Abstract
L-Arginine/NO pathway is altered in Alzheimer disease (AD). Its clinical relevance and pathway status in vascular dementia (VaD) are unknown. Using targeted metabolomics (a liquid chromatography-mass spectrometry) we assessed L-arginine, L-citrulline, dimethylamine (DMA), asymmetric dimethyl arginine (ADMA) and symmetric dimethylarginine (SDMA) in AD (n = 48), mixed-type dementia (MD; n = 34), VaD (n = 40) and non-demented individuals (n = 140) and determined their clinical relevance (the association with dementia pathology, cognitive impairment, and structural brain damage). L-Arginine, ADMA, L-arginine/ADMA, and L-citrulline levels were decreased in dementia and L-arginine, L-citrulline, age and sex were its independent predictors correctly classifying 91% of cases. L-Arginine and L-arginine/ADMA were differentiating between VaD and AD with moderate accuracy. L-Arginine, L-arginine/ADMA, SDMA, and DMA reflected structural brain changes. DMA and L-citrulline were elevated in patients with strategic infarcts and SDMA, L-arginine/ADMA, and DMA were independent predictors of Hachinski ischemic score. ADMA and SDMA accumulation reflected severity of cognitive impairment. In summary, L-Arginine/NO pathway is altered in neurodegenerative and vascular dementia in association with neurodegenerative and vascular markers of brain damage and severity of cognitive impairment.
Highlights
Blood-based biomarkers are easier to measure than those derived from cerebrospinal fluid (CSF) and still believed to reflect the brain pathophysiology
The receiver operating characteristics (ROC) curve analysis was employed to calculate the overall accuracy as well as sensitivities and specificities of the model in comparison with individual and combined determination of arginine and citrulline
If arginine and ADMA were replaced by Arg/ADMA, it was retained in the model instead of arginine and the model had very similar characteristics
Summary
Blood-based biomarkers are easier to measure than those derived from cerebrospinal fluid (CSF) and still believed to reflect the brain pathophysiology. Brain homeostasis is secured by the activity of endothelial and neuronal isoforms of nitric oxide synthase (respectively eNOS and nNOS), catalyzing a two-step oxidation of L-arginine to NO and L-citrulline[7]. ADMA is a strong and SDMA a weak competitive inhibitor of NOS enzymes. Both dimethylarginines compete with L-arginine for its transporters, diminishing its intracellular availability. This study was designed to employ targeted metabolomics and our newly developed assay[8] to evaluate the association of a panel of NO-related metabolites, namely, L-arginine, L-citrulline, ADMA, SDMA, and DMA with dementia, its probable pathology (vascular or neurodegenerative), severity of loss of cognitive function, structural changes in the brain as shown by the magnetic resonance imaging (MRI), and with brain ischemia. For the first time, the alterations in NO-related metabolites in VaD, their distinct association patterns with the severity of dementia, brain atrophy and ischemia as well as their dependence on dementia pathology
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