Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive functions. Today the diagnosis of AD relies on clinical evaluations and is only late in the disease. Biomarkers for early detection of the underlying neuropathological changes are still lacking and the biochemical pathways leading to the disease are still not completely understood. The aim of this study was to identify the metabolic changes resulting from the disease phenotype by a thorough and systematic metabolite profiling approach. For this purpose CSF samples from 79 AD patients and 51 healthy controls were analyzed by gas and liquid chromatography-tandem mass spectrometry (GC-MS and LC-MS/MS) in conjunction with univariate and multivariate statistical analyses. In total 343 different analytes have been identified. Significant changes in the metabolite profile of AD patients compared to healthy controls have been identified. Increased cortisol levels seemed to be related to the progression of AD and have been detected in more severe forms of AD. Increased cysteine associated with decreased uridine was the best paired combination to identify light AD (MMSE>22) with specificity and sensitivity above 75%. In this group of patients, sensitivity and specificity above 80% were obtained for several combinations of three to five metabolites, including cortisol and various amino acids, in addition to cysteine and uridine.
Highlights
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder of the brain characterized by loss of neurons and synapses, in regions related to memory and cognition
Because the clinical diagnosis of AD happens at a late stage of the disease, i.e. several years after the onset of the neuropathological alterations, there was an urgent need to revise these criteria in order to characterize the disease at a predementia stage
Disease samples originated from AD patients with varying degree of dementia as indicated by different scores from the MMSE: light or mild AD (MMSE.22), or strong AD (MMSE 14–22)
Summary
Alzheimer’s disease (AD) is a progressive and devastating neurodegenerative disorder of the brain characterized by loss of neurons and synapses, in regions related to memory and cognition. In vivo imaging of amyloid deposits in the brain using specific PET ligands have made strong progress in the last few years and provide valuable tools for diagnosis, patient stratification and monitoring disease progression [5,6]. The currently best CSF candidates are the amyloid-b (1– 42) fragment and the Tau protein. Combinations of these markers reach sensitivity of about 90 to 95% and specificity about 85% (for review see [7]). Using these CSF markers there is still huge overlap with other forms of dementia. Combination of several biological markers acting at different physiological levels can bring complementary information for diagnostics of various disease phenotypes and for monitoring biological drug effects
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