Cerebral blood flow resistance mapping to identify amyloid-related imaging abnormality (ARIA) risk in Alzheimer's disease

About This Grant

ABSTRACT The overall goal of this work is to refine a novel magnetic resonance imaging (MRI) protocol to assess a cerebrovascular resistance index (CVRi), to apply this protocol in patients with Alzheimer’s disease (AD) to test fundamental hypotheses regarding how CVRi is altered in the setting of elevated amyloid-beta () plaque retention, and to assess how CVRi adjusts following pharmacological reduction of cerebral . Findings are intended to serve as a necessary prerequisite for a larger, longitudinal study that will assess how CVRi may help to triage patients for emerging anti-amyloid therapies based on personalized signatures of parenchymal health. More specifically, accumulation of cerebral  in the arterial vessel walls of patients with AD can reduce vasoreactivity and increase cerebrovascular resistance, and this effect can be assessed using the CVRi defined as the ratio of the mean arterial blood pressure (MAP; mmHg) and cerebral blood flow (CBF; ml blood/100g tissue/min). CVRi has been reported to be directly related to  accumulation in the setting of AD and partly reflects vasotoxicity, vasoconstriction, and decreased response to changes in blood pressure. Furthermore, heterogeneous distribution of  can result in variable vascular resistance and capillary blood transit time heterogeneity, which our lab has shown in other populations to alter oxygen extraction at the tissue level. I have shown that it is possible to non-invasively measure altered capillary transit times by modeling arterial, tissue, and venous blood arrival on non-invasive arterial spin labeling MRI. This method has primarily been applied in patients with cerebrovascular diseases, however, in preliminary data provided here I provide evidence that vascular transit dynamics are also altered in the setting of  accumulation, elevated vascular resistance, and neurodegeneration. This issue is fundamental, as recently approved anti-amyloid therapies alter vascular dynamics and can lead to extravasation events, such as cerebral microbleeds. As such, it is becoming even more relevant to develop an understanding of how  alters vascular health and whether measures of vascular health have relevance for portending cerebral microbleeds, which occur in a significant group of treated patients. Here, I propose to refine methods for assessing the CVRi non-invasively in vivo with MRI, and to pair this assessment with our established measures of vascular transit to better characterize these relationships in patients with AD before and after pharmacological manipulation of cerebral  The study will also be overseen by mentors with complementary expertise in imaging science, cognitive neurology, amyloid angiopathy, neuroradiology, and statistics with an ongoing collaboration, and will leverage recruitment and resources available from an ongoing longitudinal neuroimaging study of anti-amyloid treatments.