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NIH grant 1R01NS144133-01A1: Interaction between high-risk atherosclerotic plaque, reduced brain perfusion, and cognitive decline
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Niranjan Balu. Award: $647418.
Start: 2026-08-27T00:00:00.
Atherosclerosis is not only a leading cause of stroke but an important cause of vascular cognitive impairment
and dementia (VCID). VCID due to carotid or intracranial atherosclerosis is a potentially treatable cause of
dementia. While symptomatic patients with high-grade stenosis are eligible for surgical treatment of their
atherosclerotic lesions, asymptomatic patients with lower grade stenosis experience cognitive decline even
though they are on contemporary medical therapy. We posit that there are two mechanisms causative of VCID
in these patients: reduced brain blood flow (H-VCID mechanism) and thromboembolism (T-VCID mechanism)
wherein high-risk plaque components from non-stenotic plaques embolize to distal brain vessels and cause brain
lesions. T-VCID often coexists with H-VCID and differs from H-VCID in its clinical implications since it results
from spontaneous, episodic, and oftentimes, irreversible brain damage. Hence preventing T-VCID requires early
identification of high-risk plaque before thromboembolic brain damage can occur. Multiple prospective studies
using vessel wall MRI to identify high-risk carotid plaque features have shown their association with higher risk
of future events. On the other hand, H-VCID due to carotid disease may be exacerbated by coexisting intracranial
atherosclerosis. Hence there is a critical need for comprehensive assessment of carotid T-VCID and H-VCID
mechanisms and the status of intracranial macro-vasculature to identify these understudied but important VCID
pathways. We will address this need using novel methods to measure blood flow changes in large and medium
sized intracranial arteries (using iCafe measures) and quantitative 3D assessment of high-risk carotid plaque
composition (using vessel wall MRI). Specifically, we will test the hypothesis that in addition to reduced brain
blood flow, high-risk plaque composition determines the severity and progression of VCID as follows. Using
quantitative measurements from baseline MRI and a VCID score using neuropsychometric testing, we will model
the interaction between H- and T-VCID and their effect on VCID score using multivariable models and mediation
analysis (Aim 1) and test the hypothesis that reduced brain blood flow and presence of high-risk plaque are both
independently associated with worse VCID scores. After two-year follow-up MRI and VCID scoring, we will test
the hypothesis that presence of high-risk plaque is predictive of faster VCIS decline, independent of degree of
stenosis (Aim 2). To identify whether there are new medical interventions that may benefit VCID in these patients,
we will follow subjects who are on medical treatment with GLP-1 Receptor Agonists (GLP-1 RA) with baseline
and follow-up MRI and VCID scoring to test the hypothesis that a greater increase in brain blood flow at 1-year
is predictive of slower VCIS decline subsequently. In doing so, we will establish the interactions of H-VCID and
T-VCID and develop a comprehensive foundation for patient specific treatment decisions to reduce the severity
and progression of VCID. We will also identify whether GLP-1 RA is a potential medical treatment that can reduce
cognitive decline in these patients who have no other existing avenues for treatment of their VCID.document fetched 2026-09-06 02:47