Abstract
Background
Accumulating evidence suggests that Alzheimer’s disease (AD) patients display metabolic dysfunction. Metabolomics is a powerful tool for studying metabolic pathways by mapping ...biochemical changes in AD, yet little is known about the association between circulating metabolites in blood and the “A/T/N” (amyloid‐β, tau, neurodegeneration) biomarkers for AD.
Method
Serum‐based targeted metabolite levels were measured in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1,531; 370 cognitively normal controls (CN), 95 significant memory concern (SMC), 271 early mild cognitive impairment (EMCI), 491 late MCI (LMCI), and 304 AD). The quality control process resulted in 139 metabolites for further analysis. We performed association analyses of circulating serum metabolites with the “A/T/N” biomarkers for AD. Biomarkers of “A” are CSF Aβ1‐42 and cortical amyloid‐β accumulation measured by Florbetapir PET, biomarkers of “T” are CSF phosphorylated tau (p‐tau), and biomarkers of “N” are atrophy on MRI and glucose metabolism on FDG PET. FDR‐based multiple comparison adjustment with the Benjamini‐Hochberg procedure was used.
Result
We found significant associations of multiple metabolites with biomarkers of amyloid‐β (“A”) and neurodegeneration (“N”) including brain amyloid deposition, glucose metabolism, and structural atrophy measured from multimodal neuroimaging scans (MRI, PET) after multiple testing adjustment. We did not observe any significant associations between metabolites and biomarkers of fibrillary tau (“T”) (Figure 1). In particular, higher levels of phosphatidylcholines (PC) were associated with greater amyloid deposition (“A”) and decreased brain glucose metabolism (“N”). Higher levels of propionyl‐L‐carnitine (C3) were associated with less amyloid deposition and increased brain glucose metabolism. Higher levels of two amino acids, two PCs, and three sphingomyelins were associated with less brain atrophy (“N”).
Conclusion
This is the first study to show serum circulating metabolites are significantly associated with neuroimaging biomarkers for AD. Perturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid‐β deposition and neurodegeneration, but not fibrillary tau suggesting that acylcarnitines and PCs are associated with earlier stages of AD as tau spreading is more closely related to AD progression.
Background
Accumulating evidence suggests that Alzheimer’s disease (AD) patients display metabolic dysfunction. Metabolomics is a powerful tool for studying metabolic pathways by mapping biochemical ...changes in AD, yet little is known about the association between circulating metabolites in blood and the “A/T/N” (amyloid‐β, tau, neurodegeneration) biomarkers for AD.
Method
Serum‐based targeted metabolite levels were measured in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1,531; 370 cognitively normal controls (CN), 95 significant memory concern (SMC), 271 early mild cognitive impairment (EMCI), 491 late MCI (LMCI), and 304 AD). The quality control process resulted in 139 metabolites for further analysis. We performed association analyses of circulating serum metabolites with the “A/T/N” biomarkers for AD. Biomarkers of “A” are CSF Aβ1‐42 and cortical amyloid‐β accumulation measured by Florbetapir PET, biomarkers of “T” are CSF phosphorylated tau (p‐tau), and biomarkers of “N” are atrophy on MRI and glucose metabolism on FDG PET. FDR‐based multiple comparison adjustment with the Benjamini‐Hochberg procedure was used.
Result
We found significant associations of multiple metabolites with biomarkers of amyloid‐β (“A”) and neurodegeneration (“N”) including brain amyloid deposition, glucose metabolism, and structural atrophy measured from multimodal neuroimaging scans (MRI, PET) after multiple testing adjustment. We did not observe any significant associations between metabolites and biomarkers of fibrillary tau (“T”) (Figure 1). In particular, higher levels of phosphatidylcholines (PC) were associated with greater amyloid deposition (“A”) and decreased brain glucose metabolism (“N”). Higher levels of propionyl‐L‐carnitine (C3) were associated with less amyloid deposition and increased brain glucose metabolism. Higher levels of two amino acids, two PCs, and three sphingomyelins were associated with less brain atrophy (“N”).
Conclusion
This is the first study to show serum circulating metabolites are significantly associated with neuroimaging biomarkers for AD. Perturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid‐β deposition and neurodegeneration, but not fibrillary tau suggesting that acylcarnitines and PCs are associated with earlier stages of AD as tau spreading is more closely related to AD progression.
Exposure to mobile source emissions is nearly ubiquitous in developed nations and is associated with multiple adverse health outcomes. There is an ongoing need to understand the specificity of ...traffic exposure associations with vascular outcomes, particularly in individuals with cardiovascular disease.
We performed a cross-sectional study using 2124 individuals residing in North Carolina, United States, who received a cardiac catheterization at the Duke University Medical Center. Traffic-related exposure was assessed via 2 metrics: (1) the distance between the primary residence and the nearest major roadway; and (2) location of the primary residence in regions defined based on local traffic patterns. We examined 4 cardiovascular disease outcomes: hypertension, peripheral arterial disease, the number of diseased coronary vessels, and recent myocardial infarction. Statistical models were adjusted for race, sex, smoking, type 2 diabetes mellitus, body mass index, hyperlipidemia, and home value. Results are expressed in terms of the odds ratio (OR). A 23% decrease in residential distance to major roadways was associated with higher prevalence of peripheral arterial disease (OR=1.29; 95% confidence interval, 1.08-1.55) and hypertension (OR=1.15; 95% confidence interval, 1.01-1.31). Associations with peripheral arterial disease were strongest in men (OR=1.42; 95% confidence interval, 1.17-1.74) while associations with hypertension were strongest in women (OR=1.21; 95% confidence interval, 0.99-1.49). Neither myocardial infarction nor the number of diseased coronary vessels were associated with traffic exposure.
Traffic-related exposure is associated with peripheral arterial disease and hypertension while no associations are observed for 2 coronary-specific vascular outcomes.
The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on ...human health.
We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization.
We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES).
An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (β = 2.17 mg/dL; 95% CI: -0.24, 4.59), and the association appeared to be limited to women (β = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with β = 0.14 mg/dL; 95% CI: -3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 8.36; 95% CI: -0.15, 16.9 and β = 5.98; 95% CI: -3.96, 15.9, for TEZ 5 and 6, respectively).
Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic ...variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
Abstract
Metabolomics in the Alzheimer’s Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer’s disease, and a unique opportunity to learn ...about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer’s disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative. Processed 18F Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer’s disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer’s disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer’s disease or if they are biomarkers for systemic changes during preclinical phases of the disease.
Nho et al. report that serum-based metabolites are associated with brain amyloid-β deposition, cognition and disease progression from mild cognitive impairment to Alzheimer’s disease in a large cohort of older adults. Results suggest that dysregulation of very long chain peripheral phospholipid metabolism is associated with earlier pathological changes in Alzheimer’s disease.
Graphical Abstract
Graphical Abstract
Alzheimer's disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, ...with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this complex disease. To interrogate the relationship between system level metabolites and disease susceptibility and progression, the AD Metabolomics Consortium (ADMC) in partnership with AD Neuroimaging Initiative (ADNI) is creating a comprehensive biochemical database for patients in the ADNI1 cohort. We used the Biocrates Bile Acids platform to evaluate the association of metabolic levels with disease risk and progression. We detail the quantitative metabolomics data generated on the baseline samples from ADNI1 and ADNIGO/2 (370 cognitively normal, 887 mild cognitive impairment, and 305 AD). Similar to our previous reports on ADNI1, we present the tools for data quality control and initial analysis. This data descriptor represents the third in a series of comprehensive metabolomics datasets from the ADMC on the ADNI.
Family health history is a strong predictor of disease risk. To reduce the morbidity and mortality of many chronic diseases, risk-stratified evidence-based guidelines strongly encourage the ...collection and synthesis of family health history to guide selection of primary prevention strategies. However, the collection and synthesis of such information is not well integrated into clinical practice. To address barriers to collection and use of family health histories, the Genomedical Connection developed and validated MeTree, a Web-based, patient-facing family health history collection and clinical decision support tool. MeTree is designed for integration into primary care practices as part of the genomic medicine model for primary care.
We describe the guiding principles, operational characteristics, algorithm development, and coding used to develop MeTree. Validation was performed through stakeholder cognitive interviewing, a genetic counseling pilot program, and clinical practice pilot programs in 2 community-based primary care clinics.
Stakeholder feedback resulted in changes to MeTree's interface and changes to the phrasing of clinical decision support documents. The pilot studies resulted in the identification and correction of coding errors and the reformatting of clinical decision support documents. MeTree's strengths in comparison with other tools are its seamless integration into clinical practice and its provision of action-oriented recommendations guided by providers' needs.
The tool was validated in a small cohort.
MeTree can be integrated into primary care practices to help providers collect and synthesize family health history information from patients with the goal of improving adherence to risk-stratified evidence-based guidelines.
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