Emerging evidence supportive of a human glymphatic system and its underlying role in cerebral waste clearance has prompted a reevaluation of neuro-fluid circulation and relevance. It has recently been suggested that fluid clearance may occur along lymphatic channels, which co-localize with the anatomic region surrounding the superior sagittal sinus [7] and compelling evidence supports the presence of trans-arachnoid molecular passage in this region [23]. Our understanding of the anatomical and functional relevance of this region remains incomplete, partly due to a lack of robust methods for evaluating this space on neuroimaging, as well as how this space changes with age, sex, and standard measures of bulk CSF flow. Here, we provide evidence that the PSD volume increases with age, and also directly relates to CSF flux through the cerebral aqueduct.
As such, these findings suggest that the PSD is an important component of the distal end of the glymphatic system whereby fluid egresses from the intracranial compartment. We observed a significant enlargement of PSD space in relation to normal aging (p-value < 0.001, \(\rho\)=0.6), CSF volume (p-value < 0.001, \(\rho\)=0.6) and CSF flux in the cerebral aqueduct (retrograde and anteretrograde, p-values < 0.001, \(\rho\)=0.32 and -50, respectively).
These findings should also be considered in the context of the growing literature on PSD anatomy. The initial work demonstrating trans-arachnoid molecular passage in the PSD region was conducted by introducing gadolinium contrast into the subarachnoid space via lumbar puncture [23], with subsequent T1 weighted imaging detailing contrast progression to the PSD. A subsequent study assessed the “peri-sinus lymphatic space volume” retrospectively assessing T1 post contrast imaging in patients suspected of having brain metastasis [24]. In this study we use submillimeter 3D T2-weighted imaging of the brain to assess similar volumes. The technique we used allows for clear distinction of the PSD from both the adjacent subarachnoid space as well as the superior sagittal sinus and feeding cortical veins (see Figures 4-5). Our delineation of this PSD volume very closely matches the 2D appearance and the 3D volumetric maps as detailed by Ringstad et al [23]. Importantly, this method obviates the need for contrast enhanced imaging to determine the PSD volume. Accordingly, this method can likely be applied to numerous noncontract imaging datasets of various patient cohorts in the public domain. We anticipate that the non-contrast nature of our method will accelerate future study of the PSD, which will in turn further define the relevance of this region in the context of glymphatic flow and CNS CSF clearance.
Our results also confirm the previous findings by Park et al that demonstrated increasing PSD volumes with age (Figure 6). Our study expands upon this work to demonstrate that these increased PSD volumes are associated with increased CSF volume, though is not related to brain parenchymal volume. This observation is significant, as it implies that increased PSD cannot be explained simply by brain volume loss and therefore my provide insight into the pathophysiology of other neurodegenerative processes. Our study benefits from a wider cohort age range compared to this previous work (mean age = 62.1, \(\sigma\) = 10.9 years, compared to our cohort with mean age = 50.4, \(\sigma\)= 18 years). We believe that the current cohort which ranged in age from 20 to 83 years enables us to detect evolution of PSD in a more comprehensive manner over the approximate adult human lifespan.
Cerebral aqueductal flux and parasagittal dural space volume
PSD volumes were significantly correlated to maximum anteretrograde and retrograde CSF flux in the cerebral aqueduct. The cerebral aqueduct and PSD are at the proximal and distal ends of the glymphatic circuit respectively. This correlation presents further evidence of an organized system of CSF circulation and metabolism and suggests of complex physiologic interplay between various anatomic structures. Further study is needed across the human lifespan and in various disease cohorts to determine the sequence of dysfunction across the various regions of the glymphatic circuit. Investigations which characterize these findings across differing neurodegenerative disease cohorts may sheds light on how aberrant CSF flow contributes to various neurodegenerative conditions.
Finally, we also assessed for a relationship between CSF flux in the cerebral aqueduct with white and gray matter volumes, CSF volume, gender, and age. Our experiments indicate that CSF volumes show significant correlation with maximum retrograde CSF flux in the cerebral aqueduct. This again supports that these findings cannot be fully explained by brain volume loss.
In one prior study investigating the relationship of different CSF dynamics at the level of the cerebral aqueduct, CSF movement was shown to be dependent on age and gender [14]. Only part of these readouts can be confirmed by our experiments, even though we see correlation with age, sex difference was inconclusive in our analysis. However, it is noteworthy that maximum anteretrograde and retrograde CSF flux have not been directly investigated in this previous study, this could explain why we did not observe gender dependencies with CSF flux in our data.
The study findings should also be considered in light of several limitations. First, we evaluated the PSD volume across the life-span cross-sectionally as is common in neuroimaging studies, rather than longitudinally. Second, while the largest cohort of PSD volume data presented to date, the sample size of 62 was moderate and presented multiple co-variates from being included in analysis. However, we characterized the health of each participant both radiologically and neurologically as described in the inclusion criteria, and all participants met rigorous healthy volunteer criteria. Given the moderate sample size, we also focused hypotheses on those that could be tested responsibly with the sample size.