{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:17:44Z","timestamp":1788862664557,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"General Secretariat of Research and Innovation","award":["Grant 2018 E01300001"],"award-info":[{"award-number":["Grant 2018 E01300001"]}]},{"award":["Grant 2018 E01300001"],"award-info":[{"award-number":["Grant 2018 E01300001"]}],"id":[{"id":"https:\/\/ror.org\/001aqnf71","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait impairment, cognitive decline, and urinary dysfunction. Despite improvements in diagnostic criteria and neuroimaging techniques, accurate diagnosis remains challenging due to clinical overlap with neurodegenerative diseases, particularly Alzheimer\u2019s disease (AD) and synucleinopathies. Biomarkers capable of improving differential diagnosis, patient selection for shunt surgery, and prognostic assessment are therefore of considerable clinical interest, as has been in AD biomarkers. This review summarizes current evidence regarding the role of \u03b1-synuclein as a potential additional marker in iNPH, focusing on its association with concomitant neurodegenerative pathology, clinical manifestations, and treatment outcomes. Available studies indicate that \u03b1-synuclein pathology may coexist with iNPH in a substantial proportion of patients, with reported positivity rates ranging from approximately 14% to 33%, depending on the detection method used. Patients with concomitant \u03b1-synuclein pathology may exhibit clinical features atypical for pure iNPH, including upper limb rigidity, olfactory dysfunction, hallucinations, autonomic dysfunction, sleep disturbances, and fluctuating cognitive impairment. However, current evidence does not support \u03b1-synuclein positivity as an independent predictor of poor response to cerebrospinal fluid (CSF) drainage or shunt surgery. On the contrary, \u03b1-synuclein presence may provide additional information regarding mixed neurodegenerative pathology and contribute to personalized clinical management. Future studies should focus on standardized detection techniques, larger multicenter cohorts, longitudinal follow-up, and integration of \u03b1-synuclein assessment with established AD biomarkers, neuroimaging findings, and clinical evaluation. Overall, \u03b1-synuclein represents a promising complementary marker in iNPH, with potential value in being taken into consideration during clinical evaluation and understanding disease heterogeneity.<\/jats:p>","DOI":"10.3390\/diagnostics16182889","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:00:04Z","timestamp":1788861604000},"page":"2889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b1-Synuclein Pathology in Idiopathic Normal Pressure Hydrocephalus: Evidence for Concomitant Synucleinopathy and Clinical Implications"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2197-2434","authenticated-orcid":false,"given":"Efstratios-Stylianos","family":"Pyrgelis","sequence":"first","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2481-3060","authenticated-orcid":false,"given":"George P.","family":"Paraskevas","sequence":"additional","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"},{"name":"2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, \u201cAttikon\u201d University General Hospital, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7432-5009","authenticated-orcid":false,"given":"Vasilios C.","family":"Constantinides","sequence":"additional","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"},{"name":"1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-9465","authenticated-orcid":false,"given":"Fotini","family":"Boufidou","sequence":"additional","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Stefanis","sequence":"additional","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"},{"name":"1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Kapaki","sequence":"additional","affiliation":[{"name":"Neurochemistry and Biological Markers Unit, 1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Hydrocephalus and cerebrospinal fluid disorders","volume":"Volume 23","author":"Bradley","year":"2015","journal-title":"Magnetic Resonance Imaging Clinics of North America"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1227\/01.NEU.0000168185.29659.C5","article-title":"Diagnosing idiopathic normal-pressure hydrocephalus: INPH guidelines, Part II","volume":"57","author":"Relkin","year":"2005","journal-title":"Neurosurgery"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2176\/nmc.st.2020-0292","article-title":"Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus","volume":"61","author":"Nakajima","year":"2021","journal-title":"Neurol. Med.-Chir."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/ana.25046","article-title":"Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration","volume":"82","author":"Espay","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1227\/NEU.0000000000001093","article-title":"Symptoms of Depression are Common in Patients With Idiopathic Normal Pressure Hydrocephalus: The INPH-CRasH Study","volume":"78","author":"Israelsson","year":"2016","journal-title":"Neurosurgery"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1212\/WNL.0b013e31828c2fda","article-title":"Idiopathic normal-pressure hydrocephalus: Pathophysiology and diagnosis by CSF biomarkers","volume":"80","author":"Jeppsson","year":"2013","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1468-1331.2006.01593.x","article-title":"Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1\u201342 in idiopathic normal pressure hydrocephalus: A discrimination from Alzheimer\u2019s disease","volume":"14","author":"Kapaki","year":"2007","journal-title":"Eur. J. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pyrgelis, E.S., Boufidou, F., Constantinides, V.C., Papaioannou, M., Papageorgiou, S.G., Stefanis, L., Paraskevas, G.P., and Kapaki, E. (2022). Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review. Diagnostics, 12.","DOI":"10.3390\/diagnostics12122976"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pyrgelis, E.S., Paraskevas, G.P., Constantinides, V.C., Boufidou, F., Papaioannou, M., Stefanis, L., and Kapaki, E. (2023). Alzheimer\u2019s Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus. Brain Sci., 13.","DOI":"10.3390\/brainsci13111593"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pyrgelis, E.-S., Paraskevas, G.P., Constantinides, V.C., Boufidou, F., Stefanis, L., and Kapaki, E. (2024). In Vivo Prevalence of Beta-Amyloid Pathology and Alzheimer\u2019s Disease Co-Pathology in Idiopathic Normal-Pressure Hydrocephalus\u2014Association with Neuropsychological Features. Biomedicines, 12.","DOI":"10.3390\/biomedicines12081898"},{"key":"ref_11","first-page":"699","article-title":"The synaptic function of \u03b1-synuclein","volume":"5","year":"2015","journal-title":"J. Park. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/bpa.12370","article-title":"Alpha-Synuclein as a Biomarker for Parkinson\u2019s Disease","volume":"26","author":"Atik","year":"2016","journal-title":"Brain Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00702-012-0784-0","article-title":"\u03b1-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system","volume":"119","author":"Mollenhauer","year":"2012","journal-title":"J. Neural Transm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1007\/s00415-021-10778-1","article-title":"Comorbid alpha synucleinopathies in idiopathic normal pressure hydrocephalus","volume":"269","author":"Sakurai","year":"2022","journal-title":"J. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/ana.26505","article-title":"Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus","volume":"92","author":"Fasano","year":"2022","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12987-022-00368-2","article-title":"In vivo assessment of Lewy body and beta-amyloid copathologies in idiopathic normal pressure hydrocephalus: Prevalence and associations with clinical features and surgery outcome","volume":"19","author":"Giannini","year":"2022","journal-title":"Fluids Barriers CNS"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1002\/mds.30184","article-title":"Anosmia and Upper Limb Rigidity\u2014A Potential Phenotype of Idiopathic Normal Pressure Hydrocephalus with Cerebrospinal Fluid \u03b1-Synuclein Seeds","volume":"40","author":"Weber","year":"2025","journal-title":"Mov. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107857","DOI":"10.1016\/j.parkreldis.2025.107857","article-title":"Prevalence and clinical impact of alpha-synuclein pathology in idiopathic normal pressure hydrocephalus: Insights from RT-QuIC assay","volume":"136","author":"Yu","year":"2025","journal-title":"Park. Relat. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wluka, V.A., Despenza, T., Liu, A.J., and Bramall, A.N. (2026). Refining the diagnostic evaluation of idiopathic normal pressure hydrocephalus with Alzheimer\u2019s and \u03b1-synuclein biomarkers. Front. Neurol., 17.","DOI":"10.3389\/fneur.2026.1736687"},{"key":"ref_21","first-page":"699","article-title":"CSF alpha-Synuclein Seed Amplification Assay results in routine clinically collected samples","volume":"16","author":"Dinter","year":"2026","journal-title":"J. Park. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.neubiorev.2020.02.023","article-title":"Neural circuits of idiopathic Normal Pressure Hydrocephalus: A perspective review of brain connectivity and symptoms meta-analysis","volume":"112","author":"Griffa","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/3-211-32318-X_48","article-title":"Guidelines for management of idiopathic normal pressure hydrocephalus: Progress to date","volume":"95","author":"Marmarou","year":"2005","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.parkreldis.2006.08.007","article-title":"Gait disturbance in normal pressure hydrocephalus: A clinical study","volume":"13","author":"Bugalho","year":"2007","journal-title":"Park. Relat. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1016\/S1388-2457(00)00362-X","article-title":"Gait analysis in idiopathic normal pressure hydrocephalus\u2014Which parameters respond to the CSF tap test?","volume":"111","author":"Stolze","year":"2000","journal-title":"Clin. Neurophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E15","DOI":"10.3171\/2016.6.FOCUS16183","article-title":"Bulbar dysfunction in normal pressure hydrocephalus: A prospective study","volume":"41","author":"Chankaew","year":"2016","journal-title":"Neurosurg. Focus"},{"key":"ref_27","first-page":"e34579","article-title":"Bulbar Dysfunction in Idiopathic Normal Pressure Hydrocephalus: A Case Report","volume":"15","author":"Usama","year":"2023","journal-title":"Cureus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22744","DOI":"10.1038\/s41598-024-72559-w","article-title":"Association between idiopathic normal pressure hydrocephalus and Alzheimer\u2019s disease: A bidirectional Mendelian randomization study","volume":"14","author":"Hu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41531-023-00473-5","article-title":"A comparative blind study between skin biopsy and seed amplification assay to disclose pathological \u03b1-synuclein in RBD","volume":"9","author":"Liguori","year":"2023","journal-title":"npj Park. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e70435","DOI":"10.1111\/jnc.70435","article-title":"Seed Amplification Assays for Parkinson\u2019s Disease: A Review of \u03b1-Synuclein Assays in Body Fluids and Tissues","volume":"170","author":"Kong","year":"2026","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4315","DOI":"10.1007\/s00330-024-11320-3","article-title":"Associations of ventriculomegaly and white matter hyperintensities with glymphatic dysfunction in idiopathic normal pressure hydrocephalus","volume":"35","author":"Wu","year":"2025","journal-title":"Eur. Radiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hiraldo-Gonz\u00e1lez, L., Trillo-Contreras, J.L., Garc\u00eda-Miranda, P., Pineda-S\u00e1nchez, R., Ram\u00edrez-Lorca, R., Rodrigo-Herrero, S., Blanco, M.O., Oliver, M., Bernal, M., and Franco-Mac\u00edas, E. (2021). Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0258165"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/18\/2889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:06:25Z","timestamp":1788861985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/18\/2889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":32,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["diagnostics16182889"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16182889","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]}}}