{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T10:15:27Z","timestamp":1774952127197,"version":"3.50.1"},"reference-count":40,"publisher":"IMR Press","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271995"],"award-info":[{"award-number":["82271995"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81730050"],"award-info":[{"award-number":["81730050"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background: Cognitive impairment (CI) is recognized as a debilitating complication of Parkinson\u2019s disease (PD). This study was designed to develop a diagnostic classification model by integrating substantia nigra hyperechogenicity (SNH) and inflammationassociated biomarkers to evaluate its diagnostic performance in distinguishing PD CI stages. Methods: Between January, 2023 and May, 2024, 184 patients with PD who underwent transcranial sonography were prospectively enrolled. Based on Montreal Cognitive Assessment (MoCA) scores, participants were categorized into three groups: cognitive impairment (PD-CI, MoCA &lt;26), mild cognitive impairment (PD-MCI, MoCA 22\u201325), and dementia (PD-dementia, MoCA \u226421). Ultrasound features and inflammationassociated biomarkers were screened with univariate analyses. Multivariate logistic regression was used to identify independent diagnostic factors, and receiver operating characteristic (ROC) curve analysis was used to assess model discrimination. Results: Multivariate regression analysis indicated that age &lt;50 years and more years of education were significantly associated factors for CI (OR = 0.170, p = 0.0350; OR = 0.8780, p = 0.0020, respectively), whereas Unified Parkinson\u2019s Disease Rating Scale Part III (UPDRSIII) score (OR = 1.024, p = 0.0270), SNH (OR = 2.550, p = 0.0030), elevated C-reactive protein (CRP) (OR = 2.038, p = 0.0350), and elevated homocysteine (Hcy) (OR = 2.830, p = 0.0020) were independent risk factors. The area uinder the curves (AUCs) for the combined SNH+CRP+Hcy model in predicting PD-CI, PD-MCI, and PD-dementia were 0.783, 0.729, and 0.823, respectively; these values were significantly superior to those for single or dual marker combinations (p &lt; 0.05), with the strongest performance for distinguishing PD-dementia. Conclusion: An SNH and inflammationassociated biomarkerbased model was developed for predicting the stage of cognitive impairment in PD. Clinical targets for individualized intervention can be provided, and clinical risk stratification and care pathways can be optimized. Furthermore, the model supports the iron deposition-neuroinflammation-CI pathway hypothesis, providing a mechanistic rationale for ultrasoundbased PD-CI diagnosis.<\/jats:p>","DOI":"10.31083\/jin46585","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:35:19Z","timestamp":1774949719000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrating Substantia Nigra Hyperechogenicity and Inflammation-Associated Biomarkers: A Classification Model for Staging Cognitive Impairment in Parkinson\u2019s Disease"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5992-5938","authenticated-orcid":true,"given":"Jiahang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1234-8744","authenticated-orcid":true,"given":"Chao","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"},{"name":"Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6745-7082","authenticated-orcid":true,"given":"Sen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5855-1652","authenticated-orcid":true,"given":"Yiqun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9887-1205","authenticated-orcid":true,"given":"Linyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"He","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-1063","authenticated-orcid":true,"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, 100070 Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Zaman V, Shields DC, Shams R, Drasites KP, Matzelle D, Haque A, et al. Cellular and molecular pathophysiology in the progression of Parkinson\u2019s disease. Metabolic Brain Disease. 2021; 36: 815\u2013827.","DOI":"10.1007\/s11011-021-00689-5"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, et al. Parkinson disease-associated cognitive impairment. Nature Reviews. Disease Primers. 2021; 7: 47.","DOI":"10.1038\/s41572-021-00280-3"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Chandler JM, Nair R, Biglan K, Ferries EA, Munsie LM, Changamire T, et al. Characteristics of Parkinson\u2019s Disease in Patients with and without Cognitive Impairment. Journal of Parkinson\u2019s Disease. 2021; 11: 1381\u20131392.","DOI":"10.3233\/JPD-202190"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Vossius C, Larsen JP, Janvin C, Aarsland D. The economic impact of cognitive impairment in Parkinson\u2019s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2011; 26: 1541\u20131544.","DOI":"10.1002\/mds.23661"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Jellinger KA. Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks. International Journal of Molecular Sciences. 2023; 25: 498.","DOI":"10.3390\/ijms25010498"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Schumacher J, Kanel P, Dyrba M, Storch A, Bohnen NI, Teipel S, et al. Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson\u2019s disease. Brain: a Journal of Neurology. 2023; 146: 4964\u20134973.","DOI":"10.1093\/brain\/awad226"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Delgado-Alvarado M, Ferrer-Gallardo VJ, Paz-Alonso PM, Caballero-Gaudes C, Rodr\u00edguez-Oroz MC. Interactions between functional networks in Parkinson\u2019s disease mild cognitive impairment. Scientific Reports. 2023; 13: 20162.","DOI":"10.1038\/s41598-023-46991-3"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Peri\u00f1\u00e1n MT, Mac\u00edas-Garc\u00eda D, Jes\u00fas S, Mart\u00edn-Rodr\u00edguez JF, Mu\u00f1oz-Delgado L, Jimenez-Jaraba MV, et al. Homocysteine levels, genetic background, and cognitive impairment in Parkinson\u2019s disease. Journal of Neurology. 2023; 270: 477\u2013485.","DOI":"10.1007\/s00415-022-11361-y"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Lin WZ, Yu D, Xiong LY, Zebarth J, Wang R, Fischer CE, et al. Homocysteine, neurodegenerative biomarkers, and APOE \u03b54 in neurodegenerative diseases. Alzheimer\u2019s & Dementia: the Journal of the Alzheimer\u2019s Association. 2025; 21: e14376.","DOI":"10.1002\/alz.14376"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Gu L, Luo WY, Xia N, Zhang JN, Fan JK, Yang HM, et al. Upregulated mGluR5 induces ER stress and DNA damage by regulating the NMDA receptor subunit NR2B. Journal of Biochemistry. 2022; 171: 349\u2013359.","DOI":"10.1093\/jb\/mvab140"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Rosell-D\u00edaz M, Santos-Gonz\u00e1lez E, Motger-Albert\u00ed A, Gallardo-Nuell L, Arnoriaga-Rodr\u00edguez M, Coll-Mart\u00ednez C, et al. Lower serum ferritin levels are associated with worse cognitive performance in aging. The Journal of Nutrition, Health & Aging. 2024; 28: 100190.","DOI":"10.1016\/j.jnha.2024.100190"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Li Y, Ruan X, Sun M, Yuan M, Song J, Zhou Z, et al. Iron deposition participates in LPS-induced cognitive impairment by promoting neuroinflammation and ferroptosis in mice. Experimental Neurology. 2024; 379: 114862.","DOI":"10.1016\/j.expneurol.2024.114862"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Hemmati-Dinarvand M, Taher-Aghdam AA, Mota A, Zununi Vahed S, Samadi N. Dysregulation of serum NADPH oxidase1 and ferritin levels provides insights into diagnosis of Parkinson\u2019s disease. Clinical Biochemistry. 2017; 50: 1087\u20131092.","DOI":"10.1016\/j.clinbiochem.2017.09.014"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Shen J, Amari N, Zack R, Skrinak RT, Unger TL, Posavi M, et al. Plasma MIA, CRP, and Albumin Predict Cognitive Decline in Parkinson\u2019s Disease. Annals of Neurology. 2022; 92: 255\u2013269.","DOI":"10.1002\/ana.26410"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Hou C, Yang F, Li S, Ma HY, Li FX, Zhang W, et al. A nomogram based on neuron-specific enolase and substantia nigra hyperechogenicity for identifying cognitive impairment in Parkinson\u2019s disease. Quantitative Imaging in Medicine and Surgery. 2024; 14: 3581\u20133592.","DOI":"10.21037\/qims-23-1778"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Papu\u0107 E, Rejdak K. Increased Cerebrospinal Fluid S100B and NSE Reflect Neuronal and Glial Damage in Parkinson\u2019s Disease. Frontiers in Aging Neuroscience. 2020; 12: 156.","DOI":"10.3389\/fnagi.2020.00156"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Hou C, Zhang W, Li HB, Li S, Nie F, Wang XM, et al. Spatial variations and precise location of substantia nigra hyperechogenicity in Parkinson\u2019s disease using TCS-MR fusion imaging. NPJ Parkinson\u2019s Disease. 2025; 11: 78.","DOI":"10.1038\/s41531-025-00910-7"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Yin Y, Tian N, Deng Z, Wang J, Kuang L, Tang Y, et al. Targeted Microglial Membrane-Coated MicroRNA Nanosponge Mediates Inhibition of Glioblastoma. ACS Nano. 2024; 18: 29089\u201329105.","DOI":"10.1021\/acsnano.4c10509"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Kals M, Reigo A, Teder-Laving M, Vaht M, Estonian Biobank research team, Nikopensius T, et al. Polygenic Risk Score Combined with Transcranial Sonography Refines Parkinson\u2019s Disease Risk Prediction. Movement Disorders Clinical Practice. 2025; 12: 928\u2013937.","DOI":"10.1002\/mdc3.70011"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson\u2019s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2015; 30: 1591\u20131601.","DOI":"10.1002\/mds.26424"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Skorvanek M, Goldman JG, Jahanshahi M, Marras C, Rektorova I, Schmand B, et al. Global scales for cognitive screening in Parkinson\u2019s disease: Critique and recommendations. Movement Disorders: Official Journal of the Movement Disorder Society. 2018; 33: 208\u2013218.","DOI":"10.1002\/mds.27233"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Lilja G, Ull\u00e9n S, Dankiewicz J, Friberg H, Levin H, Nordstr\u00f6m EB, et al. Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial. JAMA Neurology. 2023; 80: 1070\u20131079.","DOI":"10.1001\/jamaneurol.2023.2536"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Avila P\u00e9rez S, Koppelmans V, Duff KM, Ruitenberg MF. One-year practice effects predict long-term cognitive outcomes in Parkinson\u2019s disease. Journal of Parkinson\u2019s Disease. 2025; 15: 858\u2013867.","DOI":"10.1177\/1877718X251339585"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Bartova P, Skoloudik D, Bar M, Ressner P, Hlustik P, Herzig R, et al. Transcranial sonography in movement disorders. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2008; 152: 251\u2013258.","DOI":"10.5507\/bp.2008.039"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Gallagher J, Gochanour C, Caspell-Garcia C, Dobkin RD, Aarsland D, Alcalay RN, et al. Long-Term Dementia Risk in Parkinson Disease. Neurology. 2024; 103: e209699.","DOI":"10.1212\/WNL.0000000000209699"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Chen CL, Cheng SY, Montaser-Kouhsari L, Wu WC, Hsu YC, Tai CH, et al. Advanced brain aging in Parkinson\u2019s disease with cognitive impairment. NPJ Parkinson\u2019s Disease. 2024; 10: 62.","DOI":"10.1038\/s41531-024-00673-7"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Kotagal V, Bohnen NI, M\u00fcller MLTM, Koeppe RA, Frey KA, Langa KM, et al. Educational attainment and motor burden in Parkinson\u2019s disease. Movement Disorders: Official Journal of the Movement Disorder Society. 2015; 30: 1143\u20131147.","DOI":"10.1002\/mds.26272"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Casaletto KB, Renter\u00eda MA, Pa J, Tom SE, Harrati A, Armstrong NM, et al. Late-Life Physical and Cognitive Activities Independently Contribute to Brain and Cognitive Resilience. Journal of Alzheimer\u2019s Disease: JAD. 2020; 74: 363\u2013376.","DOI":"10.3233\/JAD-191114"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Wang Y, Jiang Z, Chu C, Zhang Z, Wang J, Li D, et al. Push-pull effects of basal ganglia network in Parkinson\u2019s disease inferred by functional MRI. NPJ Parkinson\u2019s Disease. 2024; 10: 224.","DOI":"10.1038\/s41531-024-00835-7"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Ferrazzoli D, Ortelli P, Volpe D, Cucca A, Versace V, Nardone R, et al. The Ties That Bind: Aberrant Plasticity and Networks Dysfunction in Movement Disorders-Implications for Rehabilitation. Brain Connectivity. 2021; 11: 278\u2013296.","DOI":"10.1089\/brain.2020.0971"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Hayek D, Ziegler G, Kleineidam L, Brosseron F, Nemali A, Vockert N, et al. Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition. Molecular Psychiatry. 2024; 29: 992\u20131004.","DOI":"10.1038\/s41380-023-02387-3"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Luo J, le Cessie S, Blauw GJ, Franceschi C, Noordam R, van Heemst D. Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a Mendelian randomization study. GeroScience. 2022; 44: 2259\u20132270.","DOI":"10.1007\/s11357-022-00602-7"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Allen WE, Blosser TR, Sullivan ZA, Dulac C, Zhuang X. Molecular and spatial signatures of mouse brain aging at single-cell resolution. Cell. 2023; 186: 194\u2013208.e18.","DOI":"10.1016\/j.cell.2022.12.010"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"McGregor MM, Nelson AB. Circuit Mechanisms of Parkinson\u2019s Disease. Neuron. 2019; 101: 1042\u20131056.","DOI":"10.1016\/j.neuron.2019.03.004"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Yang B, Zhu Y, Li K, Wang F, Liu B, Zhou Q, et al. Machine learning model base on metabolomics and proteomics to predict cognitive impairment in Parkinson\u2019s disease. NPJ Parkinson\u2019s Disease. 2024; 10: 187.","DOI":"10.1038\/s41531-024-00795-y"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Yang X, Wang M, Liu W, Hou M, Zhao J, Huang X, et al. Quantitative susceptibility mapping in rats with minimal hepatic encephalopathy: Does iron overload aggravate cognitive impairment by promoting neuroinflammation? NeuroImage. 2023; 283: 120418.","DOI":"10.1016\/j.neuroimage.2023.120418"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Wilcockson TDW, Roy S. Could Alcohol-Related Cognitive Decline Be the Result of Iron-Induced Neuroinflammation? Brain Sciences. 2024; 14: 520.","DOI":"10.3390\/brainsci14060520"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Zhang C, Hu Y, Cao X, Deng Y, Wang Y, Guan M, et al. Lower water-soluble vitamins and higher homocysteine are associated with neurodegenerative diseases. Scientific Reports. 2025; 15: 18866.","DOI":"10.1038\/s41598-025-03859-y"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Uchida Y, Kan H, Sakurai K, Arai N, Kato D, Kawashima S, et al. Voxel-based quantitative susceptibility mapping in Parkinson\u2019s disease with mild cognitive impairment. Movement Disorders: Official Journal of the Movement Disorder Society. 2019; 34: 1164\u20131173.","DOI":"10.1002\/mds.27717"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Thomas GEC, Leyland LA, Schrag AE, Lees AJ, Acosta-Cabronero J, Weil RS. Brain iron deposition is linked with cognitive severity in Parkinson\u2019s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2020; 91: 418\u2013425.","DOI":"10.1136\/jnnp-2019-322042"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/3\/10.31083\/JIN46585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:36:00Z","timestamp":1774949760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/25\/3\/10.31083\/JIN46585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,9]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026]]}},"alternative-id":["S0219-6352(26)01072-7"],"URL":"https:\/\/doi.org\/10.31083\/jin46585","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,9]]},"article-number":"46585"}}