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- Duits, F. H., et al.
(författare)
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Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer's disease
- 2018
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. Methods: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 +/- 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis x protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD). Results: There was a main effect for diagnosis (p < 0.01) and an interaction between diagnosis and protein (p < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; beta values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (beta = -0.93 [SE 0.22]) and control subjects (beta = 0.46 [SE 0.19]). Conclusions: Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.
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- Skillbäck, Tobias, et al.
(författare)
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A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.
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