Distinct brain alterations and neurodegenerative processes in cognitive impairment associated with post-acute sequelae of COVID-19

Dayoung Seo, Yangsean Choi, Eunseon Jeong, Sanghwi Bang, Ji-Sung Lee, In-Hye Jang, Lynkyung Choi, Jin Hee Kim, Wangyoung Shin, Bo-Ra Seo, Shina Kim, Hee-Jae Jung, Ji-Yon Kim, Hyunjin Kim, Young-Min Lim, Ji-Soo Kwon, Euijin Chang, Jacob Lee, Tae-In Kam, Su-Hyung Park, Eun-Jae Lee () and Sung-Han Kim ()
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Dayoung Seo: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Yangsean Choi: University of Ulsan College of Medicine, Department of Radiology, Asan Medical Center
Eunseon Jeong: University of Ulsan College of Medicine, Asan Medical Institute of Convergence Science and Technology
Sanghwi Bang: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Ji-Sung Lee: University of Ulsan College of Medicine, Clinical Research Center, Asan Medical Center
In-Hye Jang: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Lynkyung Choi: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Jin Hee Kim: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Wangyoung Shin: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Bo-Ra Seo: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Shina Kim: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Hee-Jae Jung: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Ji-Yon Kim: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Hyunjin Kim: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Young-Min Lim: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Ji-Soo Kwon: University of Ulsan College of Medicine, Department of Infectious Diseases, Asan Medical Center
Euijin Chang: University of Ulsan College of Medicine, Department of Infectious Diseases, Asan Medical Center
Jacob Lee: Hallym University College of Medicine, Department of Infectious Diseases, Kangnam Sacred Heart Hospital
Tae-In Kam: Korea Advanced Institute of Science and Technology, Department of Brain & Cognitive Sciences
Su-Hyung Park: Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering
Eun-Jae Lee: University of Ulsan College of Medicine, Department of Neurology, Asan Medical Center
Sung-Han Kim: University of Ulsan College of Medicine, Department of Infectious Diseases, Asan Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Although brain alterations have been reported in post-acute sequelae of SARS-CoV-2 (PASC), their prevalence and relationship to neurodegeneration remain unclear. We analyzed blood proteins and brain MRI from individuals approximately one year after mild COVID-19, categorized as Cog-PASC (with cognitive impairment), Other-PASC (without cognitive impairment), or non-PASC controls, across exploration, covariate-matched, and independent validation cohorts. In the exploration cohort, Cog-PASC showed elevated astroglial damage–associated proteins and structural and microstructural alterations across multiple cortical and subcortical regions, including cortical thinning in the cingulate and insular cortices, increased paramagnetic susceptibility in the hippocampus, and enlarged choroid plexus volume. In the age-, sex-, and education–matched cohort, cortical thinning and increased susceptibility in the cingulate remained significant. Blood proteomics revealed broader alterations involving oxidative stress responses and synaptic function in Cog-PASC, linked to neurodegenerative pathways. In the validation cohort, increased neuronal and astroglial damage-associated proteins, cortical thinning in the cingulate and insular cortices, and increased hippocampal susceptibility were demonstrated, along with enlarged choroid plexus, confirming the reproducibility of these neurodegeneration-associated alterations. These findings suggest distinct neurodegenerative processes in Cog-PASC not observed in other-PASC subtypes, even after mild COVID-19 infection.

Date: 2025
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DOI: 10.1038/s41467-025-65597-z

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