Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

Brain, Год журнала: 2022, Номер 146(4), С. 1592 - 1601

Опубликована: Сен. 10, 2022

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status predict future progression dementia. The study included 135 patients with baseline diagnosis mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average 4.9 years. Seventy-one participants had Aβ-status (i.e. CSF Aβ42/40) at baseline; 45 these Aβ-positive progressed dementia during follow-up. P-tau concentrations determined in plasma CSF. P-tau217 p-tau181 both immunoassays developed by Lilly Research Laboratories (Lilly) mass spectrometry Washington University (WashU). was also analysed Simoa immunoassay Janssen Development (Janss). P-tau181 from ADxNeurosciences (ADx), Lumipulse Fujirebio (Fuji) Splex Mesoscale Discovery (Splex). Both quantified Gothenburg (UGOT). We found that spectrometry-based (p-tau217WashU) exhibited significantly better performance than all other p-tau when detecting Aβ [area under curve (AUC) = 0.947; Pdiff < 0.015] or (AUC 0.932; 0.027). Among immunoassays, p-tau217Lilly highest AUCs (0.886-0.889), which not different p-tau217Janss, p-tau181ADx p-tau181WashU (AUCrange 0.835-0.872; > 0.09), but higher compared AUC p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji p-tau181Splex 0.642-0.813; ≤ 0.029). Correlations between values strongest p-tau217WashU (R 0.891) 0.755; 0.003 versus p-tau217WashU) weak moderate rest (Rrange 0.320-0.669). In conclusion, our findings suggest among tested assays, measures perform best identifying those will subsequently progress Several (p-tau217Lilly, p-tau181WashU) showed relatively high consistent accuracy across outcomes. results further indicate performing metrics rival gold standards Aβ-PET If validated, significant impacts diagnosis, screening treatment future.

Язык: Английский

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Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials

The Lancet Neurology, Год журнала: 2022, Номер 21(8), С. 726 - 734

Опубликована: Май 25, 2022

Язык: Английский

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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Nature Medicine, Год журнала: 2022, Номер 28(12), С. 2555 - 2562

Опубликована: Дек. 1, 2022

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages the disease. Distinctive may be optimal for identification AD or monitoring progression. that correlate with changes cognition atrophy during course could used clinical trials to identify successful interventions thereby accelerate development efficient therapies. When disease-modifying treatments become approved use, blood-based might also inform on treatment implementation management practice. In BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 amyloid-β42/40 ratio were more changed at lower thresholds amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent over 4–6 years disease, no such observed p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein neurofilament light. Only longitudinal increases associated deterioration brain AD. The selective increase its associations cognitive decline was confirmed an independent cohort (Wisconsin Registry Prevention). These findings support differential association strongly highlight as a surrogate marker progression prodromal AD, impact new treatments.

Язык: Английский

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Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility

Nature Reviews Neurology, Год журнала: 2022, Номер 18(7), С. 400 - 418

Опубликована: Май 18, 2022

Язык: Английский

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Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration

Brain, Год журнала: 2022, Номер 146(3), С. 1152 - 1165

Опубликована: Дек. 27, 2022

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies agreements with their corresponding CSF neuroimaging in the amyloid/tau/neurodegeneration [A/T/(N)] framework Alzheimer's disease. However, blood-based neurodegeneration marker neurofilament light is not specific to disease while total-tau shows lack of correlation total-tau. Recent studies suggest that blood originates principally from peripheral, non-brain sources. We sought address this challenge by generating an anti-tau antibody selectively binds brain-derived avoids peripherally expressed 'big tau' isoform. applied develop ultrasensitive assay tau, validated it five independent cohorts (n = 609) including a blood-to-autopsy cohort, biomarker-classified memory clinic cohorts. In paired samples, serum were significantly correlated (rho 0.85, P < 0.0001), 0.23, 0.3364). showed equivalent performance as separate biomarker-positive participants biomarker-negative controls. Furthermore, plasma accurately distinguished autopsy-confirmed other neurodegenerative diseases (area under curve 86.4%) did 54.3%). These performances presence concomitant pathologies. Plasma 0.52-0.67, 0.003), but -0.14-0.17, 0.501), was associated global regional plaque neurofibrillary tangle counts. results further verified two where differentiated range disorders, frontotemporal lobar degeneration atypical parkinsonian disorders up 99.6%). Notably, plasma/serum only diseases. Across cohorts, AT(N) cognitive function. Brain-derived new biomarker outperforms and, unlike light, specificity disease-type neurodegeneration. Thus, demonstrates potential complete scheme blood, will be useful evaluate disease-dependent processes clinical research purposes.

Язык: Английский

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Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Март 16, 2023

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, healthcare systems. Although AD can be identified diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence clinical symptoms, challenges regarding practicality accessibility hinder widespread availability implementation. Consequently, many people suspected cognitive impairment due to do not receive biomarker-supported diagnosis. Blood have capacity help expand access diagnostics worldwide. One such promising biomarker plasma phosphorylated tau (p-tau), which has demonstrated specificity versus non-AD neurodegenerative diseases, will extremely important inform diagnosis eligibility for therapies recently been approved. This review provides an update diagnostic prognostic performances p-tau181, p-tau217 p-tau231, associations in vivo autopsy-verified pathological hallmarks. Additionally, we discuss potential applications unanswered questions p-tau therapeutic trials, given recent addition toolbox participant screening, recruitment during-trial monitoring. Outstanding include assay standardization, threshold generation verification diverse cohorts reflective wider community attending memory clinics included trials.

Язык: Английский

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Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(5)

Опубликована: Март 13, 2023

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates not yet fully determined. To investigate and compare independent associations between multiple (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, NfL) neuropathologic measures of amyloid tau, we included 105 participants from the Arizona Study Aging Neurodegenerative Disorders (AZSAND) with antemortem samples a postmortem exam, 48 whom had longitudinal p-tau217 p-tau181. When simultaneously including plaque tangle loads, Aβ42/40 ratio p-tau231 were only associated plaques (ρAβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 0.28[0.10, 0.43]), GFAP was tangles (ρGFAP 0.39[0.17, 0.57]), p-tau181 both (ρp-tau217 0.40[0.21, 0.56], ρp-tau181 0.36[0.15, 0.50]) 0.52[0.34, 0.66]; 0.36[0.17, 0.52]). A model combining showed highest accuracy predicting presence change (ADNC, AUC[95%CI] 0.89[0.82, 0.96]) load (R2 0.55), while alone optimal 0.45). Our results suggest that high-performing assays might be an combination to assess Alzheimer's-related pathology in vivo.

Язык: Английский

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Predicting amyloid PET and tau PET stages with plasma biomarkers

Brain, Год журнала: 2023, Номер 146(5), С. 2029 - 2044

Опубликована: Фев. 15, 2023

Abstract Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid tau PET has face validity; however, this would be more practical plasma biomarkers. Our objectives were, first, to examine approaches and, second, prediction stages Participants (n = 1136) were enrolled in either Mayo Clinic Study Aging or Research Center; had a concurrent PET, blood draw; met criteria cognitively unimpaired 864), mild cognitive impairment 148) syndrome dementia 124). The latter two groups combined into impaired group 272). We used multinomial regression models estimate discrimination [concordance (C) statistics] among three (low, intermediate, high), four (Braak 0, 1–2, 3–4, 5–6) stage (none/low versus intermediate/high severity) as predictors separately within individuals. Plasma analytes, p-tau181, Aβ1–42 Aβ1–40 (analysed Aβ42/Aβ40 ratio), glial fibrillary acidic protein neurofilament light chain measured on HD-X Simoa Quanterix platform. p-tau217 was also subset 355) participants Lilly Meso Scale Discovery assay. Models all analytes along risk factors (age, sex APOE) most often provided best (C 0.78–0.82). p-tau181 similar 0.72–0.85 C 0.73–0.86). Discriminating proxy from none/low neuropathological change excellent but not better than only 0.88 0.87 0.91 0.90 impaired). outperformed assay discriminating high intermediate 0.85 0.74) did improve over model 0.83). can discriminate between surrogate accuracy acceptable range. Combinations are single many predictions exception that alone usually performed equivalently combinations discrimination.

Язык: Английский

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Plasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 24, 2023

Abstract Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer’s disease (AD). However, whether these can predict AD in Chinese populations is yet to be fully explored. We therefore tested the performance plasma 126 participants with preclinical 123 controls 8–10 years follow-up from China Cognition Aging Study. Aβ42, p-tau181, NfL were significantly correlated cerebrospinal fluid counterparts altered AD. Combining successfully discriminated controls. These findings validated a replication cohort including 51 familial mutation carriers 52 non-carriers Familial Disease Network. Here we show that may useful for predicting 8 before clinical onset populations.

Язык: Английский

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Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 23, 2024

Abstract Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize forms additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that specific without cross-reactivity p-tau217. Here, we examined diagnostic utility p-tau212. In five cohorts ( n = 388 participants), showed performances for diagnosis detection both amyloid pathology, autopsy as well in memory clinic populations. The accuracy fold changes were similar those higher than p-tau181 p-tau231. Immunofluorescent staining brain tissue slices prominent reactivity neurofibrillary tangles co-localized p-tau202/205. These findings support peripherally accessible biomarker pathophysiology.

Язык: Английский

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