{
  "abstract": "Importance: Cognitive abnormalities may emerge during prodromal neuronal a-synuclein disease (NSD), but their domain specificity and longitudinal course are uncertain. Objective: To characterize baseline cognition and longitudinal change in prodromal NSD compared with healthy controls, NSD-negative genetic carriers, and sporadic Parkinson disease (PD). Design: Longitudinal cohort study using Parkinson's Precision Medicine Initiative (PPMI) data, with first visits from July 2010 through April 2026 and up to 4 years of follow-up. Setting: Multicenter cohort. Participants: Healthy controls (HC; n=244), GBA1 or LRRK2 nonmanifesting carriers without NSD (n=323), prodromal NSD participants recruited through hyposmia or isolated rapid eye movement sleep behavior disorder cohorts (n=1640), and sporadic PD (n=824). Exposures: NSD status and clinical cohort. Main Outcomes and Measures: Cognitive summary scores for verbal memory, executive function, processing speed, language, and visuospatial function, and PPMI-defined mild cognitive impairment (MCI). Models adjusted for age, sex, education, and APOE {varepsilon}4 status. Results: Among 3031 participants (mean [SD] age, 66.6 [7.0] years; 1322 female [43.6%]), prodromal NSD participants had lower baseline verbal-memory performance than HC (adjusted difference, -0.20 SD; 95% CI, -0.34 to -0.07; adjusted P = .007); NSD-negative genetic carriers did not differ from HC. No other cognitive domain was lower than HC at baseline or longitudinally. In the primary age-adjusted analysis, verbal-memory trajectory differed from HC over 4 years (P = .009), whereas in a smaller age-matched sensitivity subset through year 3, it did not (P = .62); the baseline difference persisted (adjusted difference, -0.28 SD; 95% CI, -0.46 to -0.10; P = .003). Adjusted MCI probability increased from 10.2% to 15.1% in prodromal NSD, compared with 8.4% to 5.0% in HC and 13.4% to 17.7% in PD. The increase was greater than in HC (ratio of annual odds ratios, 1.28; 95% CI, 1.04 to 1.58; adjusted P = .04) but not PD (P = .62). Conclusions and Relevance: Prodromal NSD was associated with modestly lower verbal memory and increasing MCI probability relative to HC, without lower performance in other cognitive domains. The baseline verbal-memory difference was robust, whereas the longitudinal trajectory finding was not reproduced in the smaller age-matched sensitivity subset.",
  "abstract_shown": true,
  "affiliations": [
    "Cleveland Clinic"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "S. Anis"
    },
    {
      "name": "E. Zimmerman"
    },
    {
      "name": "S. A. Sperling"
    },
    {
      "name": "J. L. Alberts"
    },
    {
      "name": "D. Weintraub"
    },
    {
      "name": "T. Simuni"
    },
    {
      "name": "A. Siderowf"
    },
    {
      "name": "H. H. Fernandez"
    },
    {
      "name": "on behalf of the Parkinson's Precision Medicine Initiative"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7akwmsqbaveny.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.05.26367361",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1.full",
  "id": "7akwmsqbaveny",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1",
  "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",
      "neurology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7akwmsqbaveny.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:20:29Z",
      "native_id": "10.64898/2026.11.05.26367361",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.11.05.26367361v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Cognitive Performance in Prodromal Neuronal α Synuclein Disease",
  "title_text": "Cognitive Performance in Prodromal Neuronal α Synuclein Disease",
  "type": "preprint",
  "updated_at": "2026-11-08T00:21:01Z",
  "url": "https://research.draconitic.com/paper/7akwmsqbaveny",
  "venue": "medRxiv",
  "versions": []
}