{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:52:12Z","timestamp":1787028732887,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Parkinson\u2019s disease is associated with cognitive decline, misfolded protein deposition and brain atrophy. We herein hypothesized that structural abnormalities may be mediators between plasma misfolded proteins and cognitive functions. Neuropsychological assessments including five domains (attention, executive, speech and language, memory and visuospatial functions), ultra-sensitive immunomagnetic reduction-based immunoassay (IMR) measured misfolded protein levels (phosphorylated-Tau, Amyloid\u03b2-42 and 40, \u03b1-synuclein and neurofilament light chain) and auto-segmented brain volumetry using FreeSurfur were performed for 54 Parkinson\u2019s disease (PD) patients and 37 normal participants. Our results revealed that PD patients have higher plasma misfolded protein levels. Phosphorylated-Tau (p-Tau) and Amyloid\u03b2-42 (A\u03b2-42) were correlated with atrophy of bilateral cerebellum, right caudate nucleus, and right accumbens area (RAA). In mediation analysis, RAA atrophy completely mediated the relationship between p-Tau and digit symbol coding (DSC). RAA and bilateral cerebellar cortex atrophy partially mediated the A\u03b2-42 and executive function (DSC and abstract thinking) relationship. Our study concluded that, in PD, p-Tau deposition adversely impacts DSC by causing RAA atrophy. A\u03b2-42 deposition adversely impacts executive functions by causing RAA and bilateral cerebellum atrophy.<\/jats:p>","DOI":"10.3390\/jpm11080702","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T04:29:14Z","timestamp":1627014554000},"page":"702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Chiun-Chieh","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Hsiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Hsien","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Yun","family":"Lin","sequence":"additional","affiliation":[{"name":"Philosophy in Nursing, School of Nursing, Shu Zen College of Medicine and Management, Number 452, Hwan-Chio Rd, Luju Dist, Kaohsiung 821, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Hsien","family":"Chou","sequence":"additional","affiliation":[{"name":"Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Che","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/j.1460-9568.2009.06873.x","article-title":"The second brain and Parkinson\u2019s disease","volume":"30","author":"Lebouvier","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.parkreldis.2014.10.026","article-title":"Parkinson\u2019s disease severity levels and MDS-Unified Parkinson\u2019s Disease Rating Scale","volume":"21","author":"Mario","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fneur.2012.00088","article-title":"Cognitive impairment and dementia in Parkinson\u2019s disease: Clinical features, diagnosis, and management","volume":"3","author":"Meireles","year":"2012","journal-title":"Front. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1002\/gps.4623","article-title":"Cognitive impairment in Parkinson\u2019s disease: Impact on quality of life of carers","volume":"32","author":"Lawson","year":"2017","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fnagi.2020.00112","article-title":"Plasma Levels of \u03b1-Synuclein, A\u03b2-40 and T-tau as Biomarkers to Predict Cognitive Impairment in Parkinson\u2019s Disease","volume":"12","author":"Chen","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.semcdb.2011.04.002","article-title":"Misfolded protein aggregates: Mechanisms, structures and potential for disease transmission","volume":"22","author":"Soto","year":"2011","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1136\/jnnp-2016-314857","article-title":"Plasma \u03b1-synuclein predicts cognitive decline in Parkinson\u2019s disease","volume":"88","author":"Lin","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/jnnp.55.3.181","article-title":"Accuracy of clinical diagnosis of idiopathic Parkinson\u2019s disease: A clinico-pathological study of 100 cases","volume":"55","author":"Hughes","year":"1992","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/mds.20213","article-title":"Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations The Movement Disorder Society Task Force on rating scales for Parkinson\u2019s disease","volume":"19","author":"Goetz","year":"2004","journal-title":"Mov. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1002\/mds.22340","article-title":"Movement Disorder Society-sponsored revision of the Unified Parkinson\u2019s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results","volume":"23","author":"Goetz","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_11","first-page":"1941034","article-title":"Reliability of Three Disability Scales for Detection of Independence Loss in Parkinson\u2019s Disease","volume":"2016","author":"Bjornestad","year":"2016","journal-title":"Parkinsons Dis."},{"key":"ref_12","first-page":"180","article-title":"Cognitive Abilities Screening Instrument, Chinese Version 2.0 (CASI C-2.0): Administration and clinical application","volume":"21","author":"Lin","year":"2012","journal-title":"Acta Neurol Taiwan"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.4103\/TPSY.TPSY_9_19","article-title":"The correlations between results of short-form wechsler adult intelligence Scale-III and demographic\/clinical factors in patients with schizophrenia: Preliminary findings","volume":"33","author":"Lin","year":"2019","journal-title":"Taiwan J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12951-016-0198-5","article-title":"Development of an ultra-high sensitive immunoassay with plasma biomarker for differentiating Parkinson disease dementia from Parkinson disease using antibody functionalized magnetic nanoparticles","volume":"14","author":"Yang","year":"2016","journal-title":"J. Nanobiotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.3233\/JAD-170810","article-title":"Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer\u2019s Disease","volume":"61","author":"Yang","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1016\/j.neuroimage.2012.02.084","article-title":"Within-subject template estimation for unbiased longitudinal image analysis","volume":"61","author":"Reuter","year":"2012","journal-title":"NeuroImage"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.dadm.2019.05.001","article-title":"Plasma tau complements CSF tau and P-tau in the diagnosis of Alzheimer\u2019s disease","volume":"11","author":"Fossati","year":"2019","journal-title":"Alzheimers Dement (Amst)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.jalz.2018.01.004","article-title":"Plasma amyloid levels within the Alzheimer\u2019s process and correlations with central biomarkers","volume":"14","author":"Hanon","year":"2018","journal-title":"Alzheimers Dement"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.expneurol.2010.06.017","article-title":"Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson\u2019s disease brains with and without dementia","volume":"225","author":"Wills","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41531-017-0023-3","article-title":"Imaging tau pathology in Parkinsonisms","volume":"3","author":"Coakeley","year":"2017","journal-title":"NPJ Parkinsons Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/2051-5960-2-40","article-title":"Tau accumulation in the nucleus accumbens in tangle-predominant dementia","volume":"2","author":"Kawakami","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3389\/fneur.2018.00809","article-title":"Tau Pathology in Parkinson\u2019s Disease","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: Structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12603-019-1162-5","article-title":"What is the Physiological Function of Amyloid-Beta Protein?","volume":"23","author":"Morley","year":"2019","journal-title":"J. Nutr. Health Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/sj.npp.1301485","article-title":"Acute beta-amyloid administration disrupts the cholinergic control of dopamine release in the nucleus accumbens","volume":"33","author":"Preda","year":"2008","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3389\/fnagi.2018.00175","article-title":"The Relation between Brain Amyloid Deposition, Cortical Atrophy, and Plasma Biomarkers in Amnesic Mild Cognitive Impairment and Alzheimer\u2019s Disease","volume":"10","author":"Fan","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3233\/JPD-191766","article-title":"Integrated Plasma and Neuroimaging Biomarkers Associated with Motor and Cognition Severity in Parkinson\u2019s Disease","volume":"10","author":"Chen","year":"2020","journal-title":"J. Parkinsons Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/jon.12327","article-title":"Regional Cerebral Gray Matter Volume in HIV-Positive Patients with Executive Function Deficits","volume":"26","author":"Zimmermann","year":"2016","journal-title":"J. Neuroimaging Off. J. Am. Soc. Neuroimaging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1152\/jn.01131.2015","article-title":"Viral vector-based tools advance knowledge of basal ganglia anatomy and physiology","volume":"115","author":"Sizemore","year":"2016","journal-title":"J. Neurophysiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.tins.2008.08.002","article-title":"Limbic and cortical information processing in the nucleus accumbens","volume":"31","author":"Goto","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1093\/cercor\/bhp135","article-title":"Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity","volume":"19","author":"Krienen","year":"2009","journal-title":"Cereb. Cortex"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1080\/14734220601169707","article-title":"Cerebellar involvement in executive control","volume":"6","author":"Bellebaum","year":"2007","journal-title":"Cerebellum"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Caspell-Garcia, C., Simuni, T., Tosun-Turgut, D., Wu, I.W., Zhang, Y., Nalls, M., Singleton, A., Shaw, L.A., Kang, J.H., and Trojanowski, J.Q. (2017). Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175674"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/brain\/awu036","article-title":"Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson\u2019s disease longitudinally","volume":"137","author":"Hanganu","year":"2014","journal-title":"Brain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s10020-021-00301-7","article-title":"Clinical implications for dopaminergic and functional neuroimage research in cognitive symptoms of Parkinson\u2019s disease","volume":"27","author":"Hirano","year":"2021","journal-title":"Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4103\/2224-4018.141836","article-title":"Mavridis\u2019 atrophy in Parkinson\u2019s disease: \u201cThe peak of the iceberg\u201d","volume":"2","author":"Mavridis","year":"2014","journal-title":"J. Transl. Intern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.3174\/ajnr.A4055","article-title":"Subcortical atrophy is associated with cognitive impairment in mild Parkinson disease: A combined investigation of volumetric changes, cortical thickness, and vertex-based shape analysis","volume":"35","author":"Mak","year":"2014","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1093\/jnen\/nlw070","article-title":"Distribution and Load of Amyloid-\u03b2 Pathology in Parkinson Disease and Dementia with Lewy Bodies","volume":"75","author":"Hepp","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"08","DOI":"10.31080\/ASNE.2020.03.0172","article-title":"Visuospatial and Executive Deficits in Parkinson\u2019s Disease: A Review","volume":"3","year":"2020","journal-title":"Acta Sci. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s12311-011-0321-y","article-title":"From movement to thought: Executive function, embodied cognition, and the cerebellum","volume":"11","author":"Koziol","year":"2012","journal-title":"Cerebellum"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fnsys.2019.00061","article-title":"The Cortico-Basal Ganglia-Cerebellar Network: Past, Present and Future Perspectives","volume":"13","author":"Milardi","year":"2019","journal-title":"Front. Syst. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41583-018-0002-7","article-title":"The basal ganglia and the cerebellum: Nodes in an integrated network","volume":"19","author":"Bostan","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neuron.2019.10.010","article-title":"Amyloid-Beta (A\u03b2) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with A\u03b2 Pathology","volume":"105","author":"Bassil","year":"2020","journal-title":"Neuron"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1001\/jamaneurol.2017.3713","article-title":"Associations Between Tau, \u03b2-Amyloid, and Cognition in Parkinson Disease","volume":"75","author":"Winer","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"444","DOI":"10.4172\/2161-0460.1000444","article-title":"The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders","volume":"8","author":"Irwin","year":"2018","journal-title":"J. Alzheimers Dis. Parkinsonism"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3233\/JAD-180390","article-title":"Brain Amyloid Contribution to Cognitive Dysfunction in Early-Stage Parkinson\u2019s Disease: The PPMI Dataset","volume":"66","author":"Fiorenzato","year":"2018","journal-title":"J. Alzheimers Dis."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/8\/702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:42Z","timestamp":1760164422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/8\/702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["jpm11080702"],"URL":"https:\/\/doi.org\/10.3390\/jpm11080702","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]}}}