Extreme perivascular space burden in healthy youth as normative variation

<title>Abstract</title> <p>Purpose Perivascular spaces (PVS) are increasingly quantified as neuroimaging biomarkers related to glymphatic dysfunction. However, their normative distribution in healthy youth, especially in the upper tail, remains unclear. We aimed (1) to characterize the distribution of total PVS burden and define its upper-tail in neurologically healthy youth, and (2) examine whether upper-tail PVS extremes are associated with structural, behavioral, or cognitive deviations. Materials &amp; Methods T1- and T2-weighted MRI from 80 neurologically healthy participants were processed with an automated enhanced-PVS-contrast pipeline to derive total PVS volume (mm³). Upper-tail individuals were defined using percentile thresholds (P75/P85/P95). Regression models compared high-PVS with non-high-PVS participants on global structural measures and behavioral outcomes. The most extreme cases were visually reviewed on source images for segmentation artifacts or radiological abnormalities. Results PVS burden was strongly right-skewed, with a small subset exhibiting very high values. Across P75/P85/P95 thresholds, upper-tail individuals showed no consistent differences in whole-brain cerebrospinal fluid or ventricular volumes, or behavioral measures. Visual review found no obvious abnormalities or major segmentation artifacts in the most extreme cases. Continuous PVS burden showed no clear association with behavioral outcomes. Conclusion Extremely large PVS volumes can occur as part of the normative distribution in healthy youth and do not necessarily imply concurrent abnormalities in global structural volumes or behavioral performance. These results argue against automatically excluding individuals with upper-tail PVS burden as “invalid outliers” in youth cohorts and highlight the value of combining normative benchmarking with targeted quality control and robustness checks.</p>