular disease or cancer.²

The predominant research focus in Alzheimer disease (AD), the most common cause of clinically diagnosed dementia in the elderly, has been on the pathobiology of amyloid plaques and neurofibrillary tangles, with relatively little attention paid to the neurovascular components of the disease. It is notable that disturbances in blood flow delivery³ and blood-brain barrier (BBB) permeability⁴ appear to occur before the onset of symptoms and before evidence of neurodegeneration. Furthermore, recent autopsy studies have revealed that brain infarcts are found in almost half of patients diagnosed with AD during life, and many brains also have evidence of arterial lipid deposits (atherosclerosis) or arteriolar wall thickening (arteriolosclerosis).⁵ At the same time, improved cardiovascular health has been shown to correlate with improved brain health and reduced incidence of dementia later in life.⁶ These converging observations highlight the critical relationship between the neurovasculature and brain health.⁷ However, the mechanisms and pathogenic relevance of this apparent linkage remain elusive. Therefore, the question remains: Is cerebrovascular dysfunction an epiphenomenon of the neurodegenerative process or a pathogenic contributor?

The brain has high energy requirements that are fulfilled by oxygen and glucose delivered to a large number of functionally distinct brain regions by an intricate network of blood vessels stretching >400 miles that are densely packed into the brain substance.⁸ Considering that the brain’s requirements for oxygen and glucose vary in space and time depending on the level of brain activity, delivering the appropriate amount of blood to each region poses a staggering logistical challenge. Accordingly, the structural, functional, and molecular diversity of the cerebral vasculature is astounding, and the interaction between brain cells and the local vasculature is remarkably complex compared with that of other organs.^8,9

Historically, the brain and its vasculature have been considered separate domains, with neuroscientists concentrating on brain cells and vascular biologists on blood vessels. As a result, a rigid distinction was placed between cerebrovascular diseases (eg, stroke) and neurodegenerative diseases (eg, AD), considered mutually exclusive conditions. Over the past decade, a wealth of basic science observations have shed light on the close structural and functional interaction between brain cells and vascular cells, culminating in the establishment of the neurovascular unit concept.¹⁰ At the same time, epidemiological and clinical-pathological studies have revealed an unanticipated overlap between vascular and neurodegenerative pathologies, especially those underlying dementia, including AD.¹¹ In this scientific statement, we explore the emerging data on the cellular, molecular, and functional bases for these interactions in health and disease, and using this evidence, we will seek to identify unresolved issues and outstanding questions. Last, we highlight potential ramifications for preventing and treating the rapidly expanding burden of dementia in the United States and the world.

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