Supplementary Material for: Utilizing Reduced Labeled Proton Clearance to Identify Preclinical Alzheimer Disease with 3D ASL MRI

ABSTRACT Addressing the seminal pathophysiology in Alzheimer disease (AD) is the next logical focus for effective intervention, given the initial disappointing and more recent possibly encouraging results of monoclonal antibody trials. Endothelial cell dysfunction induced blood brain barrier leak (BBB) with associated prolonged capillary mean transit time (cMTT) and glymphatic outflow dysfunction are the most proximal events in the degeneration cascade. Sensitive and reproducible markers are required to both identify early disease and assess future treatment trial outcomes. Two participants with mild cognitive impairment (MCI) and one with AD, were evaluated clinically prior to MRI in this small case series report. From seven 3D Turbo Gradient and Spin Echo (TGSE) Pulsed Arterial Spin Echo (PASL) MRI sequences six homologous region of interest (ROI) in bitemporal, bifrontal, and biparietal lobes for each sequence were examined and plotted against time. By choosing late perfusion times during cMTT phase of perfusion linear analysis of signal decay could be utilized. A reference axial FLAIR sequence was also obtained. Slope of the linear analysis correlated to the rate of labeled proton clearance with reduced clearance occurring in AD participants compared to normal participants in our previous study. Whether similar differences in clearance rate extends to either MCI or early AD was investigated. Participants were categorized by clinical phenotype before MRI and compared to previously published phenotype cohorts: n=18 normal/healthy, n=6 AD, n=3 MCI. Significant differences in labeled proton clearance rates between AD and MCI/control phenotypes within bilateral temporal lobes (Left p=0.004, Right p=0.002) and within bilateral frontal lobes AD vs. controls (Left p=0.001, Right p=0.008) and AD vs. MCI (Left p=0.001, Right p=0.001) were found. This non-invasive MRI technique has potential for identifying MCI transition to AD.