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.

Imaging evaluation and volumetric measurement of the space surrounding the diploic veins.

PURPOSE: The diploic veins have been suggested to be involved in the excretion of cerebrospinal fluid and intracranial waste products; however, to date, there have been no reports evaluating the space surrounding the diploic veins. Therefore, we aimed to visualize the distribution of gadolinium-based contrast agent (GBCA) in the space surrounding the diploic veins and to evaluate the spatial characteristics. MATERIALS AND METHODS: Ninety-eight participants (aged 14-84 years) were scanned 4 h after intravenous GBCA injection at Nagoya University Hospital between April 2021 and December 2022. The volume of the space surrounding the diploic veins where the GBCA was distributed was measured using contrast-enhanced T1-weighted images with the application of three-axis motion-sensitized driven equilibrium. The parasagittal dura (PSD) volume adjacent to the superior sagittal sinus was also measured using the same images. Both volumes were corrected for intracranial volume. The correlation between age and the corrected volume was examined using Spearman's rank correlation coefficient; the relationship between the corrected volume and sex was assessed using the Mann-Whitney U test. RESULTS: A significant weak negative correlation was observed between the volume of the space surrounding the diploic veins and age (r = -0.330, p < 0.001). Furthermore, there was a significant weak positive correlation between the PSD volume and age (r = 0.385, p < 0.001). Both volumes were significantly greater in men than in women. There was no correlation between the volume of the space surrounding the diploic veins and the volume of the PSD. CONCLUSION: The volume of the space surrounding the diploic veins was measurable and, in contrast to the volume of the PSD, was greater in younger participants. This space may be related to intracranial excretory mechanisms and immune responses during youth, requiring further research.

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.

Interstitial Fluidopathy of the Central Nervous System: An Umbrella Term for Disorders with Impaired Neurofluid Dynamics.

Interest in interstitial fluid dynamics has increased since the proposal of the glymphatic system hypothesis. Abnormal dynamics of the interstitial fluid have been pointed out to be an important factor in various pathological statuses. In this article, we propose the concept of central nervous system interstitial fluidopathy as a disease or condition in which abnormal interstitial fluid dynamics is one of the important factors for the development of a pathological condition. We discuss the aspects of interstitial fluidopathy in various diseases, including Alzheimer's disease, Parkinson's disease, normal pressure hydrocephalus, and cerebral small vessel disease. We also discuss a method called "diffusion tensor image analysis along the perivascular space" using MR diffusion images, which is used to evaluate the degree of interstitial fluidopathy or the activity of the glymphatic system.

Diffusion-weighted image analysis along the perivascular space (DWI-ALPS) for evaluating interstitial fluid status: age dependence in normal subjects.

PURPOSE: The purpose of this study was to evaluate the interstitial fluid status in a wide range of age groups using diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, which is a simplified variation of diffusion tensor image analysis along the perivascular space (DTI-ALPS). MATERIALS AND METHODS: This retrospective study included data from 128 patients who underwent clinical magnetic resonance imaging (MRI) studies, including DWI, and were found to have no abnormal findings in the brain on MRI. Three motion-probing gradients of the DWI were applied in an orthogonal direction to the imaging plane. Apparent diffusion coefficient images in the x-, y-, and z-axes were retrospectively generated, and composite color images were created to locate the projection and association fiber area on the slice including the body of the lateral ventricle. ALPS indices were calculated, and correlations with age were evaluated using linear and second-degree regression analysis. Linear regression analysis was also performed for a subgroup of patients older than 40 years. In addition, an analysis of variance (ANOVA) test among the generations was performed. RESULTS: The linear regression analysis between age and the ALPS index showed a correlation coefficient of -0.20 for all age group and -0.51 for the subgroup older than 40 years. The second-degree regression analysis showed a correlation coefficient of 0.39. ANOVA showed that the 40's generation showed a statistically significant higher value of ALPS index compared to all other generations except for the 30's generation. While, the 70's generation showed a statistically significant lower value of the ALPS index compared to all other generations. CONCLUSIONS: The analysis of the DWI-APLS method showed a correlation between age and the ALPS index in second-degree distribution which peaked in the 40's generation. This finding in normal subjects may be fundamental in the analysis of disease cases. We tried to evaluate the glymphatic system status in a wide range of age groups using diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, and the results showed a correlation between age and the ALPS index in second-degree distribution which peaked in the 40's generation.

Reproducibility of diffusion tensor image analysis along the perivascular space (DTI-ALPS) for evaluating interstitial fluid diffusivity and glymphatic function: CHanges in Alps index on Multiple conditiON acquIsition eXperiment (CHAMONIX) study.

PURPOSE: The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method was developed to evaluate the brain's glymphatic function or interstitial fluid dynamics. This study aimed to evaluate the reproducibility of the DTI-ALPS method and the effect of modifications in the imaging method and data evaluation. MATERIALS AND METHODS: Seven healthy volunteers were enrolled in this study. Image acquisition was performed for this test-retest study using a fixed imaging sequence and modified imaging methods which included the placement of region of interest (ROI), imaging plane, head position, averaging, number of motion-proving gradients, echo time (TE), and a different scanner. The ALPS-index values were evaluated for the change of conditions listed above. RESULTS: This test-retest study by a fixed imaging sequence showed very high reproducibility (intraclass coefficient = 0.828) for the ALPS-index value. The bilateral ROI placement showed higher reproducibility. The number of averaging and the difference of the scanner did not influence the ALPS-index values. However, modification of the imaging plane and head position impaired reproducibility, and the number of motion-proving gradients affected the ALPS-index value. The ALPS-index values from 12-axis DTI and 3-axis diffusion-weighted image (DWI) showed good correlation (r = 0.86). Also, a shorter TE resulted in a larger value of the ALPS-index. CONCLUSION: ALPS index was robust under the fixed imaging method even when different scanners were used. ALPS index was influenced by the imaging plane, the number of motion-proving gradient axes, and TE in the imaging sequence. These factors should be uniformed in the planning ALPS method studies. The possibility to develop a 3-axis DWI-ALPS method using three axes of the motion-proving gradient was also suggested.

Magnetic resonance cisternography imaging findings related to the leakage of Gadolinium into the subarachnoid space.

PURPOSE: To identify magnetic resonance cisternography (MRC) imaging findings related to Gadolinium-based contrast agent (GBCA) leakage into the subarachnoid space. MATERIALS AND METHODS: The number of voxels of GBCA leakage (V-leak) on 3D-real inversion recovery images was measured in 56 patients scanned 4 h post-intravenous GBCA injection. Bridging veins (BVs) were identified on MRC. The numbers of BVs with surrounding cystic structures (BV-cyst), with arachnoid granulations protruding into the superior sagittal sinus (BV-AG-SSS) and the skull (BV-AG-skull), and including any of these factors (BV-incl) were recorded. Correlations between these variables and V-leak were examined based on the Spearman's rank correlation coefficient. Receiver-operating characteristic (ROC) curves were generated to investigate the predictive performance of GBCA leakage. RESULTS: V-leak and the number of BV-incl were strongly correlated (r = 0.609, p < 0.0001). The numbers of BV-cyst and BV-AG-skull had weaker correlations with V-leak (r = 0.364, p = 0.006; r = 0.311, p = 0.020, respectively). The number of BV-AG-SSS was not correlated with V-leak. The ROC curve for contrast leakage exceeding 1000 voxels and the number of BV-incl had moderate accuracy, with an area under the curve of 0.871. CONCLUSION: The number of BV-incl may be a predictor of GBCA leakage and a biomarker for waste drainage function without using GBCA.

Evaluating the Effect of Arterial Pulsation on Cerebrospinal Fluid Motion in the Sylvian Fissure of Patients with Middle Cerebral Artery Occlusion Using Low b-value Diffusion-weighted Imaging.

PURPOSE: Decrease in signal of the cerebrospinal fluid (CSF) on low b-value diffusion weighted image (DWI) due to non-uniform flow can provide additional information regarding CSF motion. The purpose of the current study was to evaluate whether arterial pulsations constitute the driving force of CSF motion. METHODS: We evaluated the CSF signals within the Sylvian fissure on low b-value DWI in 19 patients with unilateral middle cerebral artery (MCA) occlusion. DWI with b-value of 500 s/mm2 was evaluated for a decrease in CSF signal within the Sylvian fissure including the Sylvian vallecula and lower, middle, and higher Sylvian fissures and graded as follows: the same as contralateral side; smaller signal decrease than that on contralateral side; and no signal decrease. MR angiography (MRA) findings of MCA were graded as follows: the same as contralateral, lower signal than contralateral signal, and no signal. In 15 patients, regional cerebral blood flow (rCBF) was evaluated using single-photon emission computed tomography (SPECT) studies and graded as >90%, 90%-70%, and <70% rCBF compared to contralateral. The correlations between the gradings were evaluated using G likelihood-ratio test. RESULTS: There was no statistically significant correlation between the MRA and low b-value DWI gradings of CSF in all areas. There were statistically significant correlations between the decreases in CBF on SPECT and CSF signals in the middle Sylvian fissure. CONCLUSION: The driving force of CSF pulsation in the Sylvian sinus may be related to the pulsations of the cerebral hemisphere rather than direct arterial pulsations.

Relationship between Time-dependent Signal Changes in Parasagittal Perivenous Cysts and Leakage of Gadolinium-based Contrast Agents into the Subarachnoid Space.

PURPOSE: To investigate the association between signal changes over time in perivenous cystic structures near the superior sagittal sinus and leakage of a gadolinium-based contrast agent (GBCA) into the subarachnoid space in patients with suspected endolymphatic hydrops. METHODS: Fifty-one cystic structures in 27 cases were evaluated. The signal intensity of the cystic structures was measured on 3D real inversion recovery (3D-real IR) images obtained at pre-, and at 10 min, 4 hrs and 24 hrs post-intravenous administration (IV) of GBCA. Signal enhancement of the cystic structures from the pre-contrast images at each time point was compared in subjects with leakage (positive) versus those without leakage (negative) using an ANOVA. Fisher's exact probability test was used to compare the maximum contrast-enhanced time point between positive and negative groups. We used 5% as a threshold to determine statistical significance. RESULTS: In leakage positive subjects, mean signal enhancement of the cysts was significantly greater at 4 and 24 hrs compared to 10 min. However, although there was a trend of an increase from 4 to 24 hrs, the difference was not significant. In the leakage negative group, mean signal enhancement of the cysts was significantly higher at 4 hrs compared to 10 min and 24 hrs. There was no significant difference between 10 min and 24 hrs. In the positive group, the maximum signal increase was found in 10/38 and 28/38 cysts at 4 and 24 hrs after IV-GBCA, respectively. In the leakage negative group, the maximum signal increase was found in 10/13 and 3/13 cysts at 4 and 24 hrs, respectively (P = 0.0019). CONCLUSION: There was an association between signal changes over time after IV-GBCA in perivenous cystic structures and leakage of GBCA. Further research to clarify the impact of cystic structures on the function of the waste clearance system of the brain is warranted.

Diffusion analysis of fluid dynamics with incremental strength of motion proving gradient (DANDYISM) to evaluate cerebrospinal fluid dynamics.

PURPOSE: To visualize and analyze the dynamics of cerebrospinal fluid (CSF) motion in the cranium, we evaluated the distribution of motion-related signal dephasing by CSF on Diffusion ANalysis of fluid DYnamics with Incremental Strength of Motion proving gradient (DANDYISM) method, a composite imaging method using various low b values. MATERIALS AND METHODS: This study examined ten subjects aged 25-58. We acquired DWIs on a 3T clinical scanner with b values 0, 50, 100, 200, 300, 500, 700, and 1000 s/mm2 in total imaging time of 4 min. We constructed DANDYISM images and evaluated the CSF area distribution with decreased motion-dephasing signal using a scoring method. RESULTS: The DANDYISM images showed statistically significant higher CSF scores in the ventral posterior fossa, suprasellar cistern, and Sylvian vallecula compared to the lateral ventricle and frontal and parietal CSF spaces, indicating greater CSF movement in the former areas. CONCLUSION: The results indicated prominent CSF motions in the ventral portion of the posterior fossa, suprasellar cistern, and Sylvian fissure but smaller motions in the lateral ventricles and parietal subarachnoid space. This method may provide information of CSF dynamics in the clinical settings within short imaging time.

MR Imaging of Endolymphatic Hydrops: Utility of iHYDROPS-Mi2 Combined with Deep Learning Reconstruction Denoising.

PURPOSE: MRI of endolymphatic hydrops (EH) 4 h after intravenous administration of a single dose of gadolinium-based contrast agent is used for clinical examination in some institutions; however, further improvement in image quality would be valuable for wider clinical utility. Denoising using deep learning reconstruction (Advanced Intelligent Clear-IQ Engine [AiCE]) has been reported for CT and MR. The purpose of this study was to compare the contrast-to-noise ratio of endolymph to perilymph (CNREP) between the improved hybrid of reversed image of the positive endolymph signal and the native image of the perilymph signal multiplied with the heavily T2-weighted MR cisternography (iHYDROPS-Mi2) images, which used AiCE for the three source images (i.e. positive endolymph image [PEI], positive perilymph image [PPI], MR cisternography [MRC]) to those that did not use AiCE. We also examined if there was a difference between iHYDROPS-Mi2 images with and without AiCE for degree of visual grading of EH and in endolymphatic area [EL] ratios. METHODS: Nine patients with suspicion of EH were imaged on a 3T MR scanner. iHYDROPS images were generated by subtraction of PEI images from PPI images. iHYDROPS-Mi2 images were then generated by multiplying MRC with iHYDROPS images. The CNREP and EL ratio were measured on the iHYDROPS-Mi2 images. Degree of radiologist visual grading for EH was evaluated. RESULTS: Mean CNREP ± standard deviation was 1681.8 ± 845.2 without AiCE and 7738.6 ± 5149.2 with AiCE (P = 0.00002). There was no significant difference in EL ratio for images with and without AiCE. Radiologist grading for EH agreed completely between the 2 image types in both the cochlea and vestibule. CONCLUSION: The CNREP of iHYDROPS-Mi2 images with AiCE had more than a fourfold increase compared with that without AiCE. Use of AiCE did not adversely affect radiologist grading of EH.

Relationship between Parasagittal Perivenous Cysts and Leakage of Gadolinium-based Contrast Agents into the Subarachnoid Space around the Cortical Veins after Intravenous Administration.

PURPOSE: The purpose of this retrospective study was to investigate the relationship between the number and size of cystic structures around the cortical veins near the superior sagittal sinus and the leakage of gadolinium-based contrast agent (GBCA) around the cortical veins. METHODS: Of 190 patients (91 male and 99 female), that were scanned at 4 h after an intravenous injection of GBCA as a diagnostic examination for endolymphatic hydrops, 6 patients with GBCA leakage were younger than the previously proposed threshold age of 37.3 years for leakage. Six age-matched patients without leakage were also included for reference. In addition, we included 8 cases without leakage that were older than the hypothesized threshold of 37.3 years, as well as 8 age-matched patients with GBCA leakage into the cerebrospinal fluid space. The number of cysts was counted and the sizes were measured in these 28 patients (age: 32-60 years old, 13 men and 15 women). RESULTS: The mean number of cysts surrounding the cortical veins in the parasagittal region was 4.29 ± 1.77 vs. 1.79 ± 1.05 (P = 0.0001) in the subjects with and without GBCA leakage, respectively. The mean size of the largest cysts was at 8.89 ± 3.49 mm vs. 5.69 ± 2.29 (P = 0.009) in the subjects with and without GBCA leakage, respectively. CONCLUSION: The number and size of the perivenous cystic structures near the superior sagittal sinus is greater in subjects with GBCA leakage into the subarachnoid space compared with those without leakage. Future research regarding the histological and functional details of these parasagittal cystic structures is needed.

A case of undifferentiated carcinoma of the pancreas mimicking main-duct intraductal papillary mucinous neoplasm (IPMN).

We report here a rare case of undifferentiated carcinoma of the pancreas mimicking main-duct intraductal papillary mucinous neoplasm. In an 80-year-old woman, an approximately 8-mm papillary mass was incidentally detected at the downstream edge of a dilatated main pancreatic duct lumen on CT and MRI. Main pancreatic duct dilatation in the pancreatic body and tail and parenchymal atrophy were observed in the upstream of the mass. Histopathologically, the tumor protruded into the downstream edge of the dilatated main pancreatic duct lumen in the pancreatic body. The tumor cells had highly atypical nuclei and abundant polymorphic structures, and showed positive staining for granulocyte colony-stimulating factor, which led to the diagnosis of undifferentiated carcinoma. A total of 13 cases of undifferentiated carcinoma with intraductal tumor growth have been reported to date. The case report by Bergmann et al. has been the smallest in histopathological specimen, and the present case is the smallest in size detected by radiological images. Since early undifferentiated carcinoma of the pancreas can resemble those of main-duct intraductal papillary mucinous neoplasm in cross-sectional images, we have to consider undifferentiated carcinoma in the differential diagnosis of the solitary and papillary mass with low contrast enhancement in early phase in the main pancreatic duct.

Establishing normal diameter range of the cochlear and facial nerves with 3D-CISS at 3T.

PURPOSE: We explored normal diameter values of the cochlear (CN) and facial (FN) nerves on 3-dimensional constructive interference in steady state (3D-CISS) using a 3-tesla magnetic resonance (MR) imaging scanner. METHODS: A total of 142 patients underwent MR imaging of the inner ear at 3T. We retrospectively analyzed data from 172 ears. All ears had normal hearing and no history of ipsilateral facial palsy. Parasagittal images of 0.5-mm thickness perpendicular to the internal auditory canal were reconstructed from 0.4-mm thick axial 3D-CISS images for all ears. Two independent radiologists measured the long diameter (LD), short diameter (SD), and cross-sectional area (CSA) of each CN and FN. For each measurement, we calculated the mean value from the 2 observers and evaluated interobserver agreement. We also evaluated the correlation between nerve diameter and sex and age. RESULTS: Both observers could perform measurements in 157 CN from 172 ears (91%) and 165 FN from 172 ears (96%). For the CN, the mean LD was 1.35±0.16 mm, the mean SD was 0.99±0.18 mm, and the mean CSA was 1.07±0.30 mm2; for the FN, the mean values were 1.18±0.17 mm (LD), 0.87±0.16 mm (SD), and 0.83±0.27 mm2 (CSA). Interobserver reliability was good for each measurement (r=0.569 to 0.691, P<0.01). The diameters of the 2 nerves tended to be larger in men, but only the CSA of the FN was significantly larger in men (P<0.05). Age did not affect nerve diameter. CONCLUSION: We present normal values of CN and FN diameters on 3D-CISS at 3T. Our results warrant further study to clarify the pathophysiological state of the CN or FN using 3D-CISS.

Semi-quantification of endolymphatic size on MR imaging after intravenous injection of single-dose gadodiamide: comparison between two types of processing strategies.

PURPOSE: Many inner ear disorders, including Ménière's disease, are believed to be based on endolymphatic hydrops. We evaluated a newly proposed method for semi-quantification of endolymphatic size in patients with suspected endolymphatic hydrops that uses 2 kinds of processed magnetic resonance (MR) images. METHODS: Twenty-four consecutive patients underwent heavily T2-weighted (hT2W) MR cisternography (MRC), hT2W 3-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) with inversion time of 2250 ms (positive perilymph image, PPI), and hT2W-3D-IR with inversion time of 2050 ms (positive endolymph image, PEI) 4 hours after intravenous administration of single-dose gadolinium-based contrast material (IV-SD-GBCM). Two images were generated using 2 new methods to process PPI, PEI, and MRC. Three radiologists contoured the cochlea and vestibule on MRC, copied regions of interest (ROIs) onto the 2 kinds of generated images, and semi-quantitatively measured the size of the endolymph for the cochlea and vestibule by setting a threshold pixel value. RESULTS: Each observer noted a strong linear correlation between endolymphatic size of both the cochlea and vestibule of the 2 kinds of generated images. The Pearson correlation coefficients (r) were 0.783, 0.734, and 0.800 in the cochlea and 0.924, 0.930, and 0.933 in the vestibule (P<0.001, for all). In both the cochlea and vestibule, repeated-measures analysis of variance showed no statistically significant difference between observers. CONCLUSION: Use of the 2 kinds of generated images generated from MR images obtained 4 hours after IV-SD-GBCM might enable semi-quantification of endolymphatic size with little observer dependency.