Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study
| العنوان: | Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study |
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| المؤلفون: | Anup M. Oommen, P. Murali Doraiswamy, Cristina Legido-Quigley, Rima Kaddurah-Daouk, Yang An, Jon B. Toledo, Gabi Kastenmueller, Rebecca Baillie, Matthias Arnold, Vijay R. Varma, Richard O'Brien, Ryan M. Andrews, Ramon Casanova, Olga Pletnikova, Madhav Thambisetty, Kwangsik Nho, Andrew J. Saykin, Sudhir Varma, Juan C. Troncoso |
| المصدر: | PLoS Medicine, Vol 15, Iss 1, p e1002482 (2018) PLoS Medicine |
| بيانات النشر: | Public Library of Science (PLoS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Pathology, Physiology, lcsh:Medicine, Disease, Alzheimer's Disease, Biochemistry, Nervous System, Pathogenesis, 0302 clinical medicine, Medicine and Health Sciences, Metabolites, Longitudinal Studies, Cerebrospinal Fluid, Cognitive Impairment, Aged, 80 and over, Cognitive Neurology, Brain, Neurodegenerative Diseases, General Medicine, Lipids, Body Fluids, 3. Good health, Blood, Neurology, Disease Progression, Metabolome, Female, lipids (amino acids, peptides, and proteins), Metabolic Pathways, Anatomy, Alzheimer's disease, Research Article, medicine.medical_specialty, Cognitive Neuroscience, Neuropathology, 03 medical and health sciences, Atrophy, Alzheimer Disease, Mental Health and Psychiatry, medicine, Metabolomics, Humans, Aged, Sphingolipids, business.industry, lcsh:R, Biology and Life Sciences, medicine.disease, Sphingolipid, Metabolism, 030104 developmental biology, Endophenotype, Baltimore, Cognitive Science, Dementia, business, Biomarkers, Blood Chemical Analysis, 030217 neurology & neurosurgery, Neuroscience |
| الوصف: | Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer’s Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703–11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516–7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373–9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047–4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. Conclusions We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD. Using quantitative and targeted metabolomics, Vijay Varma and colleagues identified metabolites for which brain tissue levels were associated with Alzheimer disease (AD) neuropathology and blood concentrations were associated with AD progression in prodromal and preclinical stages. Author summary Why was this study done? Metabolomics, which measures the biochemical products of cell processes, can be used to measure alterations in biochemical pathways related to AD. Several recent studies have applied metabolomics to explore potential blood biomarkers for Alzheimer disease (AD). Prior blood biomarker studies have not linked signals in the blood to those in the brain and have relied mainly on discriminating between AD/mild cognitive impairment (MCI) and control samples. These study designs ignore the long preclinical prodrome of AD and do not provide biological insights into the evolution of AD pathology in the brain and eventual development of clinical symptoms. Our study was designed to link alterations in metabolite signals in the brain to those in the blood, explore how those alterations were associated with distinct endophenotypes of AD, and identify the key biological pathways implicated. What did the research do and find? We used quantitative and targeted metabolomics assays on brain tissue samples (N = 44) and machine-learning methods to identify a brain metabolite signature of AD, i.e., a 26-metabolite panel that discriminated AD and control samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed the same 26 metabolites in blood from two longitudinal cohorts that represent prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767) and preclinical (Baltimore Longitudinal Study of Aging [BLSA], N = 207) AD and tested their associations with MRI measures, CSF biomarkers, risk of conversion to incident AD, and cognitive performance. We found that higher blood concentrations of sphingolipid species were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. These metabolites map to several biologically relevant pathways in AD, including tau phosphorylation, Aβ metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. What do these findings mean? Our study design represents a novel approach for identifying markers of disease progression in AD and potential avenues for therapeutic intervention. Perturbations in sphingolipid metabolism are consistently associated with preclinical and prodromal AD, as well as with AD pathology at autopsy, providing compelling evidence for their significant role in AD pathogenesis. |
| اللغة: | English |
| تدمد: | 1549-1676 1549-1277 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::27bf8e7ede6f54924a665279d273e677 http://europepmc.org/articles/PMC5784884?pdf=render |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....27bf8e7ede6f54924a665279d273e677 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15491676 15491277 |
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