{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T09:22:02Z","timestamp":1793784122398,"version":"4.6.1"},"reference-count":98,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Cognitive impairment in patients with Parkinson\u2019s disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and\/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut\u2013brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment.<\/jats:p>","DOI":"10.3390\/medicina59101756","type":"journal-article","created":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T16:58:09Z","timestamp":1696179489000},"page":"1756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Cognitive Impairment in Parkinson\u2019s Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches"],"prefix":"10.3390","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8584-5488","authenticated-orcid":false,"given":"Yildiz","family":"Degirmenci","sequence":"first","affiliation":[{"name":"Department of Neurology, School of Medicine, Istanbul Health and Technology University, 34093 Istanbul, Turkey"},{"name":"Parkinson\u2019s Disease and Movement Disorders Unit, Neurology Clinic, Sisli Kolan International Hospital, 34384 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-3384","authenticated-orcid":false,"given":"Efthalia","family":"Angelopoulou","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0772-811X","authenticated-orcid":false,"given":"Vasiliki Epameinondas","family":"Georgakopoulou","sequence":"additional","affiliation":[{"name":"COVID-19 Unit, Department of Infectious Diseases, Laiko General Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-8711","authenticated-orcid":false,"given":"Anastasia","family":"Bougea","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","article-title":"Parkinson\u2019s disease: Clinical features and diagnosis","volume":"79","author":"Jankovic","year":"2008","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/mds.21813","article-title":"Nonmotor symptoms as presenting complaints in Parkinson\u2019s disease: A clinicopathological study","volume":"23","author":"Williams","year":"2008","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nrn.2017.62","article-title":"Non-motor features of Parkinson disease","volume":"18","author":"Schapira","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2045","DOI":"10.1212\/WNL.0000000000006576","article-title":"Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study","volume":"91","author":"Backstrom","year":"2018","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1177\/0891988716654985","article-title":"Parkinson Disease and Dementia","volume":"29","author":"Kramberger","year":"2016","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rissardo, J.P.C., and Caprara, A.L.F. (2023). Risk factors for Parkinson\u2019s disease dementia. Ann. Mov. Disord., 1\u20134.","DOI":"10.4103\/aomd.aomd_52_22"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/ana.23659","article-title":"Neuropathologic substrates of Parkinson disease dementia","volume":"72","author":"Irwin","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"743754","DOI":"10.3389\/fnagi.2021.743754","article-title":"Parkinson\u2019s Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron","volume":"13","author":"Han","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.parkreldis.2013.09.025","article-title":"The influence of age and gender on motor and non-motor features of early Parkinson\u2019s disease: Initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort","volume":"20","author":"Tomlinson","year":"2014","journal-title":"Park. Relat. Disord."},{"key":"ref_10","first-page":"1234","article-title":"Neuropathology of dementia in patients with Parkinson\u2019s disease: A systematic review of autopsy studies","volume":"90","author":"Smith","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.parkreldis.2016.03.006","article-title":"Longitudinal changes in cognition in early Parkinson\u2019s disease patients with REM sleep behavior disorder","volume":"27","author":"Chahine","year":"2016","journal-title":"Park. Relat. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101508","DOI":"10.1016\/j.arr.2021.101508","article-title":"Subjective cognitive decline in idiopathic Parkinson s disease: A systematic review","volume":"74","author":"Oedekoven","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nandipati, S., and Litvan, I. (2016). Environmental Exposures and Parkinson\u2019s Disease. Int. J. Environ. Res. Public Health, 13.","DOI":"10.3390\/ijerph13090881"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1007\/s00702-022-02511-7","article-title":"GBA-associated PD: Chances and obstacles for targeted treatment strategies","volume":"129","author":"Hoglinger","year":"2022","journal-title":"J. Neural Transm."},{"key":"ref_15","first-page":"349","article-title":"APOE, MAPT, and COMT and Parkinson\u2019s Disease Susceptibility and Cognitive Symptom Progression","volume":"6","author":"Paul","year":"2016","journal-title":"J. Park. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"620585","DOI":"10.3389\/fneur.2020.620585","article-title":"Association of SNCA Parkinson\u2019s Disease Risk Polymorphisms with Disease Progression in Newly Diagnosed Patients","volume":"11","author":"Szwedo","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1212\/WNL.0000000000000425","article-title":"CSF Abeta42 predicts early-onset dementia in Parkinson disease","volume":"82","author":"Alves","year":"2014","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1007\/s13311-020-00963-x","article-title":"Approach to Cognitive Impairment in Parkinson\u2019s Disease","volume":"17","author":"Zhang","year":"2020","journal-title":"Neurotherapeutics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1080\/13803395.2015.1073227","article-title":"Parkinson\u2019s disease dementia: Diagnostic criteria and risk factor review","volume":"37","author":"Vasconcellos","year":"2015","journal-title":"J. Clin. Exp. Neuropsychol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41572-021-00280-3","article-title":"Parkinson disease-associated cognitive impairment","volume":"7","author":"Aarsland","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.cger.2020.01.001","article-title":"Cognitive Impairment and Dementia in Parkinson Disease","volume":"36","author":"Goldman","year":"2020","journal-title":"Clin. Geriatr. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s11940-013-0281-2","article-title":"Treatment of psychosis and dementia in Parkinson\u2019s disease","volume":"16","author":"Goldman","year":"2014","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rissardo, J.P., Durante, I., Sharon, I., and Fornari Caprara, A.L. (2022). Pimavanserin and Parkinson\u2019s Disease Psychosis: A Narrative Review. Brain Sci., 12.","DOI":"10.3390\/brainsci12101286"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/23279095.2014.925902","article-title":"Subjective Cognitive Complaints in Parkinson Disease Without Dementia: A Preliminary Study","volume":"22","author":"Koster","year":"2015","journal-title":"Appl. Neuropsychol. Adult"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/ane.13158","article-title":"Subjective cognitive complaints in patients with Parkinson\u2019s disease","volume":"140","author":"Kjeldsen","year":"2019","journal-title":"Acta Neurol. Scand."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1177\/1533317518791401","article-title":"Mild Cognitive Impairment in Clinical Practice: A Review Article","volume":"33","author":"Jongsiriyanyong","year":"2018","journal-title":"Am. J. Alzheimers Dis. Other Dement."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1750-3639.2009.00369.x","article-title":"The epidemiology of dementia associated with Parkinson\u2019s disease","volume":"20","author":"Aarsland","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"943438","DOI":"10.3389\/fnagi.2022.943438","article-title":"Mild cognitive impairment in patients with Parkinson\u2019s disease: An updated mini-review and future outlook","volume":"14","author":"Yu","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"576091","DOI":"10.1155\/2013\/576091","article-title":"Mild cognitive impairment in Parkinson\u2019s disease: A review of current concepts","volume":"2013","author":"Palavra","year":"2013","journal-title":"Neurol. Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.parkreldis.2018.05.013","article-title":"Metabolic syndrome contributes to cognitive impairment in patients with Parkinson\u2019s disease","volume":"55","author":"Peng","year":"2018","journal-title":"Park. Relat. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/jnnp-2018-319008","article-title":"Cognitive decline in Parkinson\u2019s disease: The impact of the motor phenotype on cognition","volume":"90","author":"Wojtala","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/mds.26084","article-title":"Diagnosing PD-MCI by MDS Task Force criteria: How many and which neuropsychological tests?","volume":"30","author":"Goldman","year":"2015","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1212\/WNL.0b013e3182929f62","article-title":"White matter microstructure deteriorates across cognitive stages in Parkinson disease","volume":"80","author":"Melzer","year":"2013","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.3389\/fphys.2018.01093","article-title":"Abnormal Spontaneous Brain Activity in Early Parkinson\u2019s Disease with Mild Cognitive Impairment: A Resting-State fMRI Study","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Da Silva, F.C., Iop, R.D.R., de Oliveira, L.C., Boll, A.M., de Alvarenga, J.G.S., Gutierres Filho, P.J.B., de Melo, L., Xavier, A.J., and da Silva, R. (2018). Effects of physical exercise programs on cognitive function in Parkinson\u2019s disease patients: A systematic review of randomized controlled trials of the last 10 years. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193113"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3389\/fnagi.2019.00303","article-title":"Parkinson\u2019s Disease-Mild Cognitive Impairment (PD-MCI): A Useful Summary of Update Knowledge","volume":"11","author":"Cammisuli","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40035-016-0058-0","article-title":"Meta-analysis of risk factors for Parkinson\u2019s disease dementia","volume":"5","author":"Xu","year":"2016","journal-title":"Transl. Neurodegener."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0072-9752(07)83018-1","article-title":"Clinical features, pathophysiology and treatment of dementia associated with Parkinson\u2019s disease","volume":"83","author":"Emre","year":"2007","journal-title":"Handb. Clin. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1212\/WNL.54.6.1272","article-title":"APOE and the risk of PD with or without dementia in a population-based study","volume":"54","author":"Harhangi","year":"2000","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0197-4580(01)00269-X","article-title":"Parkinson\u2019s disease: The thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology","volume":"23","author":"Rub","year":"2002","journal-title":"Neurobiol. Aging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/mds.10565","article-title":"What causes mental dysfunction in Parkinson\u2019s disease?","volume":"18","author":"Emre","year":"2003","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1056\/NEJMoa041470","article-title":"Rivastigmine for dementia associated with Parkinson\u2019s disease","volume":"351","author":"Emre","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/mds.27602","article-title":"Update on treatments for nonmotor symptoms of Parkinson\u2019s disease\u2014An evidence-based medicine review","volume":"34","author":"Seppi","year":"2019","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S1474-4422(10)70194-0","article-title":"Memantine for patients with Parkinson\u2019s disease dementia or dementia with Lewy bodies: A randomised, double-blind, placebo-controlled trial","volume":"9","author":"Emre","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbr.2019.02.020","article-title":"A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects","volume":"364","author":"Tai","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.brainresbull.2017.05.015","article-title":"Ceftriaxone reverses deficits of behavior and neurogenesis in an MPTP-induced rat model of Parkinson\u2019s disease dementia","volume":"132","author":"Hsieh","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.bbr.2015.08.011","article-title":"Synergistic effects of ceftriaxone and erythropoietin on neuronal and behavioral deficits in an MPTP-induced animal model of Parkinson\u2019s disease dementia","volume":"294","author":"Huang","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1093\/hmg\/ddac038","article-title":"Ambroxol reverses tau and alpha-synuclein accumulation in a cholinergic N370S GBA1 mutation model","volume":"31","author":"Yang","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Novak, P., Pimentel Maldonado, D.A., and Novak, V. (2019). Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214364"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"118159","DOI":"10.1016\/j.lfs.2020.118159","article-title":"Intranasal insulin ameliorates cognitive impairment in a rat model of Parkinson\u2019s disease through Akt\/GSK3beta signaling pathway","volume":"259","author":"Yang","year":"2020","journal-title":"Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/mds.28389","article-title":"Long-Term Safety and Clinical Effects of Nilotinib in Parkinson\u2019s Disease","volume":"36","author":"Pagan","year":"2021","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108025","DOI":"10.1016\/j.intimp.2021.108025","article-title":"Nilotinib inhibits microglia-mediated neuroinflammation to protect against dopaminergic neuronal death in Parkinson\u2019s disease models","volume":"99","author":"Wu","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1212\/WNL.43.5.986","article-title":"The locus ceruleus and dementia in Parkinson\u2019s disease","volume":"43","author":"Zweig","year":"1993","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1212\/WNL.0b013e3181ebdd79","article-title":"Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease","volume":"75","author":"Weintraub","year":"2010","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/mds.22307","article-title":"Atomoxetine for the treatment of executive dysfunction in Parkinson\u2019s disease: A pilot open-label study","volume":"24","author":"Marsh","year":"2009","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/mdc3.12455","article-title":"A Randomized Clinical Trial of Atomoxetine for Mild Cognitive Impairment in Parkinson\u2019s Disease","volume":"4","author":"Hinson","year":"2017","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sun, C., and Armstrong, M.J. (2021). Treatment of Parkinson\u2019s Disease with Cognitive Impairment: Current Approaches and Future Directions. Behav. Sci., 11.","DOI":"10.3390\/bs11040054"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/bs.apha.2019.06.001","article-title":"Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders","volume":"86","author":"Svensson","year":"2019","journal-title":"Adv. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/mds.28879","article-title":"Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial","volume":"37","author":"Biglan","year":"2022","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1007\/s11064-023-03960-6","article-title":"Targeting Sigma-1 Receptor: A Promising Strategy in the Treatment of Parkinson\u2019s Disease","volume":"48","author":"Siddiqui","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/mds.26878","article-title":"First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers","volume":"32","author":"Schenk","year":"2017","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1001\/jamaneurol.2018.1487","article-title":"Safety and Tolerability of Multiple Ascending Doses of PRX002\/RG7935, an Anti-alpha-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial","volume":"75","author":"Jankovic","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"105511","DOI":"10.1016\/j.parkreldis.2023.105511","article-title":"Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6\/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial","volume":"114","author":"Fernandez","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_64","first-page":"2","article-title":"Targeting neurons in the gastrointestinal tract to treat Parkinson\u2019s disease","volume":"1","author":"Hauser","year":"2019","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1002\/mds.27962","article-title":"NYX-458 Improves Cognitive Performance in a Primate Parkinson\u2019s Disease Model","volume":"35","author":"Barth","year":"2020","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s13311-022-01325-5","article-title":"Fosgonimeton, a Novel Positive Modulator of the HGF\/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia","volume":"20","author":"Johnston","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1002\/mds.23738","article-title":"The effects of rasagiline on cognitive deficits in Parkinson\u2019s disease patients without dementia: A randomized, double-blind, placebo-controlled, multicenter study","volume":"26","author":"Hanagasi","year":"2011","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1176\/appi.neuropsych.15050118","article-title":"Cognitive Effects of Rasagiline in Mild-to-Moderate Stage Parkinson\u2019s Disease Without Dementia","volume":"29","author":"Frakey","year":"2017","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/WNF.0000000000000041","article-title":"Influence of the nonergot dopamine agonist piribedil on vigilance in patients With Parkinson Disease and excessive daytime sleepiness (PiViCog-PD): An 11-week randomized comparison trial against pramipexole and ropinirole","volume":"37","author":"Eggert","year":"2014","journal-title":"Clin. Neuropharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"897867","DOI":"10.3389\/fneur.2022.897867","article-title":"Distinct Bile Acid Signature in Parkinson\u2019s Disease With Mild Cognitive Impairment","volume":"13","author":"Nie","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.neuroscience.2022.02.028","article-title":"TGR5 Agonist INT-777 Alleviates Inflammatory Neurodegeneration in Parkinson\u2019s Disease Mouse Model by Modulating Mitochondrial Dynamics in Microglia","volume":"490","author":"Huang","year":"2022","journal-title":"Neuroscience"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Holanda, V.A.D., Didonet, J.J., Costa, M.B.B., do Nascimento Rangel, A.H., da Silva, E.D., and Gavioli, E.C. (2021). Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease. Pharmaceuticals, 14.","DOI":"10.3390\/ph14080775"},{"key":"ref_73","first-page":"3126","article-title":"Neuropeptide-S affects cognitive impairment and depression-like behavior on MPTP induced experimental mouse model of Parkinson\u2019s disease","volume":"51","author":"Ozkan","year":"2021","journal-title":"Turk. J. Med. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e2251","DOI":"10.1002\/brb3.2251","article-title":"Brain-derived neurotrophic factor attenuates cognitive impairment and motor deficits in a mouse model of Parkinson\u2019s disease","volume":"11","author":"Chang","year":"2021","journal-title":"Brain Behav."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1007\/s11064-021-03363-5","article-title":"Oral Administration of Silibinin Ameliorates Cognitive Deficits of Parkinson\u2019s Disease Mouse Model by Restoring Mitochondrial Disorders in Hippocampus","volume":"46","author":"Liu","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1039\/D2FO03825K","article-title":"Meta-analysis of randomized controlled trials of the effects of probiotics in Parkinson\u2019s disease","volume":"14","author":"Chu","year":"2023","journal-title":"Food Funct."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ishii, T., Furuoka, H., Kaya, M., and Kuhara, T. (2021). Oral Administration of Probiotic Bifidobacterium breve Improves Facilitation of Hippocampal Memory Extinction via Restoration of Aberrant Higher Induction of Neuropsin in an MPTP-Induced Mouse Model of Parkinson\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020167"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4641","DOI":"10.18632\/aging.102927","article-title":"Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson\u2019s disease models","volume":"12","author":"Castelli","year":"2020","journal-title":"Aging"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Park, J.S., Choe, K., Lee, H.J., Park, T.J., and Kim, M.O. (2023). Neuroprotective effects of osmotin in Parkinson\u2019s disease-associated pathology via the AdipoR1\/MAPK\/AMPK\/mTOR signaling pathways. J. Biomed. Sci., 30.","DOI":"10.1186\/s12929-023-00961-z"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.lfs.2019.02.037","article-title":"Cordycepin mitigates MPTP-induced Parkinson\u2019s disease through inhibiting TLR\/NF-kappaB signaling pathway","volume":"223","author":"Cheng","year":"2019","journal-title":"Life Sci."},{"key":"ref_81","first-page":"154649","article-title":"Cordycepin improved the cognitive function through regulating adenosine A(2A) receptors in MPTP induced Parkinson\u2019s disease mice model","volume":"110","author":"Huang","year":"2023","journal-title":"Phytomed. Int. J. Phytother. Phytopharm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"175970","DOI":"10.1016\/j.ejphar.2023.175970","article-title":"Huperzine A injection ameliorates motor and cognitive abnormalities via regulating multiple pathways in a murine model of Parkinson\u2019s disease","volume":"956","author":"Guo","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1007\/s12640-019-00151-6","article-title":"FGF21 Protects Dopaminergic Neurons in Parkinson\u2019s Disease Models Via Repression of Neuroinflammation","volume":"37","author":"Fang","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Yang, C., Wang, W., Deng, P., Wang, X., Zhu, L., Zhao, L., Li, C., and Gao, H. (CNS Neurosci. Ther., 2023). Fibroblast growth factor 21 ameliorates behavior deficits in Parkinson\u2019s disease mouse model via modulating gut microbiota and metabolic homeostasis, CNS Neurosci. Ther., ahead of print.","DOI":"10.1111\/cns.14302"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"152437","DOI":"10.1016\/j.tox.2020.152437","article-title":"Poloxamer 188-mediated anti-inflammatory effect rescues cognitive deficits in paraquat and maneb-induced mouse model of Parkinson\u2019s disease","volume":"436","author":"Ding","year":"2020","journal-title":"Toxicology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.neuropharm.2017.12.012","article-title":"Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson\u2019s disease","volume":"131","author":"Zhang","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.18632\/aging.101884","article-title":"Ginsenoside Rb1 prevents MPTP-induced changes in hippocampal memory via regulation of the alpha-synuclein\/PSD-95 pathway","volume":"11","author":"Qu","year":"2019","journal-title":"Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.freeradbiomed.2018.06.029","article-title":"Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson\u2019s disease model in mice","volume":"124","author":"Zhang","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s10787-017-0348-x","article-title":"Tangeretin inhibits neurodegeneration and attenuates inflammatory responses and behavioural deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson\u2019s disease dementia in rats","volume":"25","author":"Yang","year":"2017","journal-title":"Inflammopharmacology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"32","DOI":"10.9740\/mhc.2022.01.032","article-title":"Istradefylline: A novel agent in the treatment of \u201coff\u201d episodes associated with levodopa\/carbidopa use in Parkinson disease","volume":"12","author":"Cummins","year":"2022","journal-title":"Ment. Health Clin."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.neuropharm.2016.07.012","article-title":"An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models","volume":"110","author":"Ko","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"121711","DOI":"10.1016\/j.lfs.2023.121711","article-title":"Neuroprotective effect of Eugenia uniflora against intranasal MPTP-induced memory impairments in rats: The involvement of pro-BDNF\/p75(NTR) pathway","volume":"324","author":"Savall","year":"2023","journal-title":"Life Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1002\/ana.21461","article-title":"Why have we failed to achieve neuroprotection in Parkinson\u2019s disease?","volume":"64","author":"Olanow","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"810860","DOI":"10.3389\/fnagi.2022.810860","article-title":"The Disease Modification Conundrum in Parkinson\u2019s Disease: Failures and Hopes","volume":"14","author":"Mari","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_95","first-page":"263","article-title":"Rising to the Challenges of Clinical Trial Improvement in Parkinson\u2019s Disease","volume":"5","author":"Mathur","year":"2015","journal-title":"J. Park. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/mds.26662","article-title":"Biomarkers for dementia and mild cognitive impairment in Parkinson\u2019s disease","volume":"31","author":"Gago","year":"2016","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Angelopoulou, E., Papachristou, N., Bougea, A., Stanitsa, E., Kontaxopoulou, D., Fragkiadaki, S., Pavlou, D., Koros, C., Degirmenci, Y., and Papatriantafyllou, J. (2022). How Telemedicine Can Improve the Quality of Care for Patients with Alzheimer\u2019s Disease and Related Dementias? A Narrative Review. Medicina, 58.","DOI":"10.3390\/medicina58121705"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e040527","DOI":"10.1136\/bmjopen-2020-040527","article-title":"Azathioprine immunosuppression and disease modification in Parkinson\u2019s disease (AZA-PD): A randomised double-blind placebo-controlled phase II trial protocol","volume":"10","author":"Greenland","year":"2020","journal-title":"BMJ Open"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/59\/10\/1756\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:03:38Z","timestamp":1760130218000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/59\/10\/1756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,1]]},"references-count":98,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["medicina59101756"],"URL":"https:\/\/doi.org\/10.3390\/medicina59101756","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,1]]}}}