Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Background: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results: Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100). Conclusions: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease

Neprilysin Is Poorly Expressed in the Prefrontal Cortex of Aged Dogs with Cognitive Dysfunction Syndrome

Neprilysin (NEP) is the principal amyloid β (Aβ) degrading peptidase; this activity may protect against Alzheimer’s disease (AD), the most important age-related neurodegenerative process. The aim of this work was to analyze NEP mRNA expression in the frontal cortex of dogs with and without canine cognitive dysfunction syndrome (CDS), which is considered a natural model for AD. Expression of canine cerebral NEP mRNA was assessed by RT-PCR followed by qPCR in young, aged-cognitively unimpaired (CU), and aged-cognitively impaired (CI) dogs. On average, aged-CI dogs showed 80% (P<0.01) lower expression levels of NEP mRNA than their aged-CU counterparts. Furthermore, the standard deviation of the qPCR measurements was more than 6 times higher in the cognitively healthy animals (young and aged-CU) than in the aged-CI group. Another interesting find is the determination of a positive correlation between NEP expression and the number of cholinergic neurons in basal telencephalon, indicating a probable connection between both events in these types of neurodegeneration processes. These results suggest that high expression levels of NEP might be a protective factor for canine CDS and, most likely, for other Aβ-associated neurodegenerative diseases, such as AD

Clinical utility of an antibody‐free LC‐MS method to detect brain amyloid deposition in cognitively unimpaired individuals from the screening visit of the A4 Study

IntroductionThis study explored the ability of plasma amyloid beta (Aβ)42/Aβ40 to identify brain amyloid deposition in cognitively unimpaired (CU) individuals.MethodsPlasma Aβ was quantified with an antibody-free high-performance liquid chromatography tandem mass spectrometry method from Araclon Biotech (ABtest-MS) in a subset of 731 CU individuals from the screening visit of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study, to assess associations of Aβ42/Aβ40 with Aβ positron emission tomography (PET).ResultsA model including Aβ42/Aβ40, age, apolipoprotein E ε4, and recruitment site identified Aβ PET status with an area under the curve of 0.88 and an overall accuracy of 81%. A plasma-based pre-screening step could save up to 42% of the total number of Aβ PET scans.DiscussionABtest-MS accurately identified brain amyloid deposition in a population of CU individuals, supporting its implementation in AD secondary prevention trials to reduce recruitment time and costs. Although a certain degree of heterogeneity is inherent to large and multicentric trials, ABtest-MS could be more robust to pre-analytical bias compared to other immunoprecipitation mass spectrometry methods.HighlightsPlasma amyloid beta (Aβ)42/Aβ40 accurately identified brain Aβ deposition in cognitively unimpaired individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study.The inclusion of the recruitment site in the predictive models has a non-negligible effect.A plasma biomarker-based model could reduce recruitment costs in Alzheimer's disease secondary prevention trials.Antibody-free liquid chromatography mass spectrometry methods may be more robust to pre-analytical variability than other platforms

Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity : A cross-sectional analysis from the AB255 Study

To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer's disease

Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease

Importance: Blood-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. Objective: To 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 Participants: This 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 Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status. Results: A 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 Relevance: The 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

Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations

We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice

Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aβ42/Aβ40 and p-tau

Introduction: We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages of early Alzheimer's disease (AD). Methods: Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N = 591) and patients with mild cognitive impairment (MCI, N = 304) from two independent cohorts (BioFINDER-1, BioFINDER-2). Results: In CU, a combination of plasma Aβ42/Aβ40 and p-tau217 detected abnormal brain Aβ status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or Aβ42/Aβ40 and p-tau217 had similar AUCs (0.86–0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/). Discussion: A combination of plasma Aβ42/Aβ40 and p-tau217 discriminated Aβ status with relatively high accuracy, whereas p-tau217 showed strongest associations with Aβ pathology in MCI but not in CU

Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Background: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results: Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100). Conclusions: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease

Le Cri du peuple : journal politique quotidien

28 juin 18861886/06/28 (A3,N973)-1886/06/28