| 1. |
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| 2. |
- ten Kate, M., et al.
(författare)
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MRI predictors of amyloid pathology: results from the EMIF-AD Multimodal Biomarker Discovery study
- 2018
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: With the shift of research focus towards the pre-dementia stage of Alzheimer's disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) epsilon 4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods: We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 +/- 72, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69. 1 +/- 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 +/- 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE epsilon 4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results: In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 +/- O. 07 in MCI and an AUC of 0.74 +/- 0.08 in CN. In CN, selected features for the classifier included APOE epsilon 4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE epsilon 4 information did not improve after additionally adding imaging measures. Conclusions: Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE epsilon 4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.
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| 3. |
- Shi, L., et al.
(författare)
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Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3359-3364
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThis study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD. MethodsUsing the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR). ResultsAT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform. DiscussionThis study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.
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| 4. |
- Hong, S. J., et al.
(författare)
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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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| 5. |
- Visser, P. J., et al.
(författare)
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Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
- 2022
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
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| 6. |
- Tijms, B. M., et al.
(författare)
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Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143, s. 3776-3792
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n=127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P>0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P<0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P=0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P=0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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| 7. |
- Wesenhagen, K. E. J., et al.
(författare)
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Effects of age, amyloid, sex, and APOE epsilon 4 on the CSF proteome in normal cognition
- 2022
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E sigma 4 genotype. Methods We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. Results Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. Discussion We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology.
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| 8. |
- Delvenne, A., et al.
(författare)
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Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 807-820
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Tidskriftsartikel (refereegranskat)abstract
- Background Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods Individuals were classified based on CSF amyloid beta (A beta)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
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| 9. |
- Lovestone, S., et al.
(författare)
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The European medical information framework: A novel ecosystem for sharing healthcare data across Europe
- 2020
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Ingår i: Learning Health Systems. - : Wiley. - 2379-6146. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The European medical information framework (EMIF) was an Innovative Medicines Initiative project jointly supported by the European Union and the European Federation of Pharmaceutical Industries and Associations, that generated a common technology and governance framework to identify, assess and (re)use healthcare data, to facilitate real-world data research. The objectives of EMIF included providing a unified platform to support a wide range of studies within two verification programmes-Alzheimer's disease (EMIF-AD), and metabolic consequences of obesity (EMIF-MET). Methods The EMIF platform was built around two main data-types: electronic health record data and research cohort data, and the platform architecture composed of a set of tools designed to enable data discovery and characterisation. This included the EMIF catalogue, which allowed users to find relevant data sources, including the data-types collected. Data harmonisation via a common data model were central to the project especially for population data sources. EMIF also developed an ethical code of practice to ensure data protection, patient confidentiality and compliance with the European Data Protection Directive, and GDPR. Results Currently 18 population-based disease agnostic and 60 cohort-based Alzheimer's data partners from across 14 countries are contained within the catalogue, and this will continue to expand. The work conducted in EMIF-AD and EMIF-MET includes standardizing cohorts, summarising baseline characteristics of patients, developing diagnostic algorithms, epidemiological studies, identifying and validating novel biomarkers and selecting potential patient samples for pharmacological intervention. Conclusions EMIF was designed to provide a sustainable model as demonstrated by the sustainability plans for EMIF-AD. Although network-wide studies using EMIF were not conducted during this project to evaluate its sustainability, learning from EMIF will be used in the follow-on IMI-2 project, European Health Data and Evidence Network (EHDEN). Furthermore, EMIF has facilitated collaborations between partners and continues to promote a wider adoption of principles, technology and architecture through some of its continued work.
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| 10. |
- Neumann, A., et al.
(författare)
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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 1990-1999
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.
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| 11. |
- Bos, I., et al.
(författare)
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Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:5, s. 644-654
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We investigated relations between amyloid-beta (A beta) status, apolipoprotein E (APOE) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with A beta status (Ab beta- vs. A beta+), clinical diagnosis APOE epsilon 4 carriership, baseline cognition, and change in cognition. Results: Ng and T-tau distinguished between A beta+ from A beta- individuals in each clinical group, whereas NFL and YKL-40 were associated with A beta+ in nondemented individuals only. APOE epsilon 4 carriership did not influence NFL, Ng, and YKL-40 in A beta+ individuals. NFL was the best predictor of cognitive decline in A beta+ individuals across the cognitive spectrum. Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 12. |
- Bos, I., et al.
(författare)
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The EMIF-AD Multimodal Biomarker Discovery study: design, methods and cohort characteristics
- 2018
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer's disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants. Methods: Participants were selected from existing prospective multicenter and single-center European studies. Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (A beta) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF). Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF. Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA. Visual rating and volumetric measures were assessed on MRI. Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling. Results: We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 67.9 (SD 8.3) years. The percentage A beta+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups. Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects. For 759 (62%) individuals, clinical follow-up data were available. In each diagnostic group, the APOE e4 allele was more frequent amongst A beta+ individuals (p < 0.001). Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p< 0.001). A beta+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0.001) and MCI (p < 0.001) groups. Conclusions: The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of A beta and APOE epsilon 4 in AD pathogenesis. The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers. All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog.
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| 13. |
- Shi, Liu, et al.
(författare)
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Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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| 14. |
- Shi, Liu, et al.
(författare)
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Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
- 2019
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 15:11, s. 1478-1488
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Tidskriftsartikel (refereegranskat)abstract
- Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.4001 plasma proteins were measured in two groups of participants (discovery group=516, replication group=365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.A panel of proteins (n=44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve=0.78) and the replication group (area under the curve=0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
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| 15. |
- Shi, Liu, et al.
(författare)
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Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
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Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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| 16. |
- Tijms, B. M., et al.
(författare)
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CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals
- 2021
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Ingår i: Proteomes. - : MDPI AG. - 2227-7382. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p(181)-tau and amyloid beta 1-42 (A beta 42) CSF analysis showed that in the hyperplasticity subtype p(181)-tau increased (beta = 2.6 pg/mL per year, p = 0.01) and A beta 42 decreased over time (beta = -4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p(181)-tau increased (beta = 3.1 pg/mL per year, p = 0.01) while in the blood-brain barrier dysfunction subtype A beta 42 decreased (beta = -3.7 pg/mL per year, p = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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| 17. |
- Westwood, Sarah, et al.
(författare)
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Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort
- 2020
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 74:1, s. 213-225
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Tidskriftsartikel (refereegranskat)abstract
- We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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| 18. |
- Kim, Min, et al.
(författare)
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Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
- 2019
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 817-827
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
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| 19. |
- Konijnenberg, E., et al.
(författare)
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APOE ϵ4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ϵ4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ϵ4 genotype. Methods: We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ϵ4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ϵ4 allele (average age 75 ± 6 years). Results: One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ϵ4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ϵ4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions: These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment. © 2020 The Author(s).
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| 20. |
- Xu, Jin, et al.
(författare)
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Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
- 2021
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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| 21. |
- Homann, Jan, et al.
(författare)
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Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.
- 2022
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.
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| 22. |
- Hong, Shengjun, et al.
(författare)
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Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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| 23. |
- Karlsson, EB, et al.
(författare)
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Anomalous neutron Compton scattering in Nb hydride: Indications of proton correlations
- 1999
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Ingår i: EUROPHYSICS LETTERS. - : E D P SCIENCES. - 0295-5075. ; 46:5, s. 617-623
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Neutron Compton scattering probes properties of matter at time scales of the order of 10(-16)-10(-15) s. Very strong anomalies in the cross-sections for protons were observed for scattering on NbHx and NbHxDy. The effective proton cross-section was found
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| 24. |
- Neumann, Alexander, et al.
(författare)
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Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analysesof the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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| 25. |
- Stamate, Daniel, et al.
(författare)
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A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood : Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort
- 2019
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Ingår i: Alzheimer’s & Dementia. - : John Wiley & Sons. - 2352-8737. ; 5:C, s. 933-938
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.MethodsThis study analyzed samples from 242 cognitively normal (CN) people and 115 with AD‐type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).ResultsOn the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p‐tau and t‐tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.DiscussionThis study showed that plasma metabolites have the potential to match the AUC of well‐established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
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| 26. |
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| 27. |
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| 28. |
- Visser, Pieter Jelle, et al.
(författare)
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Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.
- 2020
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
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| 29. |
- Wesenhagen, Kirsten E. J., et al.
(författare)
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Effects of age, amyloid, sex, and APOE ε4 on the CSF proteome in normal cognition
- 2022
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : John Wiley & Sons. - 2352-8729. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype.Methods: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways.Results: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization.Discussion: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology.
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| 30. |
- Abdul-Redah, T, et al.
(författare)
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Anomalous neutron Compton scattering in metallic hydrides: new experiments
- 2000
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Ingår i: PHYSICA B. - : ELSEVIER SCIENCE BV. - 0921-4526. ; 276, s. 824-825
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Tidskriftsartikel (refereegranskat)abstract
- The time-of-flight spectra of the neutron Compton scattering of solid palladium hydrides were measured at room temperature. This experiment, which was motivated by previous measurements on liquid H2O/D2O mixtures as mel as on niobium hydrides, showed anom
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| 31. |
- Delvenne, Aurore, et al.
(författare)
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CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease
- 2024
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Ingår i: Alzheimer's & Dementia. - : John Wiley & Sons. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics.METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance.RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress.DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology.HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.
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| 32. |
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| 33. |
- Küçükali, Fahri, et al.
(författare)
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Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits
- 2023
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Ingår i: Alzheimer's & Dementia. - : John Wiley & Sons. - 1552-5260 .- 1552-5279. ; 19:6, s. 2317-2331
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
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| 34. |
- Slemmon, J Randall, et al.
(författare)
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Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total-Aβ42/Aβ40 ratio.
- 2015
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:5, s. 1049-1058
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Tidskriftsartikel (refereegranskat)abstract
- The 42 amino acid fragment of amyloid β (Aβ1-42) in cerebrospinal fluid (CSF) has continued to be important for detecting cerebral β-amyloidosis in Alzheimer's disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to APOE ε4 genotype. The current study investigated matrix interference as a contributing factor for detecting AD in APOE ε4-negative patients by comparing total extractable Aβ1-42 to free Aβ1-42. It also examined the ratio of total Aβ1-42 to Aβ1-40, since changes relative to other Aβ peptides may provide a measurement of cerebral β-amyloidosis that is neutral to changes in APP metabolism. Total Aβ1-42 lost diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1-42/Aβ1-40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some CSF samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aβ1-42/Aβ1-40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1-42/Aβ1-40 measurement, since this could minimize variability due to matrix and compensate for across patient differences. This article is protected by copyright. All rights reserved.
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| 35. |
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| 36. |
- Westwood, Sarah, et al.
(författare)
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The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer's pathology.
- 2017
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer's disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimedto characterise the shared protein signatures between IR and AD.Fifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE ε4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid β-peptide (Aβ), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers.CSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Aβ/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified.These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology.
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