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.

This study correlated mild traumatic brain injury (mTBI) cognitive changes with ASL-MRI glymphatic clearance rates (GCRs) and recovery with GCR improvement. mTBI disrupts the blood brain barrier (BBB), reducing capillary mean transit time and GCRs. mTBI is clinically diagnosed utilizing history/examination findings with no physiologic biomarkers. 3D TGSE (turbo-gradient spin-echo) pulsed arterial spin-labeling 3T MRI with 7 long inversion times (TIs) assessed the signal clearance of labeled protons 2800–4000 ms postlabeling in bifrontal, bitemporal, and biparietal regions within 7 days of mTBI and once clinically cleared to resume activities. The Sport Concussion Assessment Tool Version 5 (SKAT5) and Brief Oculomotor/Vestibular Assessment evaluated injured athletes’ cognitive function prior to MRIs. The pilot study demonstrated significant GCRs improvement (95% CI − 0.06 to − 0.03 acute phase; to CI—recovery CI 0.0772 to − 0.0497; P < 0.001 in frontal lobes; and parietal lobes (95% CI − 0.0584 to − 0.0251 acute; CI − 0.0727 to − 0.0392 recovery; P = 0.024) in 9 mTBI athletes (8 female, 1 male). Six age/activity-matched controls (4 females, 2 males) were also compared. mTBI disrupts the BBB, reducing GCR measured using the 3D ASL MRI technique. ASL MRI is a potential noninvasive biomarker of mTBI and subsequent recovery.

Mild traumatic brain injury (mTBI) is a common occurrence around the world, associated with a variety of blunt force and torsion injuries affecting all age groups. Most never reach medical attention, and the identification of acute injury and later clearance to return to usual activities is relegated to clinical evaluation—particularly in sports injuries. Advanced structural imaging is rarely performed due to the usual absence of associated acute anatomic/hemorrhagic changes. This review targets physiologic imaging techniques available to identify subtle blood–brain barrier dysfunction and white matter tract shear injury and their association with chronic traumatic encephalopathy. These techniques provide needed objective measures to assure recovery from injury in those patients with persistent cognitive/emotional symptoms and in the face of repetitive mTBI.

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 with associated prolonged capillary mean transit time (cMTT) and glymphatic outflow dysfunction is 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 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 extend 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 versus controls (left p = 0.001, right p = 0.008) and AD versus MCI (left p = 0.001, right p = 0.001) were found. This noninvasive MRI technique has potential for identifying MCI transition to AD.