Glymphatic fluid transport is suppressed by the aquaporin-4 inhibitor AER-271.

The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.

A mesothelium divides the subarachnoid space into functional compartments.

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.

23 Na-T1 quantification with saturation recovery TrueFISP and variable flip angle GRE at 3T: A phantom study.

PURPOSE: The aim of the current study was to compare the reproducibility of sodium (23 Na)-T1 estimation using a centric-reordered saturation recovery (SR) true fast imaging with steady-state precession (TrueFISP) and a variable flip angle (VFA) spoiled gradient echo (GRE). Additionally, we evaluated the effect of spatial averaging on 23 Na-T1 estimation by the two methods. METHODS: Measurements were performed in the phantom, consisting of 10 dm3 volume rectangular polyethylene container filled with distilled water solution of 0.6% NaCl + 0.004% CuSO4 , using a dual-tunable 23 Na/1 H coil at 3 Tesla. 23 Na images were acquired for FOV = 384 × 384 mm2 and voxel size = 6 × 6 × 6 mm3 using: (1) TrueFISP: TR/TE = 900/1.5 ms, flip angle = 90°, bandwidth = 450 Hz/px, and (2) GRE: TR/TE = 30/1.5 ms, bandwidth = 350 Hz/px. 23 Na-T1 weightings were obtained with nonselective saturation prepulses delayed from the center of the k-space acquisition by 25/40/60/130/280 ms (SR-TrueFISP) and by applying different nominal flip angles: 10°/30°/50°/70°/90° (VFA-GRE). Both sequences were acquired twice, applying 20 and 30 spatial averages. The resulting images were B1 -corrected with a double-angle GRE method. RESULTS: Image acquisition varied from 5:41 to 9:37 for TrueFISP and from 12:48 to 19:12 min for GRE using 20 and 30 spatial averages, respectively. Higher averaging increased the acquisition time by 53% and mean SNR at scan < 10%, without an effect on 23 Na-T1 estimations with both methods (SR-Truefisp |Δ| = 1.58 ms, VFA-GRE |Δ| = 0.53 ms; for SNR P < .001). Overall, mean ± SD of 23 Na-T1 was found as 51 ± 3 ms with SR-TrueFISP and 53 ± 2 ms with VFA-GRE. CONCLUSION: Both SR-TrueFISP and VFA-GRE provided similar 23 Na-T1 estimates based on the phantom measurements with isotropic resolution.

Evaluation of Urinary Sphincter Function by Rapid Magnetic Resonance Diffusion Tensor Imaging.

PURPOSE: This study aimed to assess the feasibility of a rapid diffusion tensor imaging (DTI) for evaluation of the female urinary sphincter function based on differentiation between rest and muscle contraction. METHODS: Magnetic resonance imaging (MRI) of the lower pelvis was performed at 3 Tesla in 10 healthy female volunteers (21-36 years; body mass index, 20.8±3.6 kg/m2) between June and July 2019. High-resolution T1- and T2-weighted images were acquired for anatomical reference, and following DTI performed in 4 experiment phases: twice during rest (denoted rest-1, rest-2) and contraction (contraction-1, contraction-2). Manual segmentation of the urinary sphincter and the levator ani muscles were performed by 2 independent readers. Mean diffusivity (MD) and fractional anisotropy (FA) values derived from DTI volumes were compared in search for significant differences between the experiment phases. Interreader agreement was assessed by intraclass correlation coefficient (ICC). RESULTS: Kruskal-Wallis test showed significant differences between MD values among all the experiment phases, by both independent readers (1st: X2 [3,76]=17.16, P<0.001 and 2nd: X2 [3,76]=15.88, P<0.01). Post hoc analysis revealed differences in MD values by both readers between: rest-1 vs. contraction-1 (least P<0.05), rest-1 vs. contraction-2 (P<0.01), rest-2 vs. contraction-1 (P<0.03), rest-2 vs. contraction-2 (P=0.02) with overall mean 'rest' to 'contraction' ΔMD=20.6%. No MD or FA differences were found between rest-1 vs. rest-2 and contraction-1 vs. contraction-2 among all the experiment phases, and interreader agreement was ICC=0.85 (MD) and ICC=0.79 (FA). CONCLUSION: Rapid DTI might prospectively act as a supporting tool for the evaluation of female pelvic floor muscle function, and incontinence assessment.

Higuchi Fractal Dimension of Heart Rate Variability During Percutaneous Auricular Vagus Nerve Stimulation in Healthy and Diabetic Subjects.

Analysis of heart rate variability (HRV) can be applied to assess the autonomic nervous system (ANS) sympathetic and parasympathetic activity. Since living systems are non-linear, evaluation of ANS activity is difficult by means of linear methods. We propose to apply the Higuchi fractal dimension (HFD) method for assessment of ANS activity. HFD measures complexity of the HRV signal. We analyzed 45 RR time series of 84 min duration each from nine healthy and five diabetic subjects with clinically confirmed long-term diabetes mellitus type II and with diabetic foot ulcer lasting more than 6 weeks. Based on HRV time series complexity analysis we have shown that HFD: (1) discriminates healthy subjects from patients with diabetes mellitus type II; (2) assesses the impact of percutaneous auricular vagus nerve stimulation (pVNS) on ANS activity in normal and diabetic conditions. Thus, HFD may be used during pVNS treatment, to provide stimulation feedback for on-line regulation of therapy in a fast and robust way.

A Quantitative Method Using Head Noncontrast CT Scans to Detect Hyperacute Nonvisible Ischemic Changes in Patients With Stroke.

PURPOSE: Because clinical evaluation of noncontrast computed tomography (CT) has a poor sensitivity in the evaluation of acute ischemic stroke, computer-aided diagnosis may be able to facilitate the performance. Recently, we introduced a computational method for the detection and localization of visible infarcts. Herein, we aimed to evaluate and extend a previous method, the Stroke Imaging Marker (SIM), to localize nonvisible hyperacute ischemia. MATERIALS AND METHODS: On the basis of the SIM and its components-the ratio of percentile differences in subranges of Hounsfield Unit (HU) distribution (P-ratio), ratio of voxels count in ranges of brain CT intensity, median HU attenuation value-the infarct localization was performed in 140 early and follow-up scans of 70 patients. In none of the early scans was the infarct visible to a radiologist or an experienced stroke neuroradiologist. The infarcted hemisphere detection rate (HDR) and sensitivity of infarct localization were measured by overlapping the region of detected tissue in the initial scan, with the gold standard set for the fully visible stroke in the follow-up scan. RESULTS: The best performance of the algorithm was found for the P-ratio including seven percentile subranges within the range of 35th-75th percentile. The modified SIM provided a 76% ischemic HDR and 54% sensitivity in spatial localization of hyperacute ischemia (68% among properly detected infarct sides). CONCLUSION: The improved SIM is a dedicated and potentially useful tool for hyperacute nonvisible brain infarct detection from CT scans and may contribute to reduction of image-to-needle time in patients eligible for revascularization therapy.

Characterization of intraventricular and intracerebral hematomas in non-contrast CT.

Characterization of hematomas is essential in scan reading, manual delineation, and designing automatic segmentation algorithms. Our purpose is to characterize the distribution of intraventricular (IVH) and intracerebral hematomas (ICH) in NCCT scans, study their relationship to gray matter (GM), and to introduce a new tool for quantitative hematoma delineation. We used 289 serial retrospective scans of 51 patients. Hematomas were manually delineated in a two-stage process. Hematoma contours generated in the first stage were quantified and enhanced in the second stage. Delineation was based on new quantitative rules and hematoma profiling, and assisted by a dedicated tool superimposing quantitative information on scans with 3D hematoma display. The tool provides: density maps (40-85HU), contrast maps (8/15HU), mean horizontal/vertical contrasts for hematoma contours, and hematoma contours below a specified mean contrast (8HU). White matter (WM) and GM were segmented automatically. IVH/ICH on serial NCCT is characterized by 59.0HU mean, 60.0HU median, 11.6HU standard deviation, 23.9HU mean contrast, -0.99HU/day slope, and -0.24 skewness (changing over time from negative to positive). Its 0.1(st)-99.9(th) percentile range corresponds to 25-88HU range. WM and GM are highly correlated (R (2)=0.88; p<10(-10)) whereas the GM-GS correlation is weak (R (2)=0.14; p<10(-10)). The intersection point of mean GM-hematoma density distributions is at 55.6±5.8HU with the corresponding GM/hematoma percentiles of 88(th)/40(th). Objective characterization of IVH/ICH and stating the rules quantitatively will aid raters to delineate hematomas more robustly and facilitate designing algorithms for automatic hematoma segmentation. Our two-stage process is general and potentially applicable to delineate other pathologies on various modalities more robustly and quantitatively.