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Alterations in metabolic pathways and networks in Alzheimer's disease
- Source :
- Translational Psychiatry
- Publication Year :
- 2013
-
Abstract
- The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.
- Subjects :
- Purine
Male
Metabolite
Pharmacology
Neuropsychological Tests
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
partial network reconstruction
0302 clinical medicine
Metabolomics
Alzheimer Disease
medicine
Dementia
Humans
Cognitive Dysfunction
Vanillylmandelic acid
Prospective Studies
Biological Psychiatry
Hypoxanthine
030304 developmental biology
Aged
Aged, 80 and over
0303 health sciences
Case-control study
Middle Aged
Alzheimer's disease
medicine.disease
metabolomics
3. Good health
pathway analysis
Psychiatry and Mental health
chemistry
Biochemistry
Case-Control Studies
Female
Original Article
Psychology
030217 neurology & neurosurgery
Biomarkers
Metabolic Networks and Pathways
Chromatography, Liquid
Subjects
Details
- ISSN :
- 21583188
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Translational psychiatry
- Accession number :
- edsair.doi.dedup.....8cad6d3a4e3a3ba4bb62464a82919f65