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

Doctoral thesis
Authors Tobias Skillbäck
Date of public defense 2019-09-26
Opponent at public defense Jon Snaedal
ISBN 978-91-7833-525-1 (PDF); 978-91-7833-524-4 (TRYCK)
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Language en
Keywords Biomarkers, Dementia, Alzheimer's disease, Vascular dementia, Creutzfeldt Jakob disease, Lewy body dementia, Frontotemporal dementia, Parkinson's disease dementia
Subject categories Neurochemistry

Abstract

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 [Aβ1-42], 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.

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