Noninvasive Magnetic Resonance Imaging Measures of Glymphatic System Activity

Abstract

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

Reduced Diffusivity along Perivascular Spaces on MR Imaging Associated with Younger Age of First Use and Cognitive Impairment in Recreational Marijuana Users

“…Second, the study did not employ MRI-based tracers, considered the current gold standard for assessing glymphatic function in humans. 17 However, the ALPS index showed a high correlation with glymphatic clearance function, as determined through glymphatic MRI following intrathecal administration of gadolinium. 14 Third, it is important to note that the ALPS index does not solely assess the diffusivity of the perivenous space surrounding the deep medullary vein; it is also influenced by the adjacent white matter microstructure within the ROI.…”

“…A more recent approach, diffusion tensor imaging along the perivascular space (DTI-ALPS), based on diffusion MRI, has emerged as a promising noninvasive method for studying the human glymphatic system. 17,18 The DTI-ALPS method yields the ALPS index, representing the ratio of diffusivity along the perivascular space surrounding the deep medullary vein at the lateral ventricle body level to diffusivity in a direction perpendicular to the major fiber tracts. 17,18 At the level of the lateral ventricle body, the medullary veins run perpendicular to the ventricular wall, paralleling the direction of the perivascular space, whereas the medullary arteries and veins, as vessels of the brain parenchyma, accompany the perivascular space, which is a principal drainage pathway of the glymphatic system.…”

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

“…DTI along the PVS (DTI-ALPS) around deep medullary veins is an emerging noninvasive technique for evaluating the glymphatic system in humans. The ALPS index represents the CSF efflux function along the perivenous spaces, although additional validation studies are needed ( 138 ). Three recent studies performed in population-based cohorts or in patients with sporadic cSVD showed that the DTI-ALPS index was negatively related to the presence and severity of cSVD MRI markers (WMH, lacunes, microbleeds, visible PVS in the basal ganglia, and brain atrophy), suggestive of a declined glymphatic function ( 139 – 141 ).…”