{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T15:33:30Z","timestamp":1760369610641,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T00:00:00Z","timestamp":1585094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente"],"award-info":[{"award-number":["Ricerca Corrente"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Federal Ministry of Education and Research","award":["FTLDc 01GI1007A"],"award-info":[{"award-number":["FTLDc 01GI1007A"]}]},{"name":"EU Joint Programme - Neurodegenerative Disease Research (JPND) networks","award":["PreFrontAls, Genfi-Prox (01ED1512)"],"award-info":[{"award-number":["PreFrontAls, Genfi-Prox (01ED1512)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer\u2019s disease (AD) and Creutzfeldt\u2013Jakob disease (CJD). However, to date, no study explored this biomarker across the heterogeneous spectrum of prion disease. Using a liquid chromatography\u2212multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with prion disease (n = 84), AD (n = 38), and frontotemporal dementia (FTD) (n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits. Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median protein values similar to controls. The biomarker showed a good to optimal accuracy in the differential diagnosis between NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes, sporadic CJD VV2 demonstrated significantly higher levels of CSF ubiquitin and more numerous brain ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF ubiquitin correlated with biomarkers of neurodegeneration and astrogliosis in NDs, and was associated with disease stage but not with survival in prion disease. The differential increase of CSF free monoubiquitin in prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and neuroinflammation.<\/jats:p>","DOI":"10.3390\/biom10040497","type":"journal-article","created":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T13:10:47Z","timestamp":1585141847000},"page":"497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CSF Ubiquitin Levels Are Higher in Alzheimer\u2019s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0631-8506","authenticated-orcid":false,"given":"Samir","family":"Abu-Rumeileh","sequence":"first","affiliation":[{"name":"Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40138 Bologna, Italy"},{"name":"Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-7023","authenticated-orcid":false,"given":"Patrick","family":"Oeckl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40138 Bologna, Italy"},{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Halbgebauer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Steinacker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[{"name":"Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40138 Bologna, Italy"},{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-4267","authenticated-orcid":false,"given":"Markus","family":"Otto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"},{"name":"Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/s41593-018-0238-6","article-title":"Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases","volume":"21","author":"Jucker","year":"2018","journal-title":"Nat Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1602\/neurorx.1.2.213","article-title":"Cerebrospinal fluid protein biomarkers for Alzheimer\u2019s disease","volume":"1","author":"Blennow","year":"2004","journal-title":"NeuroRx"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/pmic.200900246","article-title":"Ubiquitin as potential cerebrospinal fluid marker of Creutzfeldt-Jakob disease","volume":"10","author":"Steinacker","year":"2010","journal-title":"Proteomics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4518","DOI":"10.1021\/pr5006058","article-title":"Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer\u2019s disease and frontotemporal lobar degeneration","volume":"13","author":"Oeckl","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_5","first-page":"11","article-title":"Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer\u2019s Disease and Parkinsonian Disorders","volume":"11","author":"Hansson","year":"2017","journal-title":"Proteomics Clin Appl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13195-019-0533-9","article-title":"Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer\u2019s and Parkinson\u2019s disease","volume":"11","author":"Brinkmalm","year":"2019","journal-title":"Alzheimers Res Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1093\/jb\/mvq044","article-title":"Regulatory mechanisms involved in the control of ubiquitin homeostasis","volume":"147","author":"Kimura","year":"2010","journal-title":"J. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/0006-8993(91)91692-T","article-title":"Brain ubiquitin is markedly elevated in Alzheimer disease","volume":"566","author":"Wang","year":"1991","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(94)91757-4","article-title":"Alzheimer disease: Correlation of cerebro-spinal fluid and brain ubiquitin levels","volume":"639","author":"Kudo","year":"1994","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1189\/jlb.0510316","article-title":"Extracellular ubiquitin: Immune modulator and endogenous opponent of damage-associated molecular pattern molecules","volume":"89","author":"Majetschak","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/ana.20639","article-title":"Subgroups of Alzheimer\u2019s disease based on cerebrospinal fluid molecular markers","volume":"58","author":"Iqbal","year":"2005","journal-title":"Ann Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/bpa.12695","article-title":"Recent advances in the histo-molecular pathology of human prion disease","volume":"29","author":"Baiardi","year":"2019","journal-title":"Brain Pathol."},{"key":"ref_13","first-page":"2","article-title":"CSF biomarkers of neuroinflammation in distinct forms and subtypes of neurodegenerative dementia","volume":"12","author":"Steinacker","year":"2019","journal-title":"Alzheimers Res Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Abu-Rumeileh, S., Halbgebauer, S., Steinacker, P., Anderl-Straub, S., Polischi, B., Ludolph, A.C., Capellari, S., Parchi, P., and Otto, M. (2020). CSF SerpinA1 in Creutzfeldt-Jakob disease and frontotemporal lobar degeneration. Ann. Clin. Transl. Neurol.","DOI":"10.1002\/acn3.50980"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/B978-0-444-63945-5.00009-X","article-title":"Sporadic Creutzfeldt-Jakob disease","volume":"153","author":"Zerr","year":"2018","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/1531-8249(199908)46:2<224::AID-ANA12>3.0.CO;2-W","article-title":"Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects","volume":"46","author":"Parchi","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00401-012-1002-8","article-title":"Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: An inter-rater study among surveillance centres in Europe and USA","volume":"124","author":"Parchi","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00415-006-0472-9","article-title":"Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis","volume":"254","author":"Green","year":"2007","journal-title":"J. Neurol."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1093\/brain\/awr179","article-title":"Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia","volume":"134","author":"Rascovsky","year":"2011","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","article-title":"Classification of primary progressive aphasia and its variants","volume":"76","author":"Hillis","year":"2011","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/21678421.2016.1267768","article-title":"Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria","volume":"18","author":"Strong","year":"2017","journal-title":"Amyotroph. Lateral Scler. Frontotemporal. Degener."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1212\/WNL.0b013e31827f0fd1","article-title":"Criteria for the diagnosis of corticobasal degeneration","volume":"80","author":"Armstrong","year":"2013","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1002\/mds.26987","article-title":"Movement Disorder Society-endorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria","volume":"32","author":"Respondek","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3233\/JAD-180409","article-title":"Cerebrospinal Fluid Biomarkers in Patients with Frontotemporal Dementia Spectrum: A Single-Center Study","volume":"66","author":"Mometto","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/mds.27872","article-title":"Movement Disorder Society-Endorsed Progressive Supranuclear Palsy Study Group. Validation of the movement disorder society criteria for the diagnosis of 4-repeat tauopathies","volume":"35","author":"Respondek","year":"2020","journal-title":"Mov Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s00401-017-1683-0","article-title":"Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: Diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A\u03b242 levels","volume":"133","author":"Lattanzio","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.1038\/s41598-017-10922-w","article-title":"High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions","volume":"7","author":"Franceschini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","first-page":"249","article-title":"Transient ischemia depletes free ubiquitin in the gerbil hippocampal CA1 neurons","volume":"148","author":"Morimoto","year":"1996","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s00702-014-1304-1","article-title":"Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: An inter-laboratory study by the BrainNet Europe consortium","volume":"122","author":"Alafuzoff","year":"2015","journal-title":"J. Neural. Transm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1093\/brain\/awh249","article-title":"Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies","volume":"127","author":"Pocchiari","year":"2004","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Staffaroni, A.M., Kramer, A.O., Casey, M., Kang, H., Rojas, J.C., Orr\u00fa, C.D., Caughey, B., Allen, I.E., Kramer, J.H., and Rosen, H.J. (2019). Association of Blood and Cerebrospinal Fluid Tau Level and Other Biomarkers With Survival Time in Sporadic Creutzfeldt-Jakob Disease. JAMA Neurol.","DOI":"10.1001\/jamaneurol.2019.1071"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13195-017-0331-1","article-title":"The CSF neurofilament light signature in rapidly progressive neurodegenerative dementias","volume":"10","author":"Capellari","year":"2018","journal-title":"Alzheimers Res Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1136\/jnnp-2017-315942","article-title":"Towards an early clinical diagnosis of sporadic CJD VV2 (ataxic type)","volume":"88","author":"Baiardi","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1111\/nan.12461","article-title":"Regional pattern of microgliosis in sporadic Creutzfeldt-Jakob disease in relation to phenotypic variants and disease progression","volume":"44","author":"Franceschini","year":"2018","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5009","DOI":"10.1007\/s12035-018-1421-1","article-title":"Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease","volume":"56","author":"Corrado","year":"2019","journal-title":"Mol Neurobiol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/497\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:11:25Z","timestamp":1760173885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,25]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["biom10040497"],"URL":"https:\/\/doi.org\/10.3390\/biom10040497","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2020,3,25]]}}}