VCID Basic Research: Role of the neurovascular unit

AD-Related Dementias Focus

Study the neurovascular unit structure and function to establish how it is impacted by VCID.

2032 RFA-NS-16-021: Mechanistic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID)(R01) PAR-18-413: Mechanistic Basis of Diffuse White Matter Disease and Small Vessel Pathology in Vascular Contributions to Cognitive Impairment and Dementia (VCID)(R01) RFA-AG-17-055: Brain Lymphatic System in Aging and Alzheimer's Disease (R01) RFA-NS-19-039: Mechanistic Basis of Diffuse White Matter Disease in VCID (re-issue) PAR-19-070: Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01) RFA-NS-20-004: Molecular Mechanisms of Blood-Brain Barrier Function and Dysfunction in Alzheimer's disease and Alzheimer's related dementias RFA-NS-20-013: White Matter Disease Etiology of Dementia in the U.S. Including in Health Disparities Populations RFA-AG-20-025: Understanding Senescence in Brain Aging and Alzheimer’s Disease (R01) NOT-NS-21-038: Hyperacute MRI Imaging Studies to Understand How Brain Changes Affect AD/ADRD-Relevant Trajectories and Outcomes Post-Stroke NOT-NS-21-039: Innovative Approaches or Technologies to Investigate Regional, Structural and Functional Heterogeneity of CNS Small Blood and Lymphatic Vessels in AD/ADRD PAR-22-235: Blood Brain Barrier Response to Antibodies Targeting Beta-Amyloid (R01 - Clinical Trial Not Allowed) PAR-23-140: Blood Brain Barrier Response to Antibodies Targeting Beta-Amyloid (R01 - Clinical Trial Not Allowed) (Reissue of PAR-22-235) RFA-NS-24-027: VCID Center Without Walls for Understanding and Leveraging Small Vessel Cerebrovascular Disease Mechanisms in ADRD (R01 - Clinical Trial Not Allowed) PAR-24-196: Mechanistic and Hemodynamic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID)(R01 - Clinical Trial Not Allowed) 2.Q In Progress Encourage basic science research that investigates the impact of aging, AD pathology, and genes on peri- and para-vascular clearance mechanisms, the NVU, and cerebrovascular function. DN 2016 ADRD Summit: Vascular Contributions to Cognitive Impairment and Dementia (VCID), Including Vascular Cognitive Impairment and Vascular Dementia (VCID) Focus Area 1: Basic Mechanisms and Experimental Models, Recommendation 2 2022 ADRD Summit: Vascular Contributions to Cognitive Impairment and Dementia (VCID) Milestone 2, Priority 3 Two molecular maps of blood vessels in the human brain reveal links to dementia News: Brain’s waste removal system may offer path to better outcomes in Alzheimer’s therapy Workshop: Blood-Brain Barrier Transport in Aging and Alzheimer’s Disease Highlight: Blood flow makes waves across the surface of the mouse brain Research on Disease Mechanisms Mechanistic Basis of Diffuse White Matter Disease and Small Vessel Pathology in Vascular Contributions to Cognitive Impairment and Dementia (VCID) R01) Mechanistic Basis of Diffuse White Matter Disease in VCID (re-issue) Diverse VCID: White Matter Lesion Etiology of Dementia in Diverse Populations Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery (DISCOVERY) Select projects funded in FY21 Select projects funded in FY22

  • At least two new projects to understand the role of perivascular and paravascular clearance pathways that may protect the brain from VCID.
  • At least three new projects to determine how normal neurovascular unit function and blood brain barrier function are impacted by VCID risk factors.

Summary of Key Accomplishments

Several recent NIH-funded studies have resulted in significant new understanding of the inter-relationship between brain cells and their blood vessels, known collectively as the "neurovascular unit", and how they are impacted in AD/ADRD. For example, in 2019, one of these studies reported that brain waste clearance pathways, also known as perivascular “glymphatic pathways,” not only contribute to the removal of beta-amyloid from the brain but are compromised by long-term hypertension in rats – a clear example of interaction between hypertension and brain waste clearance mechanisms that may result in increased risk for different types of dementia. In 2023, another study provided further evidence for coordinated neurovascular unit dysregulation in AD by profiling gene expression in individual cells from six brain regions from more than 400 human brains.

To advance further fundamental understanding of basic disease-related molecular mechanisms of VCID, with a specific focus on small cerebral vessel diseases and their impact on neurovascular unit function, NIH has issued an open funding opportunity titled “VCID Center Without Walls for Understanding and Leveraging Small Vessel Cerebrovascular Disease Mechanisms in ADRD”. This complements efforts to advance understanding of cellular and molecular mechanisms that can be targeted to protect the blood-brain barrier, and thus the brain, during therapeutic interventions aimed at beta-amyloid, including a pair of recent awards. This emerging body of work is opening new avenues of investigation and potential drug targets for VCID including when it co-occurs with Alzheimer’s dementia.

The key accomplishments summary is current as of June 2024.