Neuroimaging findings related to glymphatic system alterations in older adults with metabolic syndrome.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Reduced glymphatic flow has been observed in rat models of type 2 diabetes and hypertension, indicating the role of vascular risk factors in the glymphatic system. However, little is known about how vascular risk factors affect the human glymphatic system. The present study aims to assess the relationships between metabolic syndrome (MetS), a cluster of vascular risk factors, and the glymphatic system function using diffusion magnetic resonance imaging (MRI)-based measures of water diffusivity in the glymphatic compartments, including the brain interstitial space and perivascular spaces around the deep medullary vein. We hypothesized that vascular risk factors are associated with glymphatic dysfunction, leading to cognitive impairment in older adults. METHODS: This cross-sectional study assessed 61 older adults (age range, 65-82 years) who had participated in the Bunkyo Health Study, including 15 healthy controls (mean age, 70.87 ± 4.90 years) and 46 individuals with MetS (mean age, 71.76 ± 4.61 years). Fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. RESULTS: After adjusting for age, sex, years of education, total Fazekas scale, Pittsburgh sleep quality index (PSQI) score, and intracranial volume (ICV), a significantly (P = 0.030; Cohen's d = 1.01) higher FW was observed in individuals with MetS than in the healthy controls. Furthermore, individuals with MetS had a significantly (P = 0.031; Cohen's d = 0.86) lower ALPS index than the healthy controls, with age, sex, years of education, total Fazekas scale, PSQI score, ICV, fractional anisotropy, and mean diffusivity included as confounding factors. Higher FW was significantly associated with lower ALPS index (r = -0.37; P = 0.004). Multiple linear regression (MLR) with backward elimination analyses showed that higher diastolic blood pressure (BP; standardized ß = 0.33, P = 0.005) was independently associated with higher FW, whereas higher fasting plasma glucose levels (standardized ß = -0.63, P = 0.002) or higher Brinkman index of cigarette consumption cumulative amount (standardized ß = -0.27, P = 0.022) were associated with lower ALPS index. The lower ALPS index (standardized ß, 0.28; P = 0.040) was associated with poorer global cognitive performance, which was determined using the Japanese version of the Montreal Cognitive Assessment (MOCA-J) scores. Finally, partial correlation analyses showed a significant correlation between higher FW and lower MOCA-J scores (r = -0.35; P = 0.025) and between higher FW and higher diastolic BP (r = 0.32, P = 0.044). CONCLUSION: The present study shows the changes in diffusion MRI-based measures reflected by the higher FW and lower ALPS index in older adults with MetS, possibly due to the adverse effect of vascular risk factors on the glymphatic system. Our findings also indicate the associations between the diffusion MRI-based measures and elevated diastolic BP, hyperglycemia, smoking habit, and poorer cognitive performance. However, owing to the limitations of this study, the results should be cautiously interpreted.

Emerging Perspectives on MRI Application in Multiple Sclerosis: Moving from Pathophysiology to Clinical Practice.

MRI plays a central role in the diagnosis of multiple sclerosis (MS) and in the monitoring of disease course and treatment response. Advanced MRI techniques have shed light on MS biology and facilitated the search for neuroimaging markers that may be applicable in clinical practice. MRI has led to improvements in the accuracy of MS diagnosis and a deeper understanding of disease progression. This has also resulted in a plethora of potential MRI markers, the importance and validity of which remain to be proven. Here, five recent emerging perspectives arising from the use of MRI in MS, from pathophysiology to clinical application, will be discussed. These are the feasibility of noninvasive MRI-based approaches to measure glymphatic function and its impairment; T1-weighted to T2-weighted intensity ratio to quantify myelin content; classification of MS phenotypes based on their MRI features rather than on their clinical features; clinical relevance of gray matter atrophy versus white matter atrophy; and time-varying versus static resting-state functional connectivity in evaluating brain functional organization. These topics are critically discussed, which may guide future applications in the field.

Evaluation of alterations in interstitial fluid dynamics in cases of whole-brain radiation using the diffusion-weighted image analysis along the perivascular space method.

In the current study, we assessed changes in interstitial fluid dynamics resulting after whole-brain radiotherapy using the diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, which is a simplified variation of the diffusion tensor image ALPS (DTI-ALPS) method using diffusion-weighted imaging (DWI) with orthogonal motion-probing gradients (MPGs). This retrospective study included 47 image sets from 22 patients who underwent whole-brain radiotherapy for brain tumors. The data for the normal control group comprised 105 image sets from 105 participants with no pathological changes. DWI was performed with the three MPGs applied in an orthogonal direction to the imaging plane, and apparent diffusion coefficient images for the x-, y-, and z-axes were retrospectively generated. The ALPS index was calculated to quantify interstitial fluid dynamics. The independent t-test was used to compare the ALPS index between normal controls and patients who underwent whole-brain radiotherapy. Patients were compared in all age groups and individual age groups (20-39, 40-59, and 60-84 years). We also examined the correlation between biologically equivalent doses (BEDs) and the ALPS index, as well as the correlation between white matter hyperintensity and the ALPS index. In the comparison of all age groups, the ALPS index was significantly lower (p < 0.001) in the postradiation group (1.32 ± 0.16) than in the control group (1.44 ± 0.17), suggesting that interstitial fluid dynamics were altered in patients following whole-brain radiotherapy. Significant age group differences were found (40-59 years: p < 0.01; 60-84 years: p < 0.001), along with a weak negative correlation between BEDs (r = -0.19) and significant correlations between white matter hyperintensity and the ALPS index (r = -0.46 for periventricular white matter, r = -0.38 for deep white matter). It was concluded that the ALPS method using DWI with orthogonal MPGs suggest alteration in interstitial fluid dynamics in patients after whole-brain radiotherapy. Further systematic prospective studies are required to investigate their association with cognitive symptoms.

Contrast-Enhanced Fluid-Attenuated Inversion Recovery in Neuroimaging: A Narrative Review on Clinical Applications and Technical Advances.

While contrast-enhanced fluid-attenuated inversion recovery (FLAIR) has long been regarded as an adjunct sequence to evaluate leptomeningeal disease in addition to contrast-enhanced T1-weighted imaging, it is gradually being used for more diverse pathologies beyond leptomeningeal disease. Contrast-enhanced FLAIR is known to be highly sensitive to low concentrations of gadolinium within the fluid. Accordingly, recent research has suggested the potential utility of contrast-enhanced FLAIR in various kinds of disease, such as Meniere's disease, seizure, stroke, traumatic brain injury, and brain metastasis, in addition to being used for visualizing glymphatic dysfunction. However, its potential applications have been reported sporadically in an unorganized manner. Furthermore, the exact mechanism for its superior sensitivity to low concentrations of gadolinium has not been fully understood. Rapidly developing magnetic resonance technology and unoptimized parameters for FLAIR may challenge its accurate application in clinical practice. This review provides the fundamental mechanism of contrast-enhanced FLAIR, systematically describes its current and potential clinical application, and elaborates on technical considerations for its optimization. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 5.

Increased Dendritic Orientation Dispersion in the Left Occipital Gyrus is Associated with Atypical Visual Processing in Adults with Autism Spectrum Disorder.

In autism spectrum disorder (ASD), the complexity-specific hypothesis explains that atypical visual processing is attributable to selective functional changes in visual pathways. We investigated dendritic microstructures and their associations with functional connectivity (FC). Participants included 28 individuals with ASD and 29 typically developed persons. We explored changes in neurite orientation dispersion and density imaging (NODDI) and brain areas whose FC was significantly correlated with NODDI parameters in the explored regions of interests. Individuals with ASD showed significantly higher orientation dispersion index (ODI) values in the left occipital gyrus (OG) corresponding to the secondary visual cortex (V2). FC values between the left OG and the left middle temporal gyrus (MTG) were significantly negatively correlated with mean ODI values. The mean ODI values in the left OG were significantly positively associated with low registration of the visual quadrants of the Adolescent/Adult Sensory Profile (AASP), resulting in a significant positive correlation with passive behavioral responses of the AASP visual quadrants; additionally, the FC values between the left OG and the left MTG were significantly negatively associated with reciprocal social interaction. Our results suggest that abnormal V2 dendritic arborization is associated with atypical visual processing by altered intermediation in the ventral visual pathway.

Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.

White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel-based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion-weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age-related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age-related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello-thalamo-cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract-level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.

Glymphatic imaging using MRI.

In recent years, the existence of a mass transport system in the brain via cerebrospinal fluid (CSF) or interstitial fluid (ISF) has been suggested by many studies. The glymphatic system is hypothesized to be a waste clearance system of the CSF through the perivascular and interstitial spaces in the brain. Tracer studies have primarily been used to visualize or evaluate the waste clearance system in the brain, and evidence for this system has accumulated. The initial study that identified the glymphatic system was an in vivo tracer study in mice. In that study, fluorescent tracers were injected into the cisterna magna and visualized by two-photon microscopy. MRI has also been used to evaluate glymphatic function primarily with gadolinium-based contrast agents (GBCAs) as tracers. A number of GBCA studies evaluating glymphatic function have been conducted using either intrathecal or intravenous injections. Stable isotopes, such as 17 O-labeled water, may also be used as tracers since they can be detected by MRI. In addition to tracer studies, several other approaches have been used to evaluate ISF dynamics within the brain, including diffusion imaging. Phase contrast evaluation is a powerful method for visualizing flow within the CSF space. In order to evaluate the movement of water within tissue, diffusion-weighted MRI represents another promising technique, and several studies have utilized diffusion techniques for the evaluation of the glymphatic system. This review will discuss the findings of these diffusion studies. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019. J. Magn. Reson. Imaging 2020;51:11-24.

Computer-assisted cognitive remediation therapy increases hippocampal volume in patients with schizophrenia: a randomized controlled trial.

BACKGROUND: Cognitive remediation therapy (CRT) effectively reduces neurocognitive impairment in patients with schizophrenia, but few studies have used structural neuroimaging methods to assess its neuroanatomical effects. We investigated these effects, as well as the association between changes in cortical volume and neurocognitive performance. METHOD: Between August 2013 and September 2016, we performed a randomized controlled study comprising a CRT group (16 individuals) and a treatment-as-usual (TAU) group (15 individuals) of patients with schizophrenia. CRT participants engaged in twice-weekly computer-assisted CRT sessions and weekly group meetings for 12 weeks. T1-weighted magnetic resonance imaging was performed before and after the intervention period, and whole-brain voxel-based morphometric analysis was used to detect significant cortical gray matter volume changes. We also assessed the correlation between cortical volume changes and CRT-derived neurocognitive improvements. RESULTS: The CRT group exhibited significantly greater improvements than the TAU group in verbal fluency (P = 0.012) and global cognitive scores (P = 0.049). The CRT group also exhibited significantly greater increases in right hippocampal volume than the TAU group (P < 0.001). Changes in verbal fluency scores and right hippocampal volumes were positively correlated (r = 0.53, P = 0.001). CONCLUSION: We found that CRT significantly increased right hippocampal volumes and that these enhancements were positively correlated with changes in verbal fluency scores. Our results indicate that CRT induces cognitive improvement through hippocampal plasticity. TRIAL REGISTRATION: Registration number: UMIN000026146 , 2017/02/15, retrospectively registered.

Revisiting Current Golden Rules in Managing Acute Ischemic Stroke: Evaluation of New Strategies to Further Improve Treatment Selection and Outcome.

OBJECTIVE: Advanced stroke imaging has generated much excitement for the early diagnosis of acute ischemic stroke (AIS) and facilitation of intervention. However, its therapeutic impact has not matched its diagnostic utility; most notably, lacking significant contributions to recent major AIS clinical trials. It is time to reexamine the fundamental hypotheses from the enormous body of imaging research on which clinical practices are based and reassess the current standard clinical and imaging strategies, or golden rules, established over decades for AIS. In this article, we will investigate a possible new window of opportunity in managing AIS through a better understanding of the following: first, the potential limitations of the golden rules; second, the significance of imaging-based parenchymal hypoperfusion (i.e., lower-than-normal relative cerebral blood flow [rCBF] may not be indicative of ischemia); third, the other critical factors (e.g., rCBF, collateral circulation, variable therapeutic window, chronicity of occlusion) that reflect more individual ischemic injury for optimal treatment selection; and, fourth, the need for penumbra validation in successfully reperfused patients (not in untreated patients). CONCLUSION: Individual variations in the therapeutic window, ischemic injury (rCBF), and chronicity of vascular lesion development have not been comprehensively incorporated in the standard algorithms used to manage AIS. The current established imaging parameters have not been consistently validated with successfully reperfused patients and rCBF to quantitatively distinguish between oligemia and ischemia and between penumbra and infarct core within ischemic tissue. A novel paradigm incorporating rCBF values or indirectly incorporating relative rCBF values with higher statistically powered imaging studies to more reliably assess the severity of ischemic injury and differentiate reversibility from viability within the area of imaging-based parenchymal hypoperfusion may provide a more personalized approach to treatment, including no treatment of infarction core, to further enhance outcomes.

Structure of the Medullary Veins of the Cerebral Hemisphere and Related Disorders.

Deep medullary veins drain into subependymal veins with four convergence zones and show parallel distribution patterns adjacent to the body or inferior horn and a radial pattern in the frontal horn or trigon of the lateral ventricle. As white matter imaging develops such as diffusion tensor imaging or susceptibility-weighted imaging, requirements for understanding of white matter structures are increasing, not only for understanding of neuronal tracts but also for that of other structures including the fine anatomy of white matter vessels. Some disorders are related to deep medullary veins and show characteristic distributions of the lesions indicating the relationship to the medullary veins. When lesions show a parallel or radial distribution pattern in the certebral deep white matter, disorders related to deep medullary veins should be considered for differential diagnosis. In this review, we discuss disorders related to deep medullary veins, including (a) anomalies of the medullary veins, (b) hemorrhagic disorders related to the medullary veins (diffuse vascular injury due to high-energy trauma, deep medullary vein engorgement/thrombosis in neonates), (c) inflammatory changes that spread along the medullary veins, (d) neoplasms within the medullary veins, and (e) metabolic changes that lead to altered visualization of medullary veins. Understanding the anatomic structure of medullary veins in the cerebral hemisphere and becoming familiar with disorders in which the medullary veins play a major role in disease development may be helpful in the interpretation of brain images. ©RSNA, 2017.

Efficacy and safety of non-suture dural closure using a novel dural substitute consisting of polyglycolic acid felt and fibrin glue to prevent cerebrospinal fluid leakage-A non-controlled, open-label, multicenter clinical trial.

The objective of this study is to evaluate the efficacy and safety of non-suture dural closure using a novel dural substitute (GM111) consisting of polyglycolic acid felt with a fibrin-glue-coated area commensurate in size with the dural defect. This was a non-controlled, open-label, multicenter clinical trial. The efficacy evaluation endpoints were (1) GM111's intra-operative capability to close dural defects and (2) prevention of cerebrospinal fluid (CSF) leakage and subcutaneous CSF retention throughout the postoperative period (evaluated by diagnostic imaging). Patients meeting the following three preoperative and two intra-operative selection criteria were enrolled: (1) between 12 and <75 years of age; (2) the dura is surmised to be defective and in need of reconstruction; (3) informed written consent was obtained from the patient; (4) the surgical wound is class 1; and (5) the size of duraplasty is ≥0.2 cm2 to <100 cm2. Sixty patients were enrolled. The craniotomy site was supratentorial in 77.2%, infratentorial in 12.3% and sellar in 10.5%. The GM111 prosthesis size ranged from 0.24 to 42 cm2. To evaluate the efficacy, intra-operative closure was confirmed by Valsalva's maneuver, water infusion, etc., in all patients. CSF leakage and subcutaneous CSF retention throughout the postoperative period were found in four patients. Adverse events for which a causal relationship with GM111 could not be ruled out occurred in 8.8% of the patients. There were no instances of postoperative infection due to GM111. GM111 showed good closure capability and safety when used for non-suture dural closure.

Dural Thickening of the Internal Auditory Canal in Patients With Spontaneous Intracranial Hypotension Syndrome.

OBJECTIVE: This study aimed to assess the utility of dural thickening of the internal auditory canal (IAC) in patients with spontaneous intracranial hypotension (SIH) syndrome and determined the sensitivity and specificity of this image finding. METHODS: Magnetic resonance images were evaluated for 22 cases of definite SIH and 16 cases of unlikely SIH. On contrast-enhanced magnetic resonance imaging, pachymeningeal enhancement and dural thickening of the IAC were assessed. RESULTS: Pachymeningeal enhancement was observed in 21 of 22 patients in the definite SIH group and 1 of 16 patients in the unlikely SIH group (sensitivity, 95.5%; specificity, 93.8%). Dural thickening of the IAC was observed in 15 of 22 patients in the definite SIH group and 0 of 16 patients in the unlikely SIH group (sensitivity, 68.2%; specificity, 100%). CONCLUSIONS: Dural thickening of the IAC showed 100% specificity for SIH syndrome and can increase the accuracy of diagnosis of SIH syndrome.

Time Course of Diffusion Kurtosis in Cerebral Infarctions of Transient Middle Cerebral Artery Occlusion Rat Model.

OBJECTIVE: To evaluate the relationship between fiber bundle direction and changes in diffusion kurtosis, we evaluated the apparent diffusion kurtosis coefficients (AKCs) that were perpendicular to and parallel to the principal diffusion tensor eigenvector. MATERIALS AND METHODS: Adult male Wistar rats were subjected to 30 or 60 minutes of middle cerebral artery occlusion and imaged with a 7T Magnetic Resonance Imager System (Varian MRI System 7T/210: Agilent Technologies, CA). Diffusion kurtosis images were obtained before middle cerebral artery (MCA) reperfusion and 3, 6, and 24 hours after reperfusion to generate the apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean apparent diffusion kurtosis coefficient (mAKC), AKC axial to the eigenvector (axAKC), and AKC radial to the eigenvector (radAKC) images. The time course of the region/normal ratio was evaluated for the above parameters in the caudoputamen and white matter. RESULTS: Relative FA and relative ADC values decreased 3 hours after MCA reperfusion and remained decreased until 24 hours. Relative mAKC, axAKC, and radAKC values were increased 3 hours after MCA reperfusion, peaked after 6 hours, and slightly decreased after 24 hours. In the white matter, axAKC showed larger changes than radAKC. CONCLUSION: The time course of the diffusion kurtosis value showed earlier pseudonormalization than the ADC value of the lesions. For white matter lesions, the increase in axAKC was larger than that in radAKC, suggesting that the tissue changes after infarction mainly produce reduced diffusivity along the fibers and lead to increased inhomogeneity of the diffusion.

A case of meningococcal meningitis with multiple cerebellar microbleeds detected by susceptibility-weighted imaging.

BACKGROUND: Bacterial meningitis is a fatal infectious disease of the central nervous system complicating intravascular involvements. Multiple microbleeds are rarely identified as complications because of the limited detection threshold of conventional imaging modalities. We report the first case of meningococcal meningitis with successful identification of multiple microbleeds in the cerebellum by susceptibility-weighted imaging. CASE PRESENTATION: A 19-year-old Japanese female was brought to our emergency department because of fever and coma. A spinal tap was performed and turbid yellow fluid was collected. A diagnosis of bacterial meningitis was established and the patient was admitted to an intensive care unit. Dexamethasone and Antibiotics were administered and Neisseria meningitides was cultured from the spinal fluid. On day 10, postcontrast magnetic resonance imaging identified enhanced subarachnoid space in the cerebellum. Susceptibility-weighted imaging showed spotty low-intensity signals in the cerebellar tissue, indicating microbleeds. The patient made a full recovery from coma and was discharged without neurological sequelae on day 24. CONCLUSION: Meningococcal meningitis can cause multiple microbleeds in the cerebellum. In this report, we successfully identified microbleeds by susceptibility-weighed imaging. Using this imaging modality, further investigations will clarify its clinical incidence and significance.

Utility of High-b-Value Diffusion-Weighted Magnetic Resonance Imaging in Evaluating Reversible Medial Longitudinal Fasciculus Syndrome Caused by Acute Brainstem Ischemia.

BACKGROUND: Medial longitudinal fasciculus (MLF) syndrome refers to a gaze disorder characterized by impaired adduction on the ipsilateral side to the injured MLF, with dissociated nystagmus of the contralateral abducting eye. The most common cause of the MLF syndrome is ischemic stroke. However, acute ischemic change in the MLF may be undetectable even on diffusion-weighted magnetic resonance imaging (DW-MRI) partly because of its small size and specific brainstem location. CASE REPORT: Herein, we present the first reported case of MLF syndrome in which, compared with the standard-b-value DWI, a higher b-value DWI revealed more clearly a small infarction in the dorsal pons in the acute stage. CONCLUSIONS: We suggest that high-b-value DWI can be a useful diagnostic method for patients with MLF syndrome caused by possible brainstem ischemia and thus supportive for deciding the optimal treatment for such patients.

Decision-making deficit of a patient with axonal damage after traumatic brain injury.

Patients with traumatic brain injury (TBI) were reported to have difficulty making advantageous decisions, but the underlying deficits of the network of brain areas involved in this process were not directly examined. We report a patient with TBI who demonstrated problematic behavior in situations of risk and complexity after cerebral injury from a traffic accident. The Iowa gambling task (IGT) was used to reveal his deficits in the decision-making process. To examine underlying deficits of the network of brain areas, we examined T1-weighted structural MRI, diffusion tensor imaging (DTI) and Tc-ECD SPECT in this patient. The patient showed abnormality in IGT. DTI-MRI results showed a significant decrease in fractional anisotropy (FA) in the fasciculus between the brain stem and cortical regions via the thalamus. He showed significant decrease in gray matter volumes in the bilateral insular cortex, hypothalamus, and posterior cingulate cortex, possibly reflecting Wallerian degeneration secondary to the fasciculus abnormalities. SPECT showed significant blood flow decrease in the broad cortical areas including the ventromedial prefrontal cortex (VM). Our study showed that the patient had dysfunctional decision-making process. Microstructural abnormality in the fasciculus, likely from the traffic accident, caused reduced afferent feedback to the brain, resulting in less efficient decision-making. Our findings support the somatic-marker hypothesis (SMH), where somatic feedback to the brain influences the decision-making process.

The Glymphatic System in Humans: Investigations With Magnetic Resonance Imaging.

ABSTRACT: The concept of the glymphatic system was proposed more than a decade ago as a mechanism for interstitial fluid flow and waste removal in the central nervous system. The function of the glymphatic system has been shown to be particularly activated during sleep. Dysfunction of the glymphatic system has been implicated in several neurodegenerative diseases. Noninvasive in vivo imaging of the glymphatic system is expected to be useful in elucidating the pathophysiology of these diseases. Currently, magnetic resonance imaging is the most commonly used technique to evaluate the glymphatic system in humans, and a large number of studies have been reported. This review provides a comprehensive overview of investigations of the human glymphatic system function using magnetic resonance imaging. The studies can be divided into 3 categories, including imaging without gadolinium-based contrast agents (GBCAs), imaging with intrathecal administration of GBCAs, and imaging with intravenous administration of GBCAs. The purpose of these studies has been to examine not only the interstitial fluid movement in the brain parenchyma, but also the fluid dynamics in the perivascular and subarachnoid spaces, as well as the parasagittal dura and meningeal lymphatics. Recent research has even extended to include the glymphatic system of the eye and the inner ear. This review serves as an important update and a useful guide for future research directions.

Association between the Putative Meningeal Lymphatics at the Posterior Wall of the Sigmoid Sinus and Delayed Contrast-agent Elimination from the Cerebrospinal Fluid.

PURPOSE: To investigate the characteristics of the putative meningeal lymphatics located at the posterior wall of the sigmoid sinus (PML-PSS) in human subjects imaged before and after intravenous administration (IV) of a gadolinium-based contrast agent (GBCA). The appearance of the PML-PSS and the enhancement of the perivascular space of the basal ganglia (PVS-BG) were analyzed for an association with gender, age, and clearance of the GBCA from the cerebrospinal fluid (CSF). METHODS: Forty-two patients with suspected endolymphatic hydrops were included. Heavily T2-weighted 3D-fluid attenuated inversion recovery (hT2w-3D-FLAIR) and 3D-real inversion recovery (IR) images were obtained at pre-administration, immediately post-administration, and at 4 and 24 hours after IV-GBCA. The appearance of the PML-PSS and the presence of enhancement in the PVS-BG were analyzed for a relationship with age, gender, contrast enhancement of the CSF at 4 hours after IV-GBCA, and the washout ratio of the GBCA in the CSF from 4 to 24 hours after IV-GBCA. RESULTS: The PML-PSS and PVS-BG were seen in 23 of 42 and 21 of 42 cases, respectively, at 4 hours after IV-GBCA. In all PML-PSS positive cases, hT2w-3D-FLAIR signal enhancement was highest at 4 hours after IV-GBCA. A multivariate analysis between gender, age, CSF signal elevation at 4 hours, and washout ratio indicated that only the washout ratio was independently associated with the enhancement of the PML-PSS or PVS-BG. The odds ratios (95% CIs; P value) were 4.09 × 10-5 (2.39 × 10-8 - 0.07; 0.0078) for the PML-PSS and 1.7 × 10-4 (1.66 × 10-7 - 0.174; 0.014) for the PVS-BG. CONCLUSION: The PML-PSS had the highest signal enhancement at 4 hours after IV-GBCA. When the PML-PSS was seen, there was also often enhancement of the PVS-BG at 4 hours after IV-GBCA. Both observed enhancements were associated with delayed GBCA excretion from the CSF.

Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS): Revisiting the Meaning and Significance of the Method.

More than 5 years have passed since the Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS) method was proposed with the intention of evaluating the glymphatic system. This method is handy due to its noninvasiveness, provision of a simple index in a straightforward formula, and the possibility of retrospective analysis. Therefore, the ALPS method was adopted to evaluate the glymphatic system for many disorders in many studies. The purpose of this review is to look back and discuss the ALPS method at this moment.The ALPS-index was found to be an indicator of a number of conditions related to the glymphatic system. Thus, although this was expected in the original report, the results of the ALPS method are often interpreted as uniquely corresponding to the function of the glymphatic system. However, a number of subsequent studies have pointed out the problems on the data interpretation. As they rightly point out, a higher ALPS-index indicates predominant Brownian motion of water molecules in the radial direction at the lateral ventricular body level, no more and no less. Fortunately, the term "ALPS-index" has become common and is now known as a common term by many researchers. Therefore, the ALPS-index should simply be expressed as high or low, and whether it reflects a glymphatic system is better to be discussed carefully. In other words, when a decreased ALPS-index is observed, it should be expressed as "decreased ALPS-index" and not directly as "glymphatic dysfunction". Recently, various methods have been proposed to evaluate the glymphatic system. It has become clear that these methods also do not seem to reflect the entirety of the extremely complex glymphatic system. This means that it would be desirable to use various methods in combination to evaluate the glymphatic system in a comprehensive manner.