Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays
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SUBMITTER: Keshavan A
PROVIDER: S-EPMC7503103 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:IntroductionWe assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).MethodsIn 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter-platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n = 63).ResultsMeasurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p-tau181.DiscussionThe Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.
| S-EPMC7867115 | biostudies-literature
Project description:Backgroundβ-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.MethodsUsing automated Elecsys® assays (Roche Diagnostics) for Aβ (1-42) (Aβ42), Aβ (1-40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging.ResultsRatios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers.ConclusionStrong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.
| S-EPMC7110644 | biostudies-literature
Project description:IntroductionWe evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)1- 42-ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ1- 42 alone.MethodsWe selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ1- 42, phosphorylated tau (p-tau), and total tau (t-tau) were measured with Elecsys and Lumipulse assays, and Aβ1-40 with Lumipulse. CSF cut-points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.ResultsFor both Elecsys and Lumipulse the p-tau/Aβ1- 42, Aβ1- 42/Aβ1- 40, and t-tau/Aβ1- 42 ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aβ1- 42 alone (Elecsys 85%; Lumipulse 84%).DiscussionBiomarker ratios p-tau/Aβ1- 42, Aβ1- 42/Aβ1- 40, t-tau/Aβ1- 42 on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.
| S-EPMC8088096 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on ?-amyloid (A?) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans.MethodsAmong 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n?=?128 with overlapping CSF and A?-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. A?42, A?40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with A?-PET, was evaluated.ResultsCognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the A?-PET status in a subgroup without CSF (n?=?143), and then when we applied CSF biomarker cutoffs determined based on the A?-PET status, the CSF biomarkers (cutoffs of 642.1?pg/mL for A?42, 0.060 for A?42/A?40, 0.315 for t-tau/A?42, and 0.051 for p-tau/A?42, respectively) showed good agreement with A?-PET (overall AUC ranges of 0.840-0.898). Use of the A?-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (A?42, A?42/A?40, t-tau/A?42, and p-tau/A?42) with overall AUC ranges of 0.876-0.952. During follow-up, participants with AD-like CSF signature determined by A?-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature.ConclusionCSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with A?-PET in Koreans. The Korean-specific A?-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
| S-EPMC7802266 | biostudies-literature
Project description:ObjectiveTo determine the cutoffs that optimized the agreement between 18 F-Florbetapir positron emission tomography (PET) and A?1-42, A?1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available 18 F-Florbetapir imaging.MethodsParticipants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of A?1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18 F-Florbetapir PET and evaluated concordance between markers of the amyloid category.ResultsA?1-42, tTau and pTau (but not A?1-40) and the ratios with A?1-42 had good diagnostic agreement with 18 F-Florbetapir PET. As a marker of amyloid pathology, the A?1-42/A?1-40 ratio had higher agreement and better correlation with amyloid PET than A?1-42 alone.InterpretationCSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of A?1-42 with A?1-40 increases the agreement between markers of amyloid pathology.
| S-EPMC6764494 | biostudies-literature
Project description:IntroductionCerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use.MethodsCSF amyloid ?42 peptide (A?42), t-tau, and t-tau/A?42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240).ResultsVirtually identical t-tau/A?42 cut-points (?0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D.DiscussionLumipulse CSF biomarker measures with validated cut-points have clinical utility in identifying AD pathology.
| S-EPMC7061432 | biostudies-literature
Project description:Importance:Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure ?-amyloid (A?) 42 in cerebrospinal fluid (CSF). The agreement between CSF A?42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials. Objective:To determine the concordance between CSF A?42 levels measured using 5 different immunoassays and visual amyloid PET analysis. Design, Setting, and Participants:The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF A?42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF A? were assessed using an antibody-independent mass spectrometry-based reference measurement procedure. Main Outcomes and Measures:The concordance of CSF A?42 levels and A?42:A?40 and A?42:tau ratios with visual [18F]flutemetamol PET status. Results:Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived A?42 values showed higher correlations with the modified A?42-INNOTEST (r?=?0.97), A?42-FL (r?=?0.93), A?42-EI (r?=?0.93), and A?42-MSD (r?=?0.95) assays compared with the classic A?42-INNOTEST assay (r?=?0.88; P???.01). The signal in the classic A?42-INNOTEST assay was partly quenched by recombinant A?1-40 peptide. However, the classic A?42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P???.01). The accuracies of the newer assays improved significantly when A?42:A?40 (AUCs, 0.93-0.95; P???.01), A?42 to total tau (T-tau) (AUCs, 0.94; P???.05), or A?42 to phosphorylated tau (P-tau) (AUCs, 0.94-0.95; P???.001) ratios were used. A combination of the A?42:A?40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone. Conclusions and Relevance:Concentrations of CSF A?42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry-based reference measurement procedure and may show improved agreement with visual [18F]flutemetamol PET assessment when using the A?42:A?40 or A?42:tau ratios. These findings suggest the benefit of implementing the CSF A?42:A?40 or A?42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials.
| S-EPMC5822196 | biostudies-literature
Project description:Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of ?-amyloid (A?42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of A?42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, A?40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF A?42 levels below 530?pg?ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of A?. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ?4 and amyloid pathology in healthy older individuals.
| S-EPMC5545720 | biostudies-literature
Project description:INTRODUCTION:We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. METHODS:Cutoffs for Elecsys amyloid-?1-42 (A?), total tau/A?(1-42), and phosphorylated tau/A?(1-42) were defined against [18F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. RESULTS:CSF total tau/A?(1-42) and phosphorylated tau/A?(1-42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%-90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/A? ratios were as accurate as semiquantitative PET image assessment in predicting visual read-based outcomes. DISCUSSION:Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.
| S-EPMC6119541 | biostudies-literature
Project description:The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of ?-amyloid (CSF A?1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (?-amyloidosis) or preclinical AD stage 2+ (?-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without ?-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures.
| S-EPMC4913039 | biostudies-literature