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.
Highlights
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that involves loss of memory and cognitive abilities
For analysis of the individual metabolite fingerprints, we employed non-targeted UPLC-ToF-MS –based comprehensive metabolomic profiling to determine changes in metabolites associated with AD severity in the cerebrospinal fluid (CSF) and plasma samples from the same patients diagnosed with amnestic mild cognitive impairment (MCI) or AD and cognitively normal (CN) individuals
We applied a non-targeted mass spectrometry–based metabolomic profiling to determine global changes in metabolites and various putative metabolic pathways in CSF and plasma from the same individuals in relationship to AD progression. This is the first study that (1) evaluates progressive metabolic changes in CN, MCI and AD subjects in both CSF and plasma, (2) establishes to what extent metabolic changes in lumbar CSF are reflected in plasma, (3) identifies unique and common metabolic pathways affected by AD severity in plasma and CSF, and (4) validates plasma as a reliable biofluid for metabolic studies of brain-related disorders
Summary
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that involves loss of memory and cognitive abilities. Neuritic plaques that contain b-amyloid (Ab) aggregated peptides and intracellular neurofibrillar tangles consisting of hyperphosphorylated microtubule-associated tau protein are two major hallmarks of AD [1,2]. Clinical trials conducted over 18 months utilizing Ab-clearing monoclonal antibodies failed to slow cognitive and functional decline in AD patients despite the maintenance of amyloid burden and actual decrease in phosphotau (p-tau) levels in cerebrospinal fluid (CSF) [8,9,10]. There is an urgent need to identify alternative disease mechanisms and associated biomarkers that can help to diagnose AD in the preclinical and early clinical (i.e., mild cognitive impairment (MCI)) stages [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
