Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics

Abstract

Alzheimer’s Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.

Metabolomics in the Study of Alzheimer's Disease

“…Integrated information from CSF and plasma samples was used to select and validate reliable plasma biomarkers related to AD [123]. As expected, the number of affected pathways in both biofluids increased with disease progression.…”

“…As expected, the number of affected pathways in both biofluids increased with disease progression. Interestingly compared to control subjects near 30% and 60% of the metabolic pathways altered in the CSF of MCI and AD patients respectively, were also affected in plasma samples from the same individuals showing certain correlation between biofluids [123]. Amino acid and dipeptide content correlation between CSF and plasma was also accomplished by Fonteh et al including also urine in that case [98].…”

“…In this sense, Metabolomics can be considered a relatively little explored technology, which may offer valuable information. Recently, Trushina et al [123] established to what extent metabolic changes observed in CSF were or not reflected in plasma obtained from the same individuals.…”

Small molecule biomarkers in Alzheimer’s disease

“…Multi-platforms based on the combination of complementary chromatographic science prior to MS detection have also been employed (Czech et al, 2012;Ibanez et al, 2013;Trushina et al, 2013a). Utilizing RP and HILIC, Trushina et al, (2013a) analysed 15 AD, 15 MCI and 15CN CSF samples, and found approximately 30% of the metabolic pathways altered in MCI compared to CN, and 60% in AD compared to CN.…”

“…Utilizing RP and HILIC, Trushina et al, (2013a) analysed 15 AD, 15 MCI and 15CN CSF samples, and found approximately 30% of the metabolic pathways altered in MCI compared to CN, and 60% in AD compared to CN. This finding showed that the number of affected pathways increases with disease severity.…”