Biology subjects

Baillie, R.

Publications and source records attributed to Baillie, R..

6 recordsLinked to original sources

bioRxiv2020

Serum Metabolites Associate with Brain Amyloid Beta Deposition, Cognitive Dysfunction, and Alzheimers Disease Progression

RATIONALEMetabolomics in the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort provides a powerful tool for mapping biochemical changes in AD, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-{beta} deposition in AD. OBJECTIVESWe examined 140 serum metabolites and their associations with brain amyloid-{beta} deposition, cognition, and conversion from mild cognitive impairment (MCI) to AD. FINDINGSSerum-based targeted metabolite levels were measured in 1,531 ADNI participants. We performed association analysis of metabolites with brain amyloid-{beta} deposition measured from [18F] Florbetapir PET scans. We identified nine metabolites as significantly associated with amyloid-{beta} deposition after FDR-based multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-{beta} accumulation. However, higher levels of seven phosphatidylcholines (PC) were associated with increased amyloid deposition. In addition, PC ae C44:4 was significantly associated with cognition and conversion from MCI to AD dementia. CONCLUSIONPerturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid-{beta} deposition and cognitive performance.

neuroscience↗

bioRxiv2019

Peripheral Serum Metabolomic Profiles InformAntecedent Central Cognitive Impairment in Older Adults

The incidence of Alzheimers disease (AD) increases with age and is a significant cause of worldwide morbidity and mortality. However, the metabolic perturbations behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of six metabolites, GLCA, petroselinic acid, linoleic acid, myristic acid, palmitic acid, and palmitoleic acid as well as the DCA/CA ratio, along with the dysregulation scores of three metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences in diagnostic groups across both brain and serum (P-value < 0.05).Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median of AUC = 0.772 for the metabolite level model; median of AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials. Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.

neuroscience↗

bioRxiv2019

The Alzheimer’s Disease Metabolome: Effects of Sex and APOE ε4 genotype

Recent studies have provided evidence that late-onset Alzheimers disease (AD) can in part be considered a metabolic disease. Besides age, female sex and APOE {varepsilon}4 genotype represent strong risk factors for AD. They also both give rise to large metabolic differences, suggesting that metabolic aspects of AD pathogenesis may differ between males and females and between APOE {varepsilon}4 carriers and non-carriers. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 140 metabolites measured in serum samples of 1,517 AD neuroimaging initiative subjects, with AD biomarkers for A{beta} and tau pathology and neurodegeneration. We observed substantial sex differences in effects of 15 metabolites on AD biomarkers with partially overlapping differences for APOE {varepsilon}4 status groups. These metabolites highlighted several group-specific alterations not observed in unstratified analyses using sex and APOE {varepsilon}4 as covariates. Combined stratification by both variables uncovered further subgroup-specific metabolic effects limited to the group with presumably the highest AD risk: APOE {varepsilon}4+ females. Pathways linked to the observed metabolic alterations suggest that females experience more expressed impairment of mitochondrial energy production in AD than males. These findings indicate that dissecting metabolic heterogeneity in AD pathogenesis may enable grading of the biomedical relevance of specific pathways for specific subgroups. Extending our approach beyond simple one- or two-fold stratification may thus guide the way to personalized medicine.\n\nSignificance statementResearch provides substantial evidence that late-onset Alzheimers disease (AD) is a metabolic disease. Besides age, female sex and APOE{varepsilon}4 genotype represent strong risk factors for AD, and at the same time give rise to large metabolic differences. Our systematic investigation of sex and APOE {varepsilon}4 genotype differences in the link between metabolism and measures of pre-symptomatic AD using stratified analysis revealed several group-specific metabolic alterations that were not observed without sex and genotype stratification of the same cohort. Pathways linked to the observed metabolic alterations suggest females are more affected by impairment of mitochondrial energy production in AD than males, highlighting the importance of tailored treatment approaches towards a precision medicine approach.

bioinformatics↗

bioRxiv2018

Serum triglycerides in Alzheimer’s disease: Relation to neuroimaging and CSF biomarkers

ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimers disease (AD) and the \"A/T/N/V\" (Amyloid, Tau, Neurodegeneration, and Cerebrovascular disease) biomarkers for AD.\n\nMethodsSerum levels of 84 TG species were measured using untargeted lipid profiling of 689 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) cohort including 190 cognitively normal older adults (CN) and 339 mild cognitive impairment (MCI) and 160 AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]FDG-PET) were assessed using a multivariate generalized linear model (GLM) approach. In both cases, the Bonferroni method of adjustment was employed to correct for multiple comparisons.\n\nResultsThe 84 TGs yielded 9 principal components, two of which consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying APOE {varepsilon}4 allele, these principal components were significantly associated with CSF amyloid-{beta}1-42 values and entorhinal cortical thickness.\n\nConclusionsThis study shows PUTG component scores significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE {varepsilon}4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

neuroscience↗

bioRxiv2018

Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers

IntroductionBile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimers disease (AD) including neuroinflammation and amyloid-{beta} deposition.\n\nMethodSerum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n=1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the \"A/T/N\" (Amyloid, Tau and Neurodegeneration) biomarkers for AD: CSF biomarkers, atrophy (MRI), and brain glucose metabolism ([18F]FDG-PET).\n\nResultsOf 23 BA and relevant calculated ratios, three BA signatures were associated with CSF A{beta}1-42 (\"A\") and three with CSF p-tau181 (\"T\") (corrected p<0.05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (\"N\"), respectively (corrected p<0.05).\n\nConclusionThis is the first study to show serum-based BA metabolites are associated with \"A/T/N\" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

neuroscience↗

bioRxiv2018

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).\n\nMethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.\n\nResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.\n\nConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

neuroscience↗