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.
Highlights
Future successful treatment and mitigation of neurodegenerative diseases such as Alzheimer disease (AD) will likely need to include treatment of disease processes that may initiate, compound, and accelerate the destructive effects of accumulating misfolded prion-like proteins.The central nervous system (CNS) is but 5% of total body weight yet consumes 20% of available cardiac output [1]
TheThe firstfirst inner layerlayer of the barrierbarrier is composed of endothelial cells andcells tightand interinter-endothelial junctions composed of proteins (i.e., vascular endothelial cadherins and other endothelial junctions composed of proteins, which exclude intravascular solute, transmembrane and junctionaland adhesion molecules), exclude intravascular solute, proteins, proteins, and cellular transmigration into the interstitium
The discovery of preclinical low volume blood–brain barrier (BBB) leak caused by initial pericyte damage with consequent loss of integrity of tight endothelial junctions, to date is the earliest morphologic change in AD preceding accumulation of amyloid β-protein oligomers (Aβ) and Hp tau [2,21,37] (Figure 2)
Summary
Future successful treatment and mitigation of neurodegenerative diseases such as AD will likely need to include treatment of disease processes that may initiate, compound, and accelerate the destructive effects of accumulating misfolded prion-like proteins. Set in motion are multiple simultaneous or sequential detrimental processes resulting in reduced availability of metabolic substrate (e.g., reduced glucose transport), influx of neuro toxins and cells from blood (e.g., blood borne recycled amyloid β-protein, free iron, RBCs and inflammatory cells), and reduced clearance of metabolic waste including detrimental proteins [2,9,10,11]. This leads to development, accumulation, and spread of toxic misfolded proteins (Aβ and Hp tau) and neurodegeneration, all required for pathologic diagnosis.
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