Background:There is an urgent need to understand the pathways and processes underlying Alzheimer's disease(AD)for early diagnosis and development of effective treatments.This study was aimed to investigate Alzheim...Background:There is an urgent need to understand the pathways and processes underlying Alzheimer's disease(AD)for early diagnosis and development of effective treatments.This study was aimed to investigate Alzheimer's dementia using an unsupervised lipid,protein and gene multi-omics integrative approach.Methods:A lipidomics dataset comprising 185 AD patients,40 mild cognitive impairment(MCI)individuals and 185 controls,and two proteomics datasets(295 AD,159 MCI and 197 controls)were used for weighted gene CO-expression network analyses(WGCNA).Correlations of modules created within each modality with clinical AD diagnosis,brain atrophy measures and disease progression,as well as their correlations with each other,were analyzed.Gene ontology enrichment analysis was employed to examine the biological processes and molecular and cellular functions of protein modules associated with AD phenotypes.Lipid species were annotated in the lipid modules associated with AD phenotypes.The associations between established AD risk loci and the lipid/protein modules that showed high correlation with AD phenotypes were also explored.Results:Five of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with clinical AD diagnosis,brain atrophy measures and disease progression.The lipid modules comprising phospholipids,triglycerides,sphingolipids and cholesterol esters were correlated with AD risk loci involved in immune response and lipid metabolism.The five protein modules involved in positive regulation of cytokine production,neutrophil-mediated immunity,and humoral immune responses were correlated with AD risk loci involved in immune and complement systems and in lipid metabolism(the APOE ε4 genotype).Conclusions:Modules of tightly regulated lipids and proteins,drivers in lipid homeostasis and innate immunity,are strongly associated with AD phenotypes.展开更多
The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment ...The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.展开更多
Correction to:Translational Neurodegeneration(2022)11:24 https://doi.org/10.1186/s40035-022-00299-w Following publication of the original article[1],the authors identified some errors in the Additional files 1-5.The o...Correction to:Translational Neurodegeneration(2022)11:24 https://doi.org/10.1186/s40035-022-00299-w Following publication of the original article[1],the authors identified some errors in the Additional files 1-5.The original article[1]has been corrected.展开更多
文摘Background:There is an urgent need to understand the pathways and processes underlying Alzheimer's disease(AD)for early diagnosis and development of effective treatments.This study was aimed to investigate Alzheimer's dementia using an unsupervised lipid,protein and gene multi-omics integrative approach.Methods:A lipidomics dataset comprising 185 AD patients,40 mild cognitive impairment(MCI)individuals and 185 controls,and two proteomics datasets(295 AD,159 MCI and 197 controls)were used for weighted gene CO-expression network analyses(WGCNA).Correlations of modules created within each modality with clinical AD diagnosis,brain atrophy measures and disease progression,as well as their correlations with each other,were analyzed.Gene ontology enrichment analysis was employed to examine the biological processes and molecular and cellular functions of protein modules associated with AD phenotypes.Lipid species were annotated in the lipid modules associated with AD phenotypes.The associations between established AD risk loci and the lipid/protein modules that showed high correlation with AD phenotypes were also explored.Results:Five of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with clinical AD diagnosis,brain atrophy measures and disease progression.The lipid modules comprising phospholipids,triglycerides,sphingolipids and cholesterol esters were correlated with AD risk loci involved in immune response and lipid metabolism.The five protein modules involved in positive regulation of cytokine production,neutrophil-mediated immunity,and humoral immune responses were correlated with AD risk loci involved in immune and complement systems and in lipid metabolism(the APOE ε4 genotype).Conclusions:Modules of tightly regulated lipids and proteins,drivers in lipid homeostasis and innate immunity,are strongly associated with AD phenotypes.
基金the NIHR Newcastle Biomedical Research Centre based at Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle University.SJGL is supported by a National Health and Medical Research Council Leadership Fellowship(1195830).
文摘The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.
文摘Correction to:Translational Neurodegeneration(2022)11:24 https://doi.org/10.1186/s40035-022-00299-w Following publication of the original article[1],the authors identified some errors in the Additional files 1-5.The original article[1]has been corrected.
