Characterization of MR Imaging–Visible Perivascular Spaces in the White Matter of Healthy Adolescents at 3T

DISCUSSION

In this study, we quantify the number and morphology of white matter PVSs in a cohort of healthy adolescents under rigorous study-entry criteria. Using 3T MR imaging scans and objective quantitative methods, we demonstrate that PVSs are seen in this population in a much larger proportion of subjects than previously described in the literature.^5,6 We provide normative PVS morphologic characteristics, including total number, volume, and individual length, width, and diameter of PVSs in this age group and the distribution of lobar locations of PVS burden. We show that male adolescents have a higher total number and volume of PVSs per unit of white matter than females. We show that in adolescents, individual PVS morphology (length, width, and diameter) is not associated with age, sex, or increasing white matter volume. Finally, we report the incidence rate of asymmetric burden. These findings support the notion that PVSs are seen in MRIs of healthy individuals.

In adults, the presence of PVSs has been mainly linked to the aging process⁹ and to vascular and Alzheimer dementias.^19,20 Two studies in youth concluded that in this population, PVSs were either absent or a rare finding, present in <5% of subjects.^5,6 These early studies, although considered the first attempts at quantifying PVS in children, have limitations. Counts were performed on MRIs obtained using a 1.5T field strength, introducing a floor effect for small structures with limited contrast to surrounding tissue due to partial volume effects. Early studies used subjective visual ratings, which are subject to interrater variability and differences in interpretation and do not provide morphologic details about each individual PVS. Although children were labeled as “healthy,” MRIs were performed in subjects with entities such as benign epilepsy, headaches, or behavioral problems, which limit their generalizability.⁵ Early studies did not adjust for other important covariates such as sex or total cerebral white matter. The results presented here expand this previous work by filling existing gaps in the limited literature addressing this phenomenon. NCANDA participants met rigorous study entry criteria that provided us with important baseline clinical and demographic information on each subject. NCANDA participants underwent 3T MR imaging, which provided adequate visualization of PVSs. By incorporating objective PVS quantification, we minimized visual rater irregularities. We were also able to provide details about the morphology of each PVS, including important characteristics such as width, length, and volume.

In this cohort, males had a higher number of morphologically similar PVSs than females. Most important, age and pubertal stage were not significantly associated with PVS number or total volume. Furthermore, there was no interaction between age and sex on PVS burden. A higher prevalence of “large” (>2 mm in diameter) PVSs in males than in females has been reported in subjects aged 0–99 years using a visual rating scale.⁹ The authors, however, did not provide an analysis of sex differences across age groups. A separate study using a volumetric approach in an adult population also identified higher burden volumes in males over females in control subjects.¹ The timing and etiology of sex differences are yet to be elucidated. However, the fact that sex differences are already present in early-pubertal individuals argues in favor of a much earlier etiology than previously established. These differences may be present at birth or develop during childhood.

In agreement with previous work, PVS burden in this cohort was highest in the frontal and parietal lobes.^5,6 However, PVSs were also found in the temporal and, more rarely, the occipital lobes. The appearance of PVSs in the temporal and occipital lobes could be, in part, attributed to the better resolution of the 3T scans and the objective measurements used in our study, resulting in a higher sensitivity for PVS detection. In our cohort, PVS burden was bilaterally symmetric, and a high burden in 1 hemisphere, regardless of the measure used for burden or of the lobar location, is indicative of a high burden in the contralateral side. It is certain that the high likelihood of burden symmetry across hemispheres is a reflection of the symmetry of cerebral vasculature. However, the high interindividual variability in overall MR imaging–visible PVSs (approximately an 8-fold difference) remains unexplained. In our cohort, pubertal status and age were not associated with PVS burden. It is possible that other variables not included in this analysis may affect PVS burden. For example, sleep efficiency has been shown to affect PVS burden in adults, and it may play a role in PVS burden variability in adolescents.²¹ Last, the incidence rate of a significantly asymmetric burden in healthy adolescents should be considered 1%–3%, according to these data. This suggests that an asymmetric burden, defined as approximately >225% of PVS count or volume between hemispheres, is a rare occurrence, though the clinical significance of such a finding remains unclear.

Finally, we observed a difference in burden per unit WM between lobes. It is unlikely that WM is perfused by nearly twice as many vessels in the temporal and parietal lobes than in the frontal and occipital lobes per unit tissue; if the interpretation of a difference in burden between lobes is predicated on an uneven distribution of lobar vasculature, then the most parsimonious explanation is that these spaces are organized about the venous system. Therefore, the finding may arise from either an uneven lobar distribution of venous architecture in WM or because the parietal and temporal lobes are more susceptible to the underlying cause of PVS expansion, or both. Given that the identity, artery or vein, of the vessels in WM around which these spaces are visible remains an open question, this report may serve to inform this debate considerably, and strongly suggests that venous return is the primary system around which these spaces expand in WM. Another possibility is that the temporal and parietal lobes contain some characteristic that makes a member voxel more likely to be a PVS; in either case, the finding provides a clue to the underlying cause of the fact that some of these spaces are large enough to view on a standard clinical MR imaging instrument and some are not.

Previous studies have found no correlation between the number of PVSs and age in young individuals.^5,6 While a strong relationship between MR imaging–visible PVSs and age has been noted in patients older than 60 years,⁹ other studies suggest that the relationship may be regionally dependent²² or dependent on the resolution of the images acquired.²³ Future studies that objectively address the evolution of age- and sex-related differences in PVS burden across the life span, especially ones with longitudinal designs, are needed to further elucidate the potential clinical relevance of these findings.

This study has several limitations. The cross-sectional design of this analysis precludes the possibility of determining individual longitudinal changes in PVS burden. Future investigations, including longitudinal data from this cohort, should be conducted to better understand individual differences in the development of this phenomenon. Second, the present methodology is limited to white matter. Given evidence that PVSs do occur in other regions, including the thalamus, midbrain, cerebellum, insular cortex, extreme capsule, optic tract, and hippocampus, future studies evaluating these regions in an adolescent cohort are certainly warranted.^24,25