No abstract

With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood–brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

New approaches are required to successfully intervene therapeutically in neurodegenerative diseases. Addressing the earliest phases of disease, blood brain barrier (BBB) leak before the accumulation of misfolded proteins has significant potential for success. To do so, however, a reliable, noninvasive and economical test is required. There are two potential methods of identifying the BBB fluid leak that results in the accumulation of normally excluded substances which alter neuropil metabolism, protein synthesis and degradation with buildup of misfolded toxic proteins. The pros and cons of dynamic contrast imaging (DCI or DCE) and 3D TGSE PASL are discussed as potential early identifying methods. The results of prior publications of the 3D ASL technique and an overview of the associated physiologic challenges are discussed. Either method may serve well as reliable physiologic markers as novel therapeutic interventions directed at the vasculopathy of early neurodegenerative disease are developed. They may serve well in addressing other neurologic diseases associated with either vascular leak and/or reduced glymphatic flow.

No abstract

No abstract