Pre-Infection Mental Health, but Not Brain Volumetry, Predicts Risk of Post-COVID Condition: A Population-Based Cohort Study in the German National Cohort (NAKO)
- 1Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Abstract
BackgroundPost-COVID Condition (PCC) affected 10-30% of individuals after SARS-CoV-2 infection, and pre-infection predictors of who goes on to develop it are not well established. We compared pre-infection structural brain variation and baseline psychiatric phenotype as candidate predictors of PCC within a common multi-modal framework in the German National Cohort (NAKO). Both are candidate "first hits" under the second-hit hypothesis, which motivates the comparison; this is a prediction study, not a test of that hypothesis.
MethodsIn 8,464 SARS-CoV-2-infected NAKO neuroimaging participants, of whom 2,304 (27.2%) met PCC criteria (weighted post-COVID syndrome (PCS) score > 10.75) and the rest were symptom-free controls, ten pre-infection modalities (T1-weighted volumetric brain MRI across six parcellations, baseline mental health (PHQ-9, GAD-7), demographics, and seven further biomedical and socioeconomic domains) entered a stacked ensemble with 10 x 5 nested cross-validation (primary metric: the area under the precision-recall curve, PR-AUC). Pre-specified analyses assessed transportability to a non-imaging cohort and robustness to the mental-health symptom trajectory and to unmeasured confounding. SARS-CoV-2 infection status and the PCC outcome were ascertained by self-report; no clinically confirmed diagnoses were available.
ResultsBaseline mental health, assessed 3-8 years before infection, was the strongest predictor (38.0% of feature importance; standalone ROC-AUC = 0.640), whereas all six brain-MRI parcellations performed at or near chance (ROC-AUC 0.496-0.516). The multi-modal model achieved moderate, well-calibrated discrimination (ROC-AUC = 0.665, 95% CI 0.653-0.677; PR-AUC = 0.413, 0.392-0.434; ECE = 0.013). A four-modality non-imaging version, applied without retraining to NAKO participants without MRI, retained discrimination (ROC-AUC = 0.660, 0.654-0.665), meeting all three pre-specified equivalence criteria, the calibration intercept narrowly. The baseline mental-health odds ratio was 2.06 (1.83-2.32; E-value 2.66) and essentially unchanged under an alternative control definition (2.07); adjusting for the full mental-health symptom trajectory reduced it to a conservative lower bound of 1.38 (1.20-1.58) that remained independently significant. Baseline mental health did not predict objectively measured hyposmia in participants screened before their infection (0.89) while predicting self-reported smell loss in the same participants (1.92).
ConclusionsBaseline mental health years before infection is the strongest pre-infection predictor of PCC among the infected, and the association held across the pre-specified sensitivity analyses. Whether it acts specifically on COVID-19 sequelae is a separate question this design cannot answer, and the indirect evidence points away from specificity: the association is undiminished after mild infection but absent among the hospitalized, and baseline mental health predicts current mental-health symptom load slightly less strongly in infected than in non-infected participants. The volumetric structural candidate is not supported: prepandemic T1-weighted volumetry carried no predictive signal in this single neuroimaging cohort. Risk stratification may benefit from incorporating baseline psychiatric phenotype; whether treating it reduces PCC incidence requires interventional study.
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BibTeX
@misc{flint2026preinfection,
title = {{Pre-Infection Mental Health, but Not Brain Volumetry, Predicts Risk of Post-COVID Condition: A Population-Based Cohort Study in the German National Cohort (NAKO)}},
author = {C. Flint and C. Spreckelsen and C. Otto and R. Mikolajczyk and J. Frost and L. V. Claass and J. M. Fasshauer and M. Scholz and L. Buschmann and N. Rübsamen and M. N. Wright and L. Burk and F. Bamberg and C. L. Schlett and T. Niendorf and M. Forsting and Y. Li and K. Steindorf and S. Karrasch and M. Leitzmann and S. Haug and T. W. Bärnighausen and B. Schmidt and M. Harries and V. Melhorn and L. Krist and T. Keil and A. Peters and N. Opel},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.26362611},
url = {https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Pre-Infection Mental Health, but Not Brain Volumetry, Predicts Risk of Post-COVID Condition: A Population-Based Cohort Study in the German National Cohort (NAKO)
AU - C. Flint
AU - C. Spreckelsen
AU - C. Otto
AU - R. Mikolajczyk
AU - J. Frost
AU - L. V. Claass
AU - J. M. Fasshauer
AU - M. Scholz
AU - L. Buschmann
AU - N. Rübsamen
AU - M. N. Wright
AU - L. Burk
AU - F. Bamberg
AU - C. L. Schlett
AU - T. Niendorf
AU - M. Forsting
AU - Y. Li
AU - K. Steindorf
AU - S. Karrasch
AU - M. Leitzmann
AU - S. Haug
AU - T. W. Bärnighausen
AU - B. Schmidt
AU - M. Harries
AU - V. Melhorn
AU - L. Krist
AU - T. Keil
AU - A. Peters
AU - N. Opel
PY - 2026
DA - 2026/09/09
PB - medRxiv
DO - 10.64898/2026.09.09.26362611
UR - https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v1
AB - BackgroundPost-COVID Condition (PCC) affected 10-30% of individuals after SARS-CoV-2 infection, and pre-infection predictors of who goes on to develop it are not well established. We compared pre-infection structural brain variation and baseline psychiatric phenotype as candidate predictors of PCC within a common multi-modal framework in the German National Cohort (NAKO). Both are candidate "first hits" under the second-hit hypothesis, which motivates the comparison; this is a prediction study, not a test of that hypothesis. MethodsIn 8,464 SARS-CoV-2-infected NAKO neuroimaging participants, of whom 2,304 (27.2%) met PCC criteria (weighted post-COVID syndrome (PCS) score > 10.75) and the rest were symptom-free controls, ten pre-infection modalities (T1-weighted volumetric brain MRI across six parcellations, baseline mental health (PHQ-9, GAD-7), demographics, and seven further biomedical and socioeconomic domains) entered a stacked ensemble with 10 x 5 nested cross-validation (primary metric: the area under the precision-recall curve, PR-AUC). Pre-specified analyses assessed transportability to a non-imaging cohort and robustness to the mental-health symptom trajectory and to unmeasured confounding. SARS-CoV-2 infection status and the PCC outcome were ascertained by self-report; no clinically confirmed diagnoses were available. ResultsBaseline mental health, assessed 3-8 years before infection, was the strongest predictor (38.0% of feature importance; standalone ROC-AUC = 0.640), whereas all six brain-MRI parcellations performed at or near chance (ROC-AUC 0.496-0.516). The multi-modal model achieved moderate, well-calibrated discrimination (ROC-AUC = 0.665, 95% CI 0.653-0.677; PR-AUC = 0.413, 0.392-0.434; ECE = 0.013). A four-modality non-imaging version, applied without retraining to NAKO participants without MRI, retained discrimination (ROC-AUC = 0.660, 0.654-0.665), meeting all three pre-specified equivalence criteria, the calibration intercept narrowly. The baseline mental-health odds ratio was 2.06 (1.83-2.32; E-value 2.66) and essentially unchanged under an alternative control definition (2.07); adjusting for the full mental-health symptom trajectory reduced it to a conservative lower bound of 1.38 (1.20-1.58) that remained independently significant. Baseline mental health did not predict objectively measured hyposmia in participants screened before their infection (0.89) while predicting self-reported smell loss in the same participants (1.92). ConclusionsBaseline mental health years before infection is the strongest pre-infection predictor of PCC among the infected, and the association held across the pre-specified sensitivity analyses. Whether it acts specifically on COVID-19 sequelae is a separate question this design cannot answer, and the indirect evidence points away from specificity: the association is undiminished after mild infection but absent among the hospitalized, and baseline mental health predicts current mental-health symptom load slightly less strongly in infected than in non-infected participants. The volumetric structural candidate is not supported: prepandemic T1-weighted volumetry carried no predictive signal in this single neuroimaging cohort. Risk stratification may benefit from incorporating baseline psychiatric phenotype; whether treating it reduces PCC incidence requires interventional study.
ER -