Proteomic Profiling of Cerebrospinal Fluid by 8-Plex iTRAQ Reveals Potential Biomarker Candidates of Alzheimer’s Disease

N Guerreiro,B Williamson,S Guertin,M Minkoff,B Gomez-Mancilla

doi:10.1007/s12014-009-9030-7

N Guerreiro, B Williamson + Show 3 more

Open Access

https://doi.org/10.1007/s12014-009-9030-7

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Journal: Clinical Proteomics	Publication Date: May 12, 2009
Citations: 54	License type: CC BY 2.0

Affiliation: Novartis (Switzerland)

Abstract

AbstractIntroductionAlzheimer’s disease (AD) poses specific challenges for drug development. It has a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost.DiscussionDeterminants of clinical course, such as molecular biomarkers, are urgently needed for early detection and diagnosis, or for prognosis and monitoring disease-modifying therapies in stratified patient populations. Due to its proximity to the brain and clinical availability, cerebrospinal fluid (CSF) is likely to have the highest yield of biomarker potential for neurodegenerative diseases. In this study, we examined the feasibility of using of an 8-plex isobaric tagging approach, coupled to two-dimensional liquid chromatography and tandem mass spectrometry using the matrix-assisted laser desorption/ionization time-of-flight/time-of-flight platform, for the discovery of potential biomarker candidates in CSF. Comparative analysis identified a number of statistically significant differences in the level of proteins when comparing AD to nondemented controls. Although the study is statistically underpowered to represent the disease population, the regulation of proteins with involvement in processes such as neuronal loss, synaptic dysfunction, neuroinflammation, and tissue degeneration and remodeling reflects the ability of our method in providing biologically meaningful CSF biomarkers as candidates for larger scale biomarker verification and validation studies.

Highlights

Alzheimer’s disease (AD) poses specific challenges for drug development
Promising is the measurement of antecedent molecular biomarkers in cerebrospinal fluid (CSF) that will identify those presymptomatic individuals with mild cognitive impairment (MCI) who will convert to AD
We described the utility of the platform as a tool for profiling the CSF proteome to allow the identification of protein differences between nondemented controls (NDC) and individuals diagnosed with probable AD that can be proposed as potentially biomarker candidates for further verification and validation studies

Summary

Introduction

Alzheimer’s disease (AD) poses specific challenges for drug development It has a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. There is sufficient evidence that characteristic changes in biochemistry are present long before the onset of clinical symptoms and that many patients with mild cognitive impairment (MCI) already have significant neuropathology in the early stage of AD. Promising is the measurement of antecedent molecular biomarkers in cerebrospinal fluid (CSF) that will identify those presymptomatic individuals with MCI who will convert to AD Such molecular biomarkers which reflect the neuropathology and are modifiable by treatment would provide invaluable support for disease modification claims [3,4,5,6]

Results

Discussion

Conclusion