Pilot study utilizing MRI 3D TGSE PASL (arterial spin labeling) differentiating clearance rates of labeled protons in the CNS of patients with early Alzheimer disease from normal subjects

Joseph, Charles R; Benhatzel, Christopher M; Stern, Logan J; Hopper, Olivia M; Lockwood, Michael D.

doi:10.1007/s10334-019-00818-3

Cited by 18 publications

(51 citation statements)

References 30 publications

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“…Impairment of paravascular outflow severely hampers waste removal. Using MRI technology, measurement of outflow dynamics can theoretically be quantified as a clearance rate allowing for comparisons of normal and disease states [ 45 ].…”

Section: Glymphatic Systemmentioning

confidence: 99%

“…With leak of toxic substances in any impairment of toxin egress only amplifies the BBB and parenchymal damage. Our initial investigation suggests paravascular flow is reduced in mild AD [ 45 ].…”

Section: The Evidence Demonstrating Bbb Dysfunction In Early Admentioning

confidence: 99%

“…Since the glymphatic system has also been shown to be affected in AD in multiple animal studies and in human perfusion and recent clearance study, this line of MRI investigation will also be discussed. Contrast enhanced and Bold studies have laid the foundation for developing ASL as another means of quantifying both cerebral perfusion and investigating changes in fluid outflow [ 45 , 83 , 84 , 85 ]. Arterial spin labeling measurements have several challenges but significant advantages over conventional contrast-enhanced studies [ 84 ].…”

Section: Arterial Spin Labeling (Asl) Techniquementioning

confidence: 99%

“…Determination of transit times has been reported using Bold techniques [ 82 ]. ASL MRI’s major challenge is low SNR with resultant poor-quality images, and thus quantitating signal requires a large (ROI) to compare from one delay time to the next, to reduce sampling error [ 45 ].…”

Section: Arterial Spin Labeling (Asl) Techniquementioning

confidence: 99%

“…If the ratio of labeled protons from CSF increases compared with blood, higher signal will remain in the region of interest (ROI) given the much longer T1 CSF. By avoiding signal contamination from subarachnoid and ventricular spaces in the ROI, the source of excess labeled CSF protons is labeled fluid leaking into the interstitium (BBB leak) and sequestered there due to impaired paravascular outflow [ 45 ].…”

Section: 3—d Pasl Mri Glymphatic Clearancementioning

confidence: 99%

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Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease

Joseph

2020

Biomedicines

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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.

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Section: Glymphatic Systemmentioning

confidence: 99%

Section: The Evidence Demonstrating Bbb Dysfunction In Early Admentioning

confidence: 99%

Section: Arterial Spin Labeling (Asl) Techniquementioning

confidence: 99%

Section: Arterial Spin Labeling (Asl) Techniquementioning

confidence: 99%

Section: 3—d Pasl Mri Glymphatic Clearancementioning

confidence: 99%

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Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease

Joseph

2020

Biomedicines

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Noninvasive Magnetic Resonance Imaging Measures of Glymphatic System Activity

Kamagata,

Saito,

Andica

et al. 2023

Magnetic Resonance Imaging

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The comprehension of the glymphatic system, a postulated mechanism responsible for the removal of interstitial solutes within the central nervous system (CNS), has witnessed substantial progress recently. While direct measurement techniques involving fluorescence and contrast agent tracers have demonstrated success in animal studies, their application in humans is invasive and presents challenges. Hence, exploring alternative noninvasive approaches that enable glymphatic research in humans is imperative. This review primarily focuses on several noninvasive magnetic resonance imaging (MRI) techniques, encompassing perivascular space (PVS) imaging, diffusion tensor image analysis along the PVS, arterial spin labeling, chemical exchange saturation transfer, and intravoxel incoherent motion. These methodologies provide valuable insights into the dynamics of interstitial fluid, water permeability across the blood–brain barrier, and cerebrospinal fluid flow within the cerebral parenchyma. Furthermore, the review elucidates the underlying concept and clinical applications of these noninvasive MRI techniques, highlighting their strengths and limitations. It addresses concerns about the relationship between glymphatic system activity and pathological alterations, emphasizing the necessity for further studies to establish correlations between noninvasive MRI measurements and pathological findings. Additionally, the challenges associated with conducting multisite studies, such as variability in MRI systems and acquisition parameters, are addressed, with a suggestion for the use of harmonization methods, such as the combined association test (COMBAT), to enhance standardization and statistical power. Current research gaps and future directions in noninvasive MRI techniques for assessing the glymphatic system are discussed, emphasizing the need for larger sample sizes, harmonization studies, and combined approaches. In conclusion, this review provides invaluable insights into the application of noninvasive MRI methods for monitoring glymphatic system activity in the CNS. It highlights their potential in advancing our understanding of the glymphatic system, facilitating clinical applications, and paving the way for future research endeavors in this field.Evidence Level3Technical EfficacyStage 5

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