{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:12:47Z","timestamp":1792613567759,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010438","name":"Pozna\u0144 University of Medical Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010438","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02zbb2597","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait disturbance, cognitive impairment, and urinary incontinence; however, its diagnosis and prediction of shunt responsiveness remain challenging. This systematic review aimed to synthesize current evidence on cerebrospinal fluid (CSF) proteomic biomarkers in iNPH and to identify molecular patterns with diagnostic and prognostic relevance. A PRISMA-guided search of PubMed, Web of Science, and Google Scholar identified 14 eligible studies comprising 1171 iNPH patients. Proteomic analyses revealed substantial heterogeneity in study design and detected proteins; however, consistent patterns emerged. iNPH is associated with upregulation of inflammatory and extracellular matrix-related proteins and relative downregulation of synaptic and neuronal markers. Neurodegenerative proteins, including amyloid-\u03b2, tau, and neurofilament light chain, demonstrated value in differentiating iNPH from comorbid neurodegenerative diseases and in predicting response to ventriculoperitoneal shunting (VPS). These findings support a multifactorial model of iNPH involving impaired glymphatic clearance, neuroinflammation, blood\u2013brain barrier dysfunction, and mechanical axonal stress. Multidimensional biomarker profiles, rather than single proteins, appear to provide the greatest clinical utility, highlighting the need for standardized proteomic panels and integrative predictive models. However, given the substantial heterogeneity of the included studies and the predominantly exploratory nature of current proteomic evidence, the identified proteins should be interpreted as candidate biomarkers rather than clinically validated diagnostic or prognostic tools. Multidimensional biomarker profiles appear biologically plausible and may offer greater explanatory value than single proteins, but their clinical utility requires validation in standardized prospective cohorts. The authors therefore propose a conceptual iNPH proteomic \u201cVulnerability Model\u201d integrating CSF biomarkers to reflect the balance between reversible and irreversible pathology; this is currently a hypothetical model that requires rigorous statistical and clinical validation through large-scale prospective cohort studies before it can fulfill its potential for improving patient stratification and prediction of postoperative outcomes.<\/jats:p>","DOI":"10.3390\/molecules31132319","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:04:44Z","timestamp":1782986684000},"page":"2319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decoding the CSF Proteomic Signature of Idiopathic Normal Pressure Hydrocephalus: A Systematic Review"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6673-4145","authenticated-orcid":false,"given":"Aleksandra","family":"Kwiecie\u0144","sequence":"first","affiliation":[{"name":"Department of Neurology, Municipal Hospital in Pozna\u0144, 3 Szwajcarska Street, 61-285 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4388-9390","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Dudzic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Municipal Hospital in Pozna\u0144, 3 Szwajcarska Street, 61-285 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Lema\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Municipal Hospital in Pozna\u0144, 3 Szwajcarska Street, 61-285 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"Kalka","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Pozna\u0144 University of Medical Sciences, 10 Fredry Street, 61-701 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Dru\u017cd\u017c","sequence":"additional","affiliation":[{"name":"Department of Neurology, Municipal Hospital in Pozna\u0144, 3 Szwajcarska Street, 61-285 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6166-9424","authenticated-orcid":false,"given":"Katarzyna","family":"Hojan","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, Pozna\u0144 University of Medical Sciences, 6 \u015awi\u0119cickiego Steet, 60-781 Pozna\u0144, Poland"},{"name":"Department of Rehabilitation, Greater Poland Cancer Center, 15 Garbary Street, 61-866 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9306-0242","authenticated-orcid":false,"given":"Giorgio","family":"Palandri","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences of Bologna, Scientific Institute for Research, Hospitalization and Care, Bellaria Hospital, 3 Via Altura, 40139 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-2000","authenticated-orcid":false,"given":"Bartosz","family":"Sok\u00f3\u0142","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Municipal Hospital in Pozna\u0144, 3 Szwajcarska Street, 61-285 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-024-00561-5","article-title":"Molecular Signatures of Normal Pressure Hydrocephalus: A Large-Scale Proteomic Analysis of Cerebrospinal Fluid","volume":"21","author":"Kamalian","year":"2024","journal-title":"Fluids Barriers CNS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-023-00440-5","article-title":"Novel Cerebrospinal Fluid Biomarkers Correlating with Shunt Responsiveness in Patients with Idiopathic Normal Pressure Hydrocephalus","volume":"20","author":"Weiner","year":"2023","journal-title":"Fluids Barriers CNS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.jare.2025.04.043","article-title":"Proteomic Profiling in Cerebrospinal Fluid Reveal Biomarkers for Shunt Outcome in Idiopathic Normal-Pressure Hydrocephalus","volume":"80","author":"Ying","year":"2025","journal-title":"J. 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