{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:01:24Z","timestamp":1791907284252,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2017-0622"],"award-info":[{"award-number":["2017-0622"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer\u2019s disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography\u2013tandem mass spectrometry (LC\u2013MS\/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up.<\/jats:p>","DOI":"10.3390\/ijms22158034","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T12:18:31Z","timestamp":1627388311000},"page":"8034","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-3325","authenticated-orcid":false,"given":"Enrica","family":"Torretta","sequence":"first","affiliation":[{"name":"IRCCS Istituto Ortopedico Galeazzi, Via Galeazzi 4, 20161 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-3580","authenticated-orcid":false,"given":"Beatrice","family":"Arosio","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, Via Pace 9, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6230-8663","authenticated-orcid":false,"given":"Pietro","family":"Barbacini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, Via F.lli Cervi 93, Segrate, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-728X","authenticated-orcid":false,"given":"Daniele","family":"Capitanio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, Via F.lli Cervi 93, Segrate, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1202-5454","authenticated-orcid":false,"given":"Paolo Dionigi","family":"Rossi","sequence":"additional","affiliation":[{"name":"Fondazione Ca\u2019 Granda, IRCCS Ospedale Maggiore Policlinico, Via F.lli Cervi 93, Segrate, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-0307","authenticated-orcid":false,"given":"Manuela","family":"Moriggi","sequence":"additional","affiliation":[{"name":"Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-6191","authenticated-orcid":false,"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi, Via Capacelatro 66, 20148 Milan, Italy"},{"name":"Department of Physiopathology and Transplants, University of Milan, Via Sforza 35, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Mari","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Auxologico Italiano, Via Mercalli 28, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cesari","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, Via Pace 9, 20122 Milan, Italy"},{"name":"Geriatric Unit, IRCCS Istituti Scientifici Maugeri, Via Camaldoli 64, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2996-6912","authenticated-orcid":false,"given":"Cecilia","family":"Gelfi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Ortopedico Galeazzi, Via Galeazzi 4, 20161 Milan, Italy"},{"name":"Department of Biomedical Sciences for Health, University of Milan, Via F.lli Cervi 93, Segrate, 20090 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S203","DOI":"10.3233\/JAD-2012-112216","article-title":"The Alzheimer myth and biomarker research in dementia","volume":"31","author":"Richard","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1016\/j.wneu.2015.07.005","article-title":"Epidemiology of Idiopathic Normal Pressure Hydrocephalus: A Systematic Review of the Literature","volume":"84","year":"2015","journal-title":"World Neurosurg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/S1474-4422(03)00487-3","article-title":"Alzheimer\u2019s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: A hypothesis","volume":"2","author":"Silverberg","year":"2003","journal-title":"Lancet. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1212\/WNL.0000000000002369","article-title":"Vascular factors in suspected normal pressure hydrocephalus: A population-based study","volume":"86","author":"Jaraj","year":"2016","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/brain\/awh178","article-title":"Normal pressure hydrocephalus (NPH): Ischaemia, CSF stagnation or both","volume":"127","author":"Silverberg","year":"2004","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/ana.22015","article-title":"Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology","volume":"68","author":"Hamilton","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"312526","DOI":"10.4061\/2011\/312526","article-title":"Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus","volume":"2011","author":"Leinonen","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1600-0404.2007.00890.x","article-title":"CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus","volume":"116","author":"Lekman","year":"2007","journal-title":"Acta Neurol. Scand."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1046\/j.1440-1819.2000.00658.x","article-title":"Tau protein is a potential biological marker for normal pressure hydrocephalus","volume":"54","author":"Kudo","year":"2000","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1136\/jnnp-2019-320826","article-title":"CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics","volume":"90","author":"Jeppsson","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nrm.2017.107","article-title":"Sphingolipids and their metabolism in physiology and disease","volume":"19","author":"Hannun","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170069","DOI":"10.1098\/rsob.170069","article-title":"Sphingolipids: Membrane microdomains in brain development, function and neurological diseases","volume":"7","author":"Olsen","year":"2017","journal-title":"Open Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fania, C., Arosio, B., Capitanio, D., Torretta, E., Gussago, C., Ferri, E., Mari, D., and Gelfi, C. (2017). Protein signature in cerebrospinal fluid and serum of Alzheimer\u2019s disease patients: The case of apolipoprotein A-1 proteoforms. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179280"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13639","DOI":"10.1038\/s41598-018-31756-0","article-title":"Particular CSF sphingolipid patterns identify iNPH and AD patients","volume":"8","author":"Torretta","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3233\/JAD-170186","article-title":"Cerebrospinal Fluid Amyloid-beta 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer\u2019s Disease","volume":"60","author":"Santangelo","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.3233\/JAD-190334","article-title":"Predicting Development of Alzheimer\u2019s Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus","volume":"71","author":"Luikku","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.bbalip.2016.08.016","article-title":"Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species","volume":"1861","author":"Montgomery","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.1074\/jbc.M112.402719","article-title":"Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain","volume":"288","author":"Zigdon","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/hmg\/ddt468","article-title":"Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration","volume":"23","author":"Vitner","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.wneu.2015.10.069","article-title":"Incidence of Idiopathic Normal-Pressure Hydrocephalus in Northern Spain","volume":"87","year":"2016","journal-title":"World Neurosurg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S1474-4422(16)00067-3","article-title":"Sex differences in Alzheimer\u2019s disease and other dementias","volume":"15","author":"Mazure","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ddtec.2016.07.002","article-title":"Altered blood-brain barrier transport in neuro-inflammatory disorders","volume":"20","author":"Schenk","year":"2016","journal-title":"Drug Discov. Today Technol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00281-017-0662-9","article-title":"Complement in the pathogenesis of Alzheimer\u2019s disease","volume":"40","author":"Morgan","year":"2018","journal-title":"Semin. Immunopathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1042\/CS20020362","article-title":"Beyond lysis: How complement influences cell fate","volume":"104","author":"Cole","year":"2003","journal-title":"Clin. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.4049\/jimmunol.1301673","article-title":"Complement activation by ceramide transporter proteins","volume":"192","author":"Bode","year":"2014","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.cca.2015.04.010","article-title":"Afamin\u2014A pleiotropic glycoprotein involved in various disease states","volume":"446","author":"Dieplinger","year":"2015","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic inflammation in the etiology of disease across the life span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Han, X., Rozen, S., Boyle, S.H., Hellegers, C., Cheng, H., Burke, J.R., Welsh-Bohmer, K.A., Doraiswamy, P.M., and Kaddurah-Daouk, R. (2011). Metabolomics in early Alzheimer\u2019s disease: Identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021643"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pujol-Lereis, L.M. (2019). Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143564"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1016\/j.neurobiolaging.2014.05.019","article-title":"Cerebrospinal fluid sphingolipids, beta-amyloid, and tau in adults at risk for Alzheimer\u2019s disease","volume":"35","author":"Mielke","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3233\/JAD-200964","article-title":"Cerebrospinal Fluid C18 Ceramide Associates with Markers of Alzheimer\u2019s Disease and Inflammation at the Pre- and Early Stages of Dementia","volume":"81","author":"Teitsdottir","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1096\/fj.201700300R","article-title":"Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes","volume":"32","author":"Law","year":"2018","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3389\/fnmol.2017.00063","article-title":"APP Function and Lipids: A Bidirectional Link","volume":"10","author":"Grimm","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.jamda.2018.11.014","article-title":"Repeated Cerebrospinal Fluid Removal Procedure in Older Patients With Idiopathic Normal Pressure Hydrocephalus Ineligible for Surgical Treatment","volume":"20","author":"Rossi","year":"2019","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/S1474-4422(14)70090-0","article-title":"Advancing research diagnostic criteria for Alzheimer\u2019s disease: The IWG-2 criteria","volume":"13","author":"Dubois","year":"2014","journal-title":"Lancet. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Barbacini, P., Casas, J., Torretta, E., Capitanio, D., Maccallini, G., Hirschler, V., and Gelfi, C. (2019). Regulation of Serum Sphingolipids in Andean Children Born and Living at High Altitude (3775 m). Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112835"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/pmic.200700683","article-title":"Design and analysis issues in quantitative proteomics studies","volume":"7","author":"Karp","year":"2007","journal-title":"Proteomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1021\/pr050084g","article-title":"Impact of replicate types on proteomic expression analysis","volume":"4","author":"Karp","year":"2005","journal-title":"J. Proteome Res."},{"key":"ref_40","first-page":"395","article-title":"Genome-wide prediction and analysis of function-specific transcription factor binding sites","volume":"4","author":"Long","year":"2004","journal-title":"Silico Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8034\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:35:51Z","timestamp":1760164551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,27]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22158034"],"URL":"https:\/\/doi.org\/10.3390\/ijms22158034","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,27]]}}}