Identification of SPARC-like 1 Protein as Part of a Biomarker Panel for Alzheimer's Disease in Cerebrospinal Fluid

Abstract

We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17).

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…Notably, keratin 9 was identified by multiple research groups in the cerebrospinal fluid and has been even proposed as a biomarker for AD [151–153]. Furthermore, keratin 1 was identified in 5xFAD mouse hippocampi using proteomics [154], and keratin 1 and 9 show different expression patterns in other neurodegenerative disorders [155].…”

Fibrin deposited in the Alzheimer's disease brain promotes neuronal degeneration

“…High levels of fibrinogen in plasma increase the risk for dementia (van Oijen et al, 2005; Xu et al, 2008), and fibrinogen in cerebrospinal fluid (Craig-Schapiro et al, 2011; Vafadar-Isfahani et al, 2012) and plasma (Thambisetty et al, 2011; Yang et al, 2014) has been proposed as a useful biomarker to identify AD progression. Interestingly, fibrinogen has recently been found to be one of the few blood-based biomarkers specific for AD and not for other brain disorders (Chiam et al, 2014).…”

A comprehensive map and functional annotation of the normal human cerebrospinal fluid proteome

“…Several proteomic studies have attempted to identify biomarkers in CSF [2][3][4][5]. However, to facilitate the process of biomarker identification, it is also important to study the normal CSF proteome because knowledge of the normal protein composition and concentration provides a baseline for comparison.…”