{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T12:19:52Z","timestamp":1777983592097,"version":"3.51.4"},"posted":{"date-parts":[[2025,10,23]]},"group-title":"Neurology","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Neuronal synuclein disease (NSD) involves pathological \u03b1-synuclein presence and often dopaminergic dysfunction, initially preceding overt clinical symptoms. NSD-ISS identifies Stage 2A (no dopaminergic dysfunction) and 2B (dopaminergic dysfunction) as prodromal phases marked by subtle clinical signs without functional impairment. Intraindividual variability\/ dispersion (IIV-D), reflecting within-person inconsistency across cognitive tasks, has emerged as a potential marker of early neurodegenerative changes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>This study examined whether IIV-D differentiates NSD Stage 2 participants from healthy controls and predicts progression to more advanced NSD stages.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Data from the Parkinson\u2019s Progression Markers Initiative were used to assess performance across 11 neuropsychological tests in 934 participants (832 Stage 2; 102 controls). IIV-D was quantified using the total coefficient of variation (CoV) and a domain-specific attention\/executive CoV. Group comparisons and logistic regression assessed associations between IIV-D, clinical characteristics, and disease progression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Stage 2 participants exhibited significantly greater CoV than controls (\n                    <jats:italic>p<\/jats:italic>\n                    = .003). Higher IIV-D was associated with worse motor symptoms, non-motor burden, and functional impairment. Among Stage 2 participants, subsequent converters to Stage 3+ (n = 100) had significantly higher total CoV (\n                    <jats:italic>p<\/jats:italic>\n                    = .008) and attention\/executive CoV (\n                    <jats:italic>p<\/jats:italic>\n                    = .020) at baseline. CoV independently predicted conversion after one year (OR = 1.44,\n                    <jats:italic>p<\/jats:italic>\n                    = .008), controlling for baseline motor severity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>IIV-D, particularly CoV, may be a sensitive cognitive marker of early NSD and predict short-term disease progression. Findings support integrating cognitive dispersion metrics into early detection strategies for prodromal synucleinopathies, though replication is needed to confirm generalizability and clinical utility.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.21.25338482","type":"posted-content","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T18:55:15Z","timestamp":1761245715000},"source":"Crossref","is-referenced-by-count":1,"title":["Utilizing Intraindividual Cognitive Variability to Predict Early Neuronal Synuclein Disease Progression"],"prefix":"10.64898","author":[{"given":"Hannah L.","family":"Combs","sequence":"first","affiliation":[{"name":"Department of Neurology, Baylor College of Medicine, Houston, TX"},{"name":"Department of Neurosurgery, Baylor College of Medicine, Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Kurth","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuprita","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele K.","family":"York","sequence":"additional","affiliation":[{"name":"Department of Neurology, Baylor College of Medicine, Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Weintraub","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David-Erick","family":"Lafontant","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chelsea","family":"Caspell-Garcia","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the Parkinson\u2019s Progression Markers Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026050504450890000_2025.10.21.25338482v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"issue":"1","key":"2026050504450890000_2025.10.21.25338482v3.2","first-page":"011013","article-title":"Mean and variability in functional brain activations differentially predict executive function in older adults: an investigation employing functional near-infrared spectroscopy","volume":"5","year":"2018","journal-title":"Neurophotonics"},{"key":"2026050504450890000_2025.10.21.25338482v3.3","doi-asserted-by":"publisher","DOI":"10.1007\/s11682-015-9441-1"},{"key":"2026050504450890000_2025.10.21.25338482v3.4","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617710001748"},{"key":"2026050504450890000_2025.10.21.25338482v3.5","doi-asserted-by":"publisher","DOI":"10.1093\/arclin\/acs003"},{"key":"2026050504450890000_2025.10.21.25338482v3.6","doi-asserted-by":"publisher","DOI":"10.1007\/s004269900007"},{"issue":"1","key":"2026050504450890000_2025.10.21.25338482v3.7","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/WNN.0000000000000358","article-title":"Cognitive Intra-individual Variability in the Laboratory Is Associated With Greater Executive Dysfunction in the Daily Lives of Older Adults With HIV","volume":"37","year":"2024","journal-title":"Cogn Behav Neurol"},{"issue":"2","key":"2026050504450890000_2025.10.21.25338482v3.8","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/arclin\/acae073","article-title":"Executive Functions are Independently Associated with Cognitive Dispersion in HIV Disease","volume":"40","year":"2025","journal-title":"Arch Clin Neuropsychol"},{"key":"2026050504450890000_2025.10.21.25338482v3.9","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000577"},{"key":"2026050504450890000_2025.10.21.25338482v3.10","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000856"},{"key":"2026050504450890000_2025.10.21.25338482v3.11","doi-asserted-by":"crossref","unstructured":"Combs HL , Henry SK , Webber TA , York MK , Sober JD . \u201cCognitive functioning and intra-individual variability in essential tremor and Parkinson\u2019s disease: A comparative study\u201d. 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