Uusi väitöstyö vanhasta dementia-asiasta! Uusi biomerkitsijä löytynyt

https://gupea.ub.gu.se/handle/2077/60288

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Biochemical markers in dementia - Exploring Swedish registry data and the human proteome

Titel:	Biochemical markers in dementia - Exploring Swedish registry data and the human proteome
Författare:	Skillbäck, Tobias
E-post:	tobias.skillback@gu.se
Utgivningsdatum:	4-sep-2019
Universitet:	University of Gothenburg. Sahlgrenska Academy
Institution:	Institute of Neuroscience and Physiology. Department of Psychiatry and Neurochemistry
Delarbeten:	I. Skillbäck T, Farahmand B Y, Rosén C, Mattsson N, Nägga K, Kilander L, Religa D, Wimo A, Winblad B, Schott J M, Blennow K, Eriksdotter M and Zetterberg H. Cerebrospinal fluid tau and amyloid–β1-42 in patients with dementia. Brain 2015, 138; 2716-2731 VISA ARTIKEL II. Skillbäck T, Farahmand B Y, Bartlett J W, Rosén C, Mattsson N, Nägga K, Kilander L, Religa D, Wimo A, Winblad B, Rosengren L, Schott J M, Blennow K, Eriksdotter M, and Zetterberg H. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology, 2014, 83:1945-1953 VISA ARTIKEL III. Skillbäck T, Rosén C, Asztely F, Mattsson N, Blennow K and Zetterberg H. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease – Results from the Swedish mortality registry. JAMA Neurology 2014, 71(4):476-483 VISA ARTIKEL IV. Skillbäck T, Mattson N, Hansson K, Mirgorodskaya E, Dahlén R, van der Flier W, Scheltens P, Duits F, Hansson O, Teunissen C, Blennow K, Zetterberg H and Gobom J. A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer’s disease. Scientific reports 2017, 7:13333 VISA ARTIKEL
Datum för disputation:	2019-09-26
Disputation:	Torsdagen den 26 september 2019, kl 13.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg
Examinationsnivå:	Doctor of Philosophy (Medicine)
Publikationstyp:	Doctoral thesis
Nyckelord:	Biomarkers Dementia Alzheimer's disease Vascular dementia Creutzfeldt Jakob disease Lewy body dementia Frontotemporal dementia Parkinson's disease dementia
Sammanfattning:	Cerebrospinal fluid (CSF) biomarkers of neurodegenerative diseases have a wide scope of applications in diagnostics, prognosis assessment, disease staging, treatment evaluation and more. In this PhD project we aimed to expand the understanding of the properties of known CSF biomarkers of Alzheimer’s disease (AD) and other neurodegenerative diseases, including the most prevalent dementia disorders.  In study I, we explored CSF concentrations of three hallmark biomarkers of AD (amyloid β 1-42 [Aβ1...  total tau [T-tau] and phosphorylated tau [P-tau]) in samples collected in clinical routine from 5676 patients. We found that the most clear-cut AD-like biomarker pattern was found in patients diagnosed with AD, but that large proportions of patients with other dementia disorders also had an AD-like profile. However, this was less often seen in the frontotemporal dementia (FTD) group.  In study II, we studied CSF concentrations of neurofilament light (NfL), a biomarker of general neurodegeneration, in 3356 patients with different dementia diagnoses. We found that CSF NfL is especially high in dementias with vascular engagement, but also in frontotemporal dementia. We also found that high CSF NfL concentrations are linked to short survival, which supports the notion that high CSF NfL indicates more aggressive disease processes.  In study III, the biomarkers T-tau and P-tau were evaluated as biomarkers of Creutzfeldt-Jakob disease (CJD), a rare rapid neurodegenerative disease. We could conclude that the combination of increased T-tau levels and increased T-tau/P-tau ratios in patients with CJD has a very high specificity against important differential diagnoses to CJD. We further concluded that CJD patients exhibit rising T-tau concentrations as the disease progresses.  In study IV, we developed a new strategy for analyzing data output from explorative mass spectrometry. We used a clustering algorithm to allow for higher efficiency and were able to prove the validity of this concept by identifying and validating a new biomarker of AD, a 16 amino acids long peptide from the protein pleiotrophin (PTN151-166). We concluded that quantification-driven proteomics aided by clustering is a viable way of hypothesis generation in biomarker discovery studies. We further concluded that PTN151-166 is a promising AD biomarker candidate that our data indicates to be AD specific and able to discriminate AD from other dementia pathologies at an early stage of disease. In conclusion, the results from the studies in this thesis demonstrate the diagnostic, prognostic and investigative properties of CSF biomarkers.
ISBN:	978-91-7833-525-1 (PDF) 978-91-7833-524-4 (PRINT)
URI:	http://hdl.handle.net/2077/60288
Samling:	Doctoral Theses from Sahlgrenska Academy Doctoral Theses from University of Gothenburg / Doktorsavhandlingar från Göteborgs universitet Doctoral Theses / Doktorsavhandlingar Institutionen för neurovetenskap och fysiologi