| 1. |
- Ashton, Nicholas J., et al.
(author)
-
Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
- 2024
-
In: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
-
Journal article (peer-reviewed)abstract
- ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (A beta) and longitudinal change across 3 selected cohorts. Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. ExposuresMagnetic resonance imaging, A beta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A beta 42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A beta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A beta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A beta-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
|
|
| 2. |
- Brum, Wagner S., et al.
(author)
-
Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals
- 2024
-
In: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:2, s. 1284-1297
-
Journal article (peer-reviewed)abstract
- INTRODUCTION: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data. METHODS: We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CVI) and between-subject (CVG) BV, analytical variation, and reference change values (RCV). RESULTS: Biomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase). DISCUSSION: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability. Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context. Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level. Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.
|
|
| 3. |
- Emersic, Andreja, et al.
(author)
-
Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies
- 2024
-
In: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
-
Journal article (peer-reviewed)abstract
- INTRODUCTIONThe established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. METHODSWe investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. RESULTSN-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p <= 001). Concentrations in CJD(+AD )were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). DISCUSSIONVariable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. Highlights N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (A beta) co-pathology. N-terminal p-tau181 and p-tau231 in A beta-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.
|
|
| 4. |
- Huber, Hanna, 1989, et al.
(author)
-
Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots-A new collection method for remote settings
- 2024
-
In: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
-
Journal article (peer-reviewed)abstract
- BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (A beta) 40, A beta 42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for A beta 42. In the validation cohort, DPSvenous GFAP, NfL, p-tau181, and p-tau217 differed between CSF A beta-positive and -negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood-based biomarkers to remote settings with simplified sampling conditions, storage, and logistics.
|
|
| 5. |
- Lantero Rodriguez, Juan, et al.
(author)
-
CSF p-tau205: a biomarker of tau pathology in Alzheimer's disease.
- 2024
-
In: Acta neuropathologica. - 1432-0533. ; 147:1
-
Journal article (peer-reviewed)abstract
- Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n=47), an unselected clinical cohort (n=212) and a research cohort well-characterized by fluid and imaging biomarkers (n=262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid(Aβ) and tau pathology positive (A+T+) cases (P<0.01). In A+cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (rSp205=0.67, rSp202=0.45) than Aβ-PET (rSp205=0.40, rSp202=0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P<0.01), whereas p-tau202 only increased in Braak V-VI (P<0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V-VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R2=69.7%; CSF p-tau202: R2=85.6%) Both biomarkers associated with brain atrophy measurements globally (rSp205=-0.36, rSp202=-0.33) and regionally, and correlated with cognition (rSp205=-0.38/-0.40, rSp202=-0.20/-0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials.
|
|
| 6. |
- Lantero Rodriguez, Juan, et al.
(author)
-
Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer's Disease
- 2024
-
In: MOLECULAR NEURODEGENERATION. - 1750-1326. ; 19:1
-
Journal article (peer-reviewed)abstract
- Background Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-beta (A beta) and tau pathology. However, because these biomarkers are strongly associated with the emergence of A beta pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain. Methods NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline. Results We demonstrate that plasma NTA-tau increases across the AD continuum, especially during late stages, and displays a moderate-to-strong association with tau-PET (beta = 0.54, p < 0.001) in A beta-positive participants, while weak with A beta-PET (beta = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R-2), while having very low contribution from A beta pathology measured with CSF A beta 42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R-2 = 0.27), steeper atrophy (R-2 >= 0.18) and steeper cognitive decline (R-2 >= 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in A beta positive cognitively unimpaired (beta(std) = 0.16) and impaired (beta(std) = 0.18) at baseline compared to their A beta negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R-2 = 0.21) and cognition (R-2 = 0.20). Conclusion Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful A beta removal.
|
|
| 7. |
- Lantero Rodriguez, Juan, et al.
(author)
-
Tau protein profiling in tauopathies: a human brain study
- 2024
-
In: MOLECULAR NEURODEGENERATION. - 1750-1326. ; 19:1
-
Journal article (peer-reviewed)abstract
- Abnormal accumulation of misfolded and hyperphosphorylated tau protein in brain is the defining feature of several neurodegenerative diseases called tauopathies, including Alzheimer's disease (AD). In AD, this pathological change is reflected by highly specific cerebrospinal fluid (CSF) tau biomarkers, including both phosphorylated and non-phosphorylated variants. Interestingly, despite tau pathology being at the core of all tauopathies, CSF tau biomarkers remain unchanged in certain tauopathies, e.g., progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal neurodegeneration (CBD). To better understand commonalities and differences between tauopathies, we report a multiplex assay combining immunoprecipitation and high-resolution mass spectrometry capable of detecting and quantifying peptides from different tau protein isoforms as well as non-phosphorylated and phosphorylated peptides, including those carrying multiple phosphorylations. We investigated the tau proteoforms in soluble and insoluble fractions of brain tissue from subjects with autopsy-confirmed tauopathies, including sporadic AD (n = 10), PSP (n = 11), PiD (n = 10), and CBD (n = 10), and controls (n = 10). Our results demonstrate that non-phosphorylated tau profiles differ across tauopathies, generally showing high abundance of microtubule-binding region (MTBR)-containing peptides in insoluble protein fractions compared with controls; the AD group showed 12-72 times higher levels of MTBR-containing aggregates. Quantification of tau isoforms showed the 3R being more abundant in PiD and the 4R isoform being more abundant in CBD and PSP in the insoluble fraction. Twenty-three different phosphorylated peptides were quantified. Most phosphorylated peptides were measurable in all investigated tauopathies. All phosphorylated peptides were significantly increased in AD insoluble fraction. However, doubly and triply phosphorylated peptides were significantly increased in AD even in the soluble fraction. Results were replicated using a validation cohort comprising AD (n = 10), CBD (n = 10), and controls (n = 10). Our study demonstrates that abnormal levels of phosphorylation and aggregation do indeed occur in non-AD tauopathies, however, both appear pronouncedly increased in AD, becoming a distinctive characteristic of AD pathology.
|
|
| 8. |
- Mattsson-Carlgren, Niklas, et al.
(author)
-
Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies
- 2024
-
In: JAMA neurology. - 2168-6157 .- 2168-6149. ; 81:1, s. 69-78
-
Journal article (peer-reviewed)abstract
- Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this.To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation.The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%).Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain.Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker-guided workflow.Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC]=0.94; 95% CI, 0.90-0.97). A 2-cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC=0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n=118).This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.
|
|
| 9. |
- Montoliu-Gaya, Laia, et al.
(author)
-
Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.
- 2024
-
In: Acta neuropathologica. - 1432-0533. ; 147:1
-
Journal article (peer-reviewed)abstract
- Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD=69, non-AD=54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC=89.8), p-tau231 (AUC=83.4), and p-tau205 (AUC=81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR<1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217=15.29, ORp-tau205=5.05 and ORp-tau231=3.86) and Braak staging (ORp-tau217=14.29, ORp-tau205=5.27 and ORp-tau231=4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.
|
|
| 10. |
- Woo, M. S., et al.
(author)
-
Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals
- 2024
-
In: Alzheimers & Dementia. - 1552-5260. ; 20:2, s. 1166-1174
-
Journal article (peer-reviewed)abstract
- INTRODUCTIONWe set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (A beta) positive participants using plasma biomarkers.METHODSIn this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18F]AZD4694 and tau-PET with [18F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in A beta+ individuals.RESULTSHighest associations with tau positivity in A beta+ individuals were found for plasma pTau-217 (AUC [CI95%] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95%] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95% = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity.DISCUSSIONThe potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice.HighlightsWe found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity.We found that in A beta+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity.Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.
|
|
