Asymmetrical glymphatic dysfunction in patients with Long Covid associated neurocognitive impairment- Correlation with BBB disruption

Abstract

Background and Purpose The glymphatic system, a waste clearance pathway, has been implicated in several neurological conditions associated with neuroinflammation. COVID-19 associated neurocognitive impairment, part of the post-acute sequelae of SARS-CoV-2 infection (PASC), is strongly associated with neuroinflammation and disrupted blood-brain barrier (BBB). Several studies have implicated a synergistic interaction between the glymphatic system dysfunction and BBB disruption. In this proof-of-concept study, we investigated the relationship of the diffusion along the perivascular spaces DTI (DTI-ALPS) and increased capillary permeability metric- K trans derived from DCE perfusion in patients with PASC. Materials and Methods 14 subjects with PASC who had persisting symptoms of anosmia, ageusia, fatigue, and cognitive impairment (CI) and ten healthy age and sex matched controls were recruited. All PASC subjects underwent routine and advanced MR imaging early at two time points, (3 months +/- 2 weeks) referred as Time Point 1 (TP-1) and 10 repeated the MRI scan 12 months (+/- 2 weeks) after referred as Time Point 2 (TP-2), while the controls had MR imaging done only at TP-1. All had elaborate neurocognitive assessment. In the final analysis we included those who had DTI study at both time points (n-10). MR imaging included DCE perfusion and DTI in addition to anatomical imaging. Statistical analysis Given the small size of the sample and nonnormality of data in the descriptive analyses, nonparametric analyses were used for group comparisons. A two-sample Wilcoxon rank sum test was used to show the differences in DTI-ALPS between the patients and controls in the predefined ROI. Spearman’s correlation coefficient (rho) was used to assess the correlation between K-trans and DTI-ALPS index. Results There was significant reduction in DTI-ALPS index between the patients and controls in the left hemisphere (z=2.04, p < 0.04). However, there was no significant change over time in the index. There was a strong inverse correlation between the central white matter K trans and DTI-ALPS index (rho=0.66, p< 0.03). Conclusion Our study suggests that BBB disruption and disordered glymphatic drainage may contribute to neuroaxonal injury in patients with PASC, and DTI-ALPS index could serve as a powerful non-invasive biomarker.