{
  "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.\n\nMethodsIn 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.\n\nResultsBaseline 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).\n\nConclusionsBaseline 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 29,
  "authors": [
    {
      "name": "C. Flint"
    },
    {
      "name": "C. Spreckelsen"
    },
    {
      "name": "C. Otto"
    },
    {
      "name": "R. Mikolajczyk"
    },
    {
      "name": "J. Frost"
    },
    {
      "name": "L. V. Claass"
    },
    {
      "name": "J. M. Fasshauer"
    },
    {
      "name": "M. Scholz"
    },
    {
      "name": "L. Buschmann"
    },
    {
      "name": "N. Rübsamen"
    },
    {
      "name": "M. N. Wright"
    },
    {
      "name": "L. Burk"
    },
    {
      "name": "F. Bamberg"
    },
    {
      "name": "C. L. Schlett"
    },
    {
      "name": "T. Niendorf"
    },
    {
      "name": "M. Forsting"
    },
    {
      "name": "Y. Li"
    },
    {
      "name": "K. Steindorf"
    },
    {
      "name": "S. Karrasch"
    },
    {
      "name": "M. Leitzmann"
    },
    {
      "name": "S. Haug"
    },
    {
      "name": "T. W. Bärnighausen"
    },
    {
      "name": "B. Schmidt"
    },
    {
      "name": "M. Harries"
    },
    {
      "name": "V. Melhorn"
    },
    {
      "name": "L. Krist"
    },
    {
      "name": "T. Keil"
    },
    {
      "name": "A. Peters"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Opel"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8xfn4wq70tk3d.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.09.26362611",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v1.full",
  "id": "8xfn4wq70tk3d",
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  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "psychiatry and clinical psychology"
    ],
    [
      "openalex",
      "2728|Long-Term Effects of COVID-19"
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  "openalex": "W7212271675",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8xfn4wq70tk3d.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:18Z",
      "native_id": "10.64898/2026.09.09.26362611",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362611v2"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:psychiatry and clinical psychology",
      "subfield": "psychiatry"
    }
  ],
  "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)",
  "title_text": "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)",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:49Z",
  "url": "https://research.draconitic.com/paper/8xfn4wq70tk3d",
  "venue": "medRxiv",
  "versions": []
}