| 1. |
- Lashley, T., et al.
(författare)
-
Molecular biomarkers of Alzheimer's disease: progress and prospects
- 2018
-
Ingår i: Disease Models & Mechanisms. - : The Company of Biologists. - 1754-8403 .- 1754-8411. ; 11:5
-
Tidskriftsartikel (refereegranskat)abstract
- The neurodegenerative disorder Alzheimer's disease is characterised by the formation of beta-amyloid plaques and neurofibrillary tangles in the brain parenchyma, which cause synapse and neuronal loss. This leads to clinical symptoms, such as progressive memory deficits. Clinically, these pathological changes can be detected in the cerebrospinal fluid and with brain imaging, although reliable blood tests for plaque and tangle pathologies remain to be developed. Plaques and tangles often co-exist with other brain pathologies, including aggregates of transactive response DNA-binding protein 43 and Lewy bodies, but the extent to which these contribute to the severity of Alzheimer's disease is currently unknown. In this 'At a glance' article and poster, we summarise the molecular biornarkers that are being developed to detect Alzheimer's disease and its related pathologies. We also highlight the biornarkers that are currently in clinical use and include a critical appraisal of the challenges associated with applying these biornarkers for diagnostic and prognostic purposes of Alzheimer's disease and related neurodegenerative disorders, also in their prodromal clinical phases.
|
|
| 2. |
- Russell, C. L., et al.
(författare)
-
Combined tissue and fluid proteomics with Tandem Mass Tags to identify low-abundance protein biomarkers of disease in peripheral body fluid: An Alzheimer's Disease case study
- 2017
-
Ingår i: Rapid Communications in Mass Spectrometry. - : Wiley. - 0951-4198. ; 31:2, s. 153-159
-
Tidskriftsartikel (refereegranskat)abstract
- RationaleIdeal biomarkers are present in readily accessible samples including plasma and cerebrospinal fluid (CSF), and are directly derived from diseased tissue, therefore likely to be of relatively low abundance. Traditional unbiased proteomic approaches for biomarker discovery have struggled to detect low-abundance markers due to the high dynamic range of proteins, the predominance of hyper-abundant proteins, and the use of data-dependent acquisition mass spectrometry (MS). To overcome these limitations and improve biomarker discovery in peripheral fluids, we have developed TMTcalibrator; a novel MS workflow combining isobarically labelled diseased tissue digests in parallel with an appropriate set of labelled body fluids to increase the chance of identifying low-abundance, tissue-derived biomarkers. MethodsA disease relevant cell line was labelled with TMT (R) in a range of concentrations generating a multi-point calibration curve. Peripheral biofluid samples were labelled with the remaining tags and quantitative analysis was performed using an Orbitrap Fusion Tribrid mass spectrometer with a Top10 CID-HCD MS3 synchronous precursor selection (SPS) method. SPS allowed direct analysis of non-depleted, unfractionated CSF samples with complete profiling of six individual samples requiring only 15hours of MS time, equivalent to 1.5h per sample. ResultsUsing the TMTcalibrator workflow allowed the identification of several markers of microglia activation that are differentially quantified in the CSF of patients with Alzheimer's disease (AD). We report peptides from 41 proteins that have not previously been detected in the CSF, that appear to be regulated by at least 60% in AD. ConclusionsThis study has demonstrated the benefits of the new TMTcalibrator workflow and the results suggest this is a suitable and efficient method of detecting low-abundance peptides within biological fluids. The use of TMTcalibrator in further biomarker discovery studies should be considered to overcome some of the limitations commonly associated with more conventional approaches.
|
|
