Alterations in metabolic pathways and networks in Alzheimer’s disease

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.

Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

“…Several recent studies propose altered metabolite and lipid profiles associated with MCI and AD. [153][154][155][156] Data from animal models suggest that lipid and metabolite changes accompany both acute and chronic postconcussion periods, and could be useful for predicting recovery trajectory, 157,158 but these findings have yet to be validated in humans. Expanding the biomarker search beyond blood and CSF to saliva and urine 159 might improve the ability to obtain measurements rapidly and noninvasively, particularly from children.…”

Metabolomics in the Study of Alzheimer's Disease

“…As a result 21 of a total of 71 detected metabolites could be identified by the analysis of reference standard mixtures. Patients presenting AD and MCI showed elevated levels of methionine, whereas the methionine/reduced glutathione ratio was decreased, suggesting a glutathione depletion associated with AD pathology [108]. In that work a correlation between metabolite levels and concentration of Aβ , total tau and phospho-tau proteins in CSF was carried out.…”

“…In MCI patients who progressed to AD, decreased levels of a neuroprotective metabolite as taurine and increased levels of neurotoxic metabolites such as dopamine-quinone or methylsalsolinol were observed [103]. A less common analytical approach in Metabolomics, HPLC with electrochemical array detection (ECA), has been applied to study metabolic signatures from 114 CSF samples from three groups of patiets: 40 control individuals (healthy), 36 subjects with MCI and 38 AD patients [108]. ECA is an extremely selective and sensitive detection technique with simpler and cheaper instrumentation, but compared to NMR or MS, less structural information is obtained by LC-ECA.…”

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

“…3) indicates convergent variations in these pathways (Czech et al 2012). Importantly, the severity of the disease was correlated with decreased noradrenaline (Kaddurah-Daouk et al 2011b) and increased levels of vanillylmandelic acid, a degradation product of xanthine and dopamine (Kaddurah-Daouk et al 2013b). Also, MSEA (Tab.…”