Toward a Predictive Model of Alzheimer’s Disease Progression Using Capillary Electrophoresis–Mass Spectrometry Metabolomics

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia with an estimated worldwide prevalence of over 30 million people, and its incidence is expected to increase dramatically with an increasing elderly population. Up until now, cerebrospinal fluid (CSF) has been the preferred sample to investigate central nervous system (CNS) disorders since its composition is directly related to metabolite production in the brain. In this work, a nontargeted metabolomic approach based on capillary electrophoresis-mass spectrometry (CE-MS) is developed to examine metabolic differences in CSF samples from subjects with different cognitive status related to AD progression. To do this, CSF samples from 85 subjects were obtained from patients with (i) subjective cognitive impairment (SCI, i.e. control group), (ii) mild cognitive impairment (MCI) which remained stable after a follow-up period of 2 years, (iii) MCI which progressed to AD within a 2-year time after the initial MCI diagnostic and, (iv) diagnosed AD. A prediction model for AD progression using multivariate statistical analysis based on CE-MS metabolomics of CSF samples was obtained using 73 CSF samples. Using our model, we were able to correctly classify 97-100% of the samples in the diagnostic groups. The prediction power was confirmed in a blind small test set of 12 CSF samples, reaching a 83% of diagnostic accuracy. The obtained predictive values were higher than those reported with classical CSF AD biomarkers (Aβ42 and tau) but need to be confirmed in larger samples cohorts. Choline, dimethylarginine, arginine, valine, proline, serine, histidine, creatine, carnitine, and suberylglycine were identified as possible disease progression biomarkers. Our results suggest that CE-MS metabolomics of CSF samples can be a useful tool to predict AD progression.

UPLC-based metabonomic applications for discovering biomarkers of diseases in clinical chemistry

“…Lysine, is a strictly ketogenic amino acid that is required for the synthesis of L-carnitine. L-Carnitine is the sole transporter of fatty acids to mitochondria for energy production and carnitine level has been shown to be lower in CSF of MIC-AD and AD patients than in CSF from non-AD subjects [98].…”

Training in metabolomics research. I. Designing the experiment, collecting and extracting samples and generating metabolomics data

“…While CE-MS is very effective for hydrophilic metabolites, it is also possible to perform the electrophoresis using capillaries packed with a reverse-phase packing. [91] Direct use of cerebrospinal fluid [92] and serum [93] in CE-MS led to protein precipitation within the capillary. It was necessary to use ultrafiltration of these fluids to avoid this issue.…”

Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

“…Also, MSEA (Tab. 3) highlighted that two independent studies indicated alterations in methionine metabolism (Czech et al 2012;Ibanez et al 2012).…”