Elucidating cerebrovascular disease pathways to cognitive decline with vascular neuroimaging

ABSTRACT Cerebrovascular disease (CVD) is the second most common cause of dementia and the fifth leading cause of death in the US. At least half of clinically diagnosed Alzheimer’s disease (AD) dementia patients also have CVD upon autopsy. Despite this, clinical trial designs and treatments frequently overlook the multi-etiological nature of cognitive decline. For example, significant progress has been made in identifying and treating AD proteinopathy through anti-amyloid therapies; however, these do not treat or consider effects from comorbid CVD pathology. Past and ongoing clinical studies focused on single-etiology disease may thus suffer from insufficient diagnoses and risk estimates, and the effects of treatment may be obscured. This leaves a critical gap in dementia research for accurate diagnoses and effective treatments against vascular contributions to cognitive impairment and dementia (VCID) and AD with comorbid CVD. The knowledge gap is largely due to a lack of non-invasive vascular markers that can inform on specific CVD processes contributing to VCID and their progression. While Magnetic Resonance Imaging (MRI) serves as the gold standard non-invasive imaging modality for evaluation of CVD, commonly employed MRI-based markers in the field, such as white matter hyperintensities measured on T2-FLAIR, only evaluate non-specific sequelae of CVD (downstream tissue injury). Furthermore, structural and static markers fail to provide insight into the dynamic vascular and hemodynamic phenomena that, as observed in animal models, lead to brain tissue injury and cognitive decline. The proposed project aims to address this gap by utilizing a suite of neuroimaging tools developed by the applicant to understand CVD processes contributing to VCID and to assess vascular hypotheses in relation to the presence of any AD proteinopathy in an individual. The PI’s research program has generated novel preliminary data in AD pathology-positive individuals across the cognitive spectrum indicating presence of intracranial vascular stiffness and decreased neurovascular flow tone, which may contribute to brain tissue injury and cognitive decline. Leveraging a unique MRI dataset and newly developed methods, the project will reprocess existing raw data (k- space) to understand interactions between CVD processes, AD proteinopathy, brain tissue injury, and cognitive decline. Existing longitudinal data in more than 2,000 participants from ongoing studies, including the WI Alzheimer’s Disease Research Center (WADRC) and the WI Registry for Alzheimer’s Prevention (WRAP), will be reprocessed from the raw signal MRI data to provide a detailed spatial characterization of intracranial vascular stiffness and neurovascular flow tone dynamics in both the macro- and micro-circulation. Our goal is to determine the impact of vascular disease processes, including vascular stiffness and decreased flow tone, on brain tissue integrity and cognition in the presence and absence of AD pathology. Ultimately, the discoveries from this project will provide new insights into specific CVD pathways leading to VCID and will inform treatment strategies for AD- related cognitive decline, considering the potential confounding effects of underlying comorbid CVD.