Distinct Brain Structural Alterations And Neurodegenerative Processes In Cognitive Impairment Among Post-Acute Sequelae Of COVID-19
Dayoung Seo1, Yangsean Choi2, Eunseon Jeong1, Sanghwi Bang3, In-Hye Jang1, Lynkyung Choi3, Jin-Hee Kim3, Wangyong Shin3, Bo-Ra Seo3, Shina Kim3, Hee-Jae Jung3, Ji-Yon Kim3, Hyunjin Kim3, Young-Min Lim3, Eun-Jae Lee3, Sung-Han Kim4
1Asan Medical Institute of Convergence Science and Technology, University of Ulsan, 2Radiology, 3Neurology, 4Infectious Diseases, Asan Medical Center
Objective:
This study aimed to investigate the brain structural alterations and neurodegenerative changes according to the cognitive phenotype of post-acute sequelae of SARS-CoV-2 infection (PASC).
Background:
Brain alterations have been reported in post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. However, it is unclear whether these brain changes represent previous injury or are accompanied by ongoing neurodegenerative processes, and whether such processes are universal across PASC patients, particularly in individuals who experienced mild COVID-19.
Design/Methods:
A total of 169 participants who mostly experienced mild COVID-19 about a year ago  assessed and categorized into three groups: PASC with cognitive impairment (Cog-PASC, n = 28), PASC without cognitive impairment (Other-PASC, n = 55), and no significant PASC (n = 77). Brain magnetic resonance imaging (MRI) were used to measure cortical thickness, iron deposition, choroid plexus (CP) volume, and glymphatic function (Diffusion Tensor Imaging analysis along the perivascular space, DTI-ALPS index). Blood samples were analyzed with a Single Molecule array for brain damage and neurodegeneration: neuronal (Neurofilament Light chain,  NfL), astroglial (Glial Fibrillary Acidic Protein, GFAP) damage, and Alzheimer’s disease-related degeneration (Amyloid beta 42/40, phosphorylated tau). High-throughput proteomics (Olink) were also conducted to measure 3,072 proteins to identify important biological pathways underlying the brain disease processes. 
Results:
In the Cog-PASC group, we identified elevated levels of neuronal/astroglial damage proteins without significant changes in b-amyloid or phosphorylated tau proteins. Brain imaging further revealed increased paramagnetic susceptibility, indicating iron deposition, particularly in the cingulate and hippocampus. We also demonstrated increased choroid plexus volume in Cog-PASC compared to Other-PASC patients, associated with neuronal/astroglial damage and iron deposition. Blood proteomic analysis showed significantly altered proteins involved in oxidative stress responses and synaptic function in Cog-PASC patients, linked to neurodegenerative pathways.
Conclusions:
These findings suggest unique neurodegenerative processes in Cog-PASC, not prominent in other PASC patients, even after mild COVID-19.
10.1212/WNL.0000000000210648
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