In this study, we visualized and measured the distribution of the GBCA into the space surrounding the diploic veins on MSDE T1-weighted images. The volume of the space surrounding the diploic veins was negatively correlated with age and was greatly developed in several younger participants. These findings contrast with the positive correlation found in the present study and previous reports [11,12,13] between age and the volume of the PSD, which is thought to be involved in the excretion of intracranial waste products along with meningeal lymphatics. Recently, skull–meninges connections in the vicinity of the diploic veins have been reported in humans, and at the same time, only the skull, among all the bones in the body, has a characteristic molecular profile associated with migration and inflammation in the bone marrow system [1]. Molecular translocation from the cerebrospinal fluid to the diploe has also been observed, suggesting that the cranial diploe is involved in cerebral immune surveillance [2]. Furthermore, aquaporin 4 is expressed only in the cranial diploe among all the bones in the body [14]. In the diploe, the space surrounding the diploic veins, which we suggest may be involved in cerebral immunity and cerebrospinal fluid/intracranial waste excretion, may change in volume depending on the situation (e.g., increasing in size with increased cerebrospinal fluid excretion). Therefore, we consider that it is important to objectively measure the volume of the space surrounding the diploic veins.

The diploic veins running within the diploe of the skull were discovered in the nineteenth century by the French anatomist and surgeon Guillaume Dupuytren. The diploic veins are continuous with the SSS [3]. The diploic veins function as collateral pathways when the SSS is occluded due to meningioma or other causes [4, 5]. The diploic veins are continuous with the arachnoid protrusion into the skull, suggesting their involvement in cerebrospinal fluid excretion and intracranial waste excretion [6]. In a study on formalin-fixed cadaveric heads, diploic veins were most abundant in the parietal bone [15]. Several reports have evaluated the distribution of diploic veins on imaging, with some reporting them as more common in the occipital region [16] and others finding them to be more common in the frontal and temporal regions [17] or in the frontal and parietal bones [18]. A report that categorized the diploic veins into four pathways revealed the most common pathway to be the pteriofrontparietal pathway, which was found bilaterally in 98% of patients [19]. This is considered to be included in the range of measurements of the space surrounding the diploic veins in the present study. Although the distribution of diploic veins has been reported to be poorly correlated with age, sex, and cranial volume [18], we found a significant weak negative correlation between the volume of the space surrounding the diploic veins and age, with and without correction for intracranial volume. The space surrounding the diploic veins may play a greater role in facilitating the excretion of cerebrospinal fluid and intracranial waste products in younger individuals. In addition, the volume of the space surrounding the diploic veins tended to be significantly greater in men than in women, regardless of whether it was corrected for intracranial volume. This finding suggests that the pathways and efficiency of intracranial waste excretion may differ between men and women.

Recent studies on the mechanism of brain waste removal have reported the presence of a lymphatic system in the brain [20, 21]. Meningeal lymphatics were identified along the SSS and visualized in human participants by contrast-enhanced MRI [22]. However, later studies suggested that this visualized PSD may not be a true meningeal lymphatic vessel but a bridging space that allows for cerebrospinal fluid-mediated molecular exchange between the meningeal lymphatics and brain tissue [23, 24]. It has been suggested that PSD is involved in the excretion of interstitial fluid and waste products as a downstream pathway of the glymphatic system [25, 26], and its possible association with brain immunity has also been reported [11]. Recently, a significant correlation between the PSD volume and β-amyloid accumulation has been reported [27], increasing the importance of accurate volume measurements of the PSD. In terms of imaging of the PSD, contrast-enhanced fluid-attenuated inversion recovery (FLAIR) and T1-weighted images [22], 3D T1-weighted black-blood MRI [11, 12], and simple T2-weighted images [13] have been used. In this study, the volume of the PSD was measured using contrast-enhanced T1-weighted images with three-axis MSDE performed 4 h after intravenous GBCA injection on 3-T MRI. Our findings regarding the correlation between the PSD volume and age and greater PSD volume in men than in women were consistent with those in previous reports [11,12,13]. The PSD showed an inverse correlation with the space surrounding the diploic veins according to age, suggesting that the PSD may have a complementary function to the space surrounding the diploic veins, although no direct negative correlation was observed. In addition, the PSD volume differed significantly between men and women, regardless of whether it was corrected for intracranial volume, suggesting that the distribution of intracranial waste excretion mechanisms or cerebral immune mechanisms may differ between men and women, and further study is warranted.

In this study, various attempts were made to avoid complications and errors and to improve reproducibility when measuring the volume of the space surrounding the diploic veins and the volume of the PSD on MSDE T1-weighted images. We measured only the slices above the superior border of the lateral ventricles, similar to how we previously measured the extent of contrast leakage into the subarachnoid space [28], to make comparisons based on a standardized area where volume measurements were taken. Limiting the area also reduced the measurement effort and consequently reduced the error. When measuring the volume of the space surrounding the diploic veins, only high-signal regions with a diameter of ≥2 mm were measured. When measuring the volume of the PSD, only the high-signal areas within a 1 cm area from the outer edge of the SSS were measured. The threshold-based methods used for these measurements were described previously [12]. Thus, the inter-rater reliability of the volume measurements was sufficient owing to several factors, including the abovementioned attempts.

This study has some limitations. First, selection bias may have existed because all the included participants were patients with suspected endolymphatic hydrops, and none were completely healthy. Second, there is no standardized way to spend 4 h after GBCA injection. The effects of movement, eating, and drinking may be confounding variables that require further investigation. Third, the lack of histologic evidence regarding the space surrounding the diploic veins prohibits definitive determination of its nature, raising the possibility of alternative structures, such as bone marrow. However, given that the high-signal regions exceeding the threshold on the MSDE T1-weighted images were predominantly observed surrounding the diploic vein (Fig. 2), and reticular high-signal regions exceeding the threshold (Fig. 3) were only sporadically detected in certain participants, we consider it unlikely that they represent bone marrow. Fourth, volume measurements were obtained only for the slices above the superior margin of the lateral ventricles, and not all of the cranium could be evaluated. Fifth, the space surrounding the diploic veins, which were <2 mm in diameter or indistinguishable from the reticular high-signal regions exceeding the threshold, was not measured and may be underestimated.

In conclusion, the distribution of the GBCA into the space surrounding the diploic veins was measured on MSDE T1-weighted images, and we demonstrated that this volume was negatively correlated with age. Our findings suggest that the space surrounding the diploic veins is greater at younger ages and may play a role in the excretion of cerebrospinal fluid and waste products and in immune responses during youth.