Non-invasive MRI measurements of age-dependent in vivo human glymphatic exchange using magnetization transfer spin labeling

• Published in: NeuroImage (Orlando, Fla.) Vol. 310; p. 121142
• Main Authors: Kim, Dahan, Huang, Yujia, Liu, Jiaen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2025; Elsevier Limited; Elsevier
• Subjects: Adult; Age; Aged; Aging - metabolism; Atrophy; Brain; Brain - diagnostic imaging; Brain - metabolism; Cerebrospinal fluid; Cerebrospinal Fluid - diagnostic imaging; Cerebrospinal Fluid - metabolism; Experiments; Female; Glucose; Glymphatic System - diagnostic imaging; Glymphatic System - metabolism; Glymphatic system, cerebrospinal fluid, magnetization transfer, Alzheimer's disease; Human subjects; Humans; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Measurement techniques; Metabolism; Middle Aged; Neurodegeneration; Optimization; Parenchyma; Simulation; Solutes; Spin labeling; Spin Labels; Statistical analysis; Subarachnoid space; Water; Water exchange; Young Adult; Glymphatic system, cerebrospinal fluid, magnetization transfer, Alzheimer's disease
• DOI: 10.1016/j.neuroimage.2025.121142
• ISSN: 1053-8119; 1095-9572

•A non-invasive MRI technique was developed and optimized to yield in vivo water exchange measurements between human brain parenchyma and CSF, using repeating magnetization transfer saturation labeling of interstitial spins, followed by partial CSF saturation measurement.•Bloch simulations and phantom experiments estimated small (∼0.35 %) direct CSF saturations, far smaller than the measured saturation-based exchange measurements, limited under 0.9 % even with B0 inhomogeneities and potential CSF T2 variations.•When applied to young (n = 6, ages 25–41) and elder (n = 6, ages 53–66) healthy participants, the proposed technique found a significant (P = 0.037) difference (4.7 %±0.5 % vs. 3.5 %±1.2 %) in the exchange metric, decreasing with age (P = 0.046). These findings survived when accounted for potential dilution effect due to intra-voxel CSF volume variations.•Additional labeling nulling experiment to isolate exchange-related contributions suggested parenchyma-CSF exchange as a substantial source of the saturation-based exchange signals. The water exchange between brain parenchyma and cerebrospinal fluid (CSF) is considered to be responsible for glymphatic clearance of solutes and metabolic wastes from the brain, including amyloid-β, a biomarker in neurodegeneration. Despite the potential significance, no noninvasive technique for in vivo measurement of parenchyma-CSF water exchange has been demonstrated in humans, capable of investigating age-related changes in glymphatic clearance. To demonstrate a noninvasive, translatable MRI technique capable of measuring glymphatic water exchange in humans and to apply this technique to examine age-related changes in the glymphatic exchange measures in healthy subjects. Repeating on-resonance magnetization transfer (MT) RF pulses were applied to saturate macromolecules within the brain parenchyma and label its interstitial water, followed by measuring partial CSF saturation resulting from the parenchyma-CSF water exchange. Bloch simulations and phantom experiments determined the extent of direct CSF saturation by the MT pulses. An additional labeling nulling experiment was performed by preemptively saturating parenchyma spins to disable the following MT-based spin labeling, to examine non-exchange contributions to the observed CSF saturation. These techniques were applied to young (n = 6; ages 25–41) and elder (n = 6; ages 53–66) healthy participants to examine age-related changes in their saturation-based exchange measurements. Both Bloch simulations and phantom experiments indicated small (0.4-0.7 %) direct CSF saturation when B0 inhomogeneities and CSF T2 variations were considered. A statistically significant (P = 0.037) difference was observed in the average CSF saturation ratio within the subarachnoid space (SAS) between the young (4.7 %±0.5 %) and the elder (3.5 %±1.2 %) subjects, with their ages negatively correlating with this exchange metric (R2=0.34, P = 0.046). The substantial saturation reductions in the labeling nulling experiment (40–50 % in young; 10–30 % in elder) suggested parenchyma-CSF exchange as a substantial source of the observed saturation signal. These findings survived when the exchange metrics were compensated for potential atrophy-related dilution effect caused by variations in intra-voxel CSF volume. Optimized MT-based parenchyma spin labeling followed by CSF partial saturation measurement demonstrated feasibility of a noninvasive MRI approach to detect glymphatic water exchange between human brain parenchyma and CSF in vivo, with statistically significant findings of age-related differences in the exchange measures.