Factors associated with severe neurological sequelae of COVID-19: Findings from the multicenter COVID-BRAIN imaging cohort

Ana Isabel Silva^1*Keenan Christopher Byrne²Lauren Pollak³Katherine Gundry¹Georgios E Manousakis⁴Abby I. Metzler⁴Christophe Lenglet¹Lynn E Eberly⁵June Kendall-Thomas⁶Orhun H. Kantarci⁶Burcu Zeydan⁶Shibani S. Mukerji⁷Sevil Yasar⁸Tetsuo Ashizawa⁹Kejal Kantarci⁶Eva-Maria Ratai²Gulin Oz¹

• ¹Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, United States
• ²Massachusetts General Hospital Athinoula A Martinos Center for Biomedical Imaging, Charlestown, United States
• ³Psychology Assessment Center, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, Boston, United States
• ⁴Department of Neurology, University of Minnesota, Minneapolis, United States
• ⁵University of Minnesota Twin Cities School of Public Health, Minneapolis, United States
• ⁶Mayo Clinic Minnesota, Rochester, United States
• ⁷Massachusetts General Hospital Department of Neurology, Boston, United States
• ⁸Johns Hopkins University, Baltimore, United States
• ⁹Houston Methodist, Houston, United States

Introduction: Neurological post-acute sequelae of COVID-19 (neuroPASC) are associated with persistent cognitive dysfunction and quality-of-life decline. We aimed to identify clinical, behavioral and sociodemographic factors associated with neuroPASC symptom burden two years after COVID-19 among individuals without prior neurological disease. Methods: In this prospective, observational study, individuals with neuroPASC (n=102) and controls without symptomatic COVID-19 (n=74), all without prior neurological, psychiatric, or post-viral conditions, were enrolled between February 2022 and June 2024 across five academic sites. An unsupervised algorithm identified clusters with differing self-reported neurological symptom burden within the neuroPASC group. Functional differences between clusters were evaluated using quality-of-life, neurological and cognitive evaluations. Demographics, behavioral history, comorbidities, and blood biomarkers were compared across clusters and controls. Multivariable logistic regression assessed predictors of neuroPASC severity, including demographics, body-mass-index, Charlson Comorbidity Index, Framingham Risk Score, pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions, COVID-19 vaccination prior to infection, hospitalization during acute infection, and cumulative alcohol use. Results: Two clusters emerged based on neurological symptom burden, labeled “high-burden” and “low-burden” neuroPASC, reflecting differences in the number and frequency of symptoms. Both clusters had deficits in quality-of-life and cognitive function compared to controls, with greater impairment in high-burden than low-burden neuroPASC. The clusters did not differ by sex, education, tobacco and cannabis use, blood pressure, body-mass-index, HbA1C, days since infection, hospitalization during COVID-19, pre-COVID vaccination rate, antibody-positivity, inflammation, and neurodegeneration biomarkers. The high-burden cluster was older and exhibited higher comorbidity burden and greater cumulative alcohol use compared with the low-burden cluster and controls. Pre-existing endocrine/metabolic and gastrointestinal/hepatobiliary conditions were more common in high-burden (63%) than in low-burden neuroPASC (35%). After adjusting for clinical and demographic factors, these pre-existing conditions remained the only independent predictor of severity, conferring a 3.5-fold increase in the odds of high-burden versus low-burden neuroPASC. Discussion: Older age, higher comorbidity burden, greater cumulative alcohol use, and endocrine/metabolic and gastrointestinal conditions, rather than acute COVID-19 severity, were observed in the high-burden neuroPASC cluster. After multivariable adjustment, only pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions remained independently associated with high-burden neuroPASC, conferring a 3.5-fold increase in odds and highlighting the need for targeted post-infection monitoring in at-risk patients.