High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis.
Ontology highlight
ABSTRACT: Objective
We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards.Methods
Using an immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan.Results
Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82-0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p = 0.01).Conclusions
Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.Classification of evidence
This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.
SUBMITTER: Schindler SE
PROVIDER: S-EPMC6946467 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ImportanceBlood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.ObjectiveTo compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.Design, setting, and participantsThis study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.Main outcomes and measuresDiscriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.ResultsA total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.Conclusions and relevanceThe results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.
| S-EPMC8453354 | biostudies-literature
Project description:Impaired brain clearance of amyloid-beta peptides (Aβ) 40 and 42 across the blood-brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer's disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Aβ accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Aβ accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Aβ transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Aβ40 increased, but Aβ42 clearance reduced; the plasma-to-brain influx of Aβ40 increased, and that of Aβ42 reduced; and the clearance of intracerebrally injected Aβ40 decreased, whereas Aβ42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Aβ40 increased and that of Aβ42 reduced; the abluminal-to-luminal permeability of Aβ40 decreased, whereas Aβ42 permeability increased. Moreover, Aβ cellular trafficking machinery was altered. In summary, Aβ40 and Aβ42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.
| S-EPMC5987944 | biostudies-literature
Project description:Beta-amyloid (Abeta) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce Abeta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Abeta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Abeta catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of beta and gamma splice forms of human MMEL were determined in HEK293T cells transduced with the human cDNAs for the two splice forms; this showed degradation of both Abeta(42) and Abeta(40) by hMMEL-beta but not hMMEL-gamma. hMMEL-beta activity was found at the extracellular surface with no significant secreted activity. hMMEL-gamma was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves Abeta near the alpha-secretase site (producing Abeta(1-17)>>Abeta(1-16)). These data establish hMMEL as a mediator of Abeta catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.
| S-EPMC2597530 | biostudies-literature
Project description:Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods We included individuals with a positive (n?=?176: 63?±?7?years, 87 (49%) females) or negative (n?=?76: 61?±?9?years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET?), mild cognitive impairment (26 PET+, 24 PET?), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p?=?0.009 and p?<?0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p?=?0.001 and p?=?0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC?=?88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized ? (s?)?=???0.40 to ??0.26; NfL: range s??=???0.35 to ??0.18; all: p?<?0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range s??=?0.22 – 0.11; all: p?<?0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman’s rho>?0.33, p?<?0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman’s rho?=???0.24, p?=?0.001). Discussion and conclusions Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.
| S-EPMC7523295 | biostudies-literature
Project description:Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-? protein (1-42) and amyloid-? protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of A?42 is more downhill, with a computed solubility that is about 10 times smaller than that of A?40. At a concentration of 40 ?M, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the A?40 aggregation landscape disappears for A?42, suggesting that the A?42 tetramer has a more diverse structural range. To further compare the landscapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on ?-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that A?40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for A?42 relative to A?40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.
| S-EPMC5805378 | biostudies-literature
Project description:Two main amyloid-β peptides of different length (Aβ40 and Aβ42) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether Aβ40 and Aβ42 co-aggregate, we used Fourier transform infrared spectroscopy in combination with 13C-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled Aβ40 and unlabeled Aβ42 (and vice versa) were co-incubated for ∼20 min and their infrared spectrum recorded. The position of the main 13C-amide I' band shifted to higher wavenumbers with increasing admixture of 12C-peptide due to the presence of 12C-amides in the vicinity of 13C-amides. The results indicate that Aβ40 and Aβ42 form mixed oligomers with a largely random distribution of Aβ40 and Aβ42 strands in their β-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the β-sheets of Aβ42.
| S-EPMC5857929 | biostudies-literature
Project description:Aggregation states of amyloid beta peptides for amyloid beta A β 1 - 40 to A β 1 - 42 and A β p 3 - 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer's disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A β p 3 - 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.
| S-EPMC6747079 | biostudies-literature
Project description:ObjectiveTo explore whether the plasma total β-amyloid (Aβ) Aβ42/Aβ40 ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.MethodsTaking plasma samples at 3 separate time points, month 18 (n = 176), month 36 (n = 169), and month 54 (n = 135), we assessed the total Aβ42/Aβ40 ratio in plasma (TP42/40) with regard to neocortical Aβ burden via PET standardized uptake value ratio (SUVR) and investigated both association with Aβ-PET status and correlation (and agreement) with SUVR.ResultsThe TP42/40 plasma ratio was significantly reduced in amyloid-PET-positive participants at all time points (p < 0.0001). Adjusting for covariates age, gender, APOE ε4 allele status, and clinical classification clearly affects the significance, with p values reduced and only comparisons at 54 months retaining significance (p = 0.006). Correlations with SUVR were similar across each time point, with Spearman ρ reaching -0.64 (p < 0.0001). Area under the curve values were highly reproducible over time points, with values ranging from 0.880 at 36 months to 0.913 at 54 months. In assessments of the healthy control group only, the same relationships were found.ConclusionsThe current study demonstrates reproducibility of the plasma assay to discriminate between amyloid-PET positive and negative over 3 time points, which can help to substantially reducing the screening rate of failure for clinical trials targeting preclinical or prodromal disease.Classification of evidenceThis study provides Class II evidence that plasma total Aβ42/Aβ40 ratio is associated with neocortical amyloid burden as measured by PET SUVR.
| S-EPMC7251518 | biostudies-literature
Project description:Plasma amyloid ? (A?) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease.Free and total A?42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed-up for 72 months and their cortical A? burden was assessed with positron emission tomography.Cross-sectional and longitudinal analyses showed an inverse association of A?42/40 plasma ratios and cortical A? burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical A? burden, which represents 110% increase over the population prevalence of cortical A? positivity.These findings support the use of plasma A?42/40 ratios as surrogate biomarkers of cortical A? deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.
| S-EPMC5602863 | biostudies-other
Project description:ObjectiveCognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease.MethodsA total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.ResultsLower baseline CSF Aβ(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aβ(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline.ConclusionsReduced CSF Aβ(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
| S-EPMC2942062 | biostudies-literature