Joga Chaganti ^1* Govinda Poudel ² Lucette A. Cysique ³ Gregory J. Dore ⁴ Anthony Kelleher ^4,5 Gael Matthews ⁴ David Darley ³ Anthony Byrne ⁵ David Jakabek ⁵ Xin Zhang ⁶ Marrissa Lewis ^3,5 Nikhil Jha ⁷ Bruce J. Brew ³

• ¹ Thomas Jefferson University, Philadelphia, United States
• ² Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia
• ³ St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
• ⁴ The Kirby Institute, Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia
• ⁵ St Vincent's Prostate Centre, Darlinghurst, New South Wales, Australia
• ⁶ Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
• ⁷ The Canberra Hospital, Canberra, Australian Capital Territory, Australia

To investigate the association between blood-brain barrier permeability, brain metabolites, microstructural integrity of the white matter and cognitive impairment (CI) in post-acute sequelae of SARS-COV-2 infection (PASC).In this multimodal longitudinal MRI study 14 PASC participants with CI and 10 healthy controls were enrolled. All completed investigations at 3 months following acute infection (3 months +/-2 weeks SD), and 10 PASC participants completed at 12 months+/-2.22 SD weeks. The assessments included a standard neurological assessment, a cognitive screen using the brief CogState battery and multimodal MRI derived metrics from Dynamic contrast enhanced (DCE) perfusion Imaging, Diffusion Tensor Imaging (DTI), and single voxel proton Magnetic Resonance Spectroscopy. These measures were compared between patients and controls and correlated with cognitive scores.At baseline, and relative to controls, PASC participants had higher K-Trans and Myo-inositol, and lower levels of Glutamate/Glutamine in the frontal white matter (FWM) (p<0.01) as well as in brain stem (p<0.05), and higher FA and lower MD in the FWM (p<0.05). In PASC participants, FA and MD decreased in the FWM at 12 months compared to baseline (p<0.05). K-Trans and metabolite concentrations did not change significantly over time. Neurocognitive scores inversely correlated with both K trans (FWM -p<0.03; brain stem p<0.03) and Glx (p=0.04).PASC with CI is associated with BBB impairment, loss of WM integrity, and inflammation at 3 months which significantly but not uniformly improved at 12 months. The loss of WM integrity is possibly mediated by BBB impairment and associated glutamatergic excitoxicity.1: Pathogenesis of post-acute SARS CoV-2 infection associated neurocognitive impairment -PASC CI is unclear.2: We believe that is the first longitudinal study to show that there is blood brain barrier disruption associated with glutamatergic excitotoxicity that is likely responsible for the neurocognitive impairment.3. Our findings support further studies of these MRI techniques as potential biomarkers for PASC CI to facilitate diagnosis, appropriate timing of potential therapy and its monitoring.