Comparative proteomic profiling of cerebrospinal fluid between living and post mortem ALS and control subjects

Abstract

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), lack definitive diagnostic tests or biomarkers of disease progression. Most studies that investigate protein abnormalities in ALS have used biofluids such as blood or cerebrospinal fluid (CSF), while some have used post mortem tissue or CSF samples. Since ALS disease progression and post mortem effects probably induce significant alterations to protein modifications or proteolysis, we directly examined the CSF proteome from ALS subjects at various lengths of time from symptom onset and at autopsy by mass spectrometry based proteomics. CSF was also obtained from both healthy agematched control subjects and at autopsy from healthy and Alzheimer's disease (AD) controls. We identified significant differences in the CSF proteome between living and post mortem ALS subjects, as well as living and post mortem control subjects. We also noted differences in the CSF proteome of ALS subjects that have exhibited symptoms for varying lengths of time and between ALS and AD subjects at end-stage of disease. This is the first study describing differences in the CSF proteome from post mortem and living ALS subjects using a mass spectrometric approach. These differences highlight the importance of utilizing CSF from living ALS subjects near the time of symptom onset for the identification of early protein biomarkers, although some protein alterations that occur early in the disease process are maintained throughout the course of disease and in post mortem samples.

A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis

“…The biomarker panel distinguished ALS cases from neurologic disease controls, consistent with previous proteomic studies. 3,8 Our data expand the previous studies and show promise that a biomarker panel could be developed for aiding in the diagnosis of ALS. Future validation studies should incorporate samples from multiple clinics and from patients with syndromes that mimic ALS.…”

“…[2][3][4][5][6][7][8] While many of these studies have provided clues about pathogenetic mechanisms involved in the disease, most have examined only a small number of proteins. Several studies have examined proteomic profiles of patients with ALS compared to various control groups.…”

“…Several studies have examined proteomic profiles of patients with ALS compared to various control groups. [8][9][10] These proteomic studies have provided valuable examples of proteins that can distinguish patients with ALS from control groups, but most proteomic techniques are better suited for abundant proteins. We provide in this study an analysis of a panel of analytes that are associated with inflammation and trophic support that may more accurately reflect early stages of disease and cell response.…”

Muscle Gene Expression Is a Marker of Amyotrophic Lateral Sclerosis Severity

“…During the last few years, transcriptomics and proteomics studies have attempted to identify, from a global perspective, specific subsets of genes and proteins that might be used as surrogate markers of disease [9][10][11][12] . Although further validation is needed, these studies highlight that it is likely more appropriate to isolate a panel of markers, rather than a single gene or protein, in order to determine disease severity.…”

Proteomics Approach to Identify Biomarkers in Neurodegenerative Diseases

“…Another protein potentially useful as a biomarker is cystatin C, a 13.4 kDa protein exhibiting increased CSF levels in ALS patients over controls. This has been proposed in one comparative study that also found reduced transthyretin peaks in ALS patients over non-ALS controls (Ranganathan et al, 2007). CSF analysis seems a good approach for the discovery of important biomarkers for ALS, as it exhibits a reduced abundance of proteins that need to be excluded from the samples before proteomic analysis over serum/ plasma.…”