Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Acta Neuropathologica, Год журнала: 2021, Номер 141(5), С. 709 - 724

Опубликована: Фев. 14, 2021

Abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise detecting Alzheimer’s disease (AD) pathophysiology. Tau at threonine 231 (p-tau231) is one such biomarker CSF but its usefulness as a blood currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the plasma p-tau231 which was validated four independent cohorts ( n = 588) different settings, including full AD continuum and non-AD neurodegenerative disorders. Plasma able to identify patients with differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults high accuracy (AUC 0.92–0.94). also distinguished disorders 0.93), well MCI 0.89). In neuropathology cohort, samples taken on avergae 4.2 years prior post-mortem very accurately identified comparison 0.99), this despite all being given dementia diagnosis during life. highly correlated p-tau231, pathology assessed by [ 18 F]MK-6240 positron emission tomography (PET), brain amyloidosis F]AZD469 PET. Remarkably, inflection point increasing function continuous PET standardized uptake value ratio, be earlier than standard thresholds positivity increase p-tau181. Furthermore, significantly increased quartiles 2–4, whereas p-tau217 p-tau181 only 3–4 4, respectively. Finally, differentiated individuals across entire Braak stage spectrum, staging 0 through I–II, not observed To conclude, novel assay identifies clinical stages equally p-tau181, increases earlier, already subtle deposition, threshold been attained, response early deposition. Thus, promising emerging potential facilitate trials vulnerable populations below apparent entorhinal

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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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

JAMA Neurology, Год журнала: 2024, Номер 81(3), С. 255 - 255

Опубликована: Янв. 22, 2024

Importance Phosphorylated 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 tests research and clinical use has been limited. Expanding access this highly accurate AD crucial wider evaluation implementation tests. Objective To determine utility novel commercially available immunoassay plasma detect pathology evaluate reference ranges abnormal amyloid β (Aβ) longitudinal change across 3 selected cohorts. Design, Setting, Participants This cohort study examined data from single-center observational cohorts: cross-sectional Translational Biomarkers in Aging Dementia (TRIAD) (visits October 2017–August 2021) Wisconsin Registry Alzheimer’s Prevention (WRAP) February 2007–November 2020) Sant Pau Initiative on Neurodegeneration (SPIN) (baseline visits March 2009–November 2021). included individuals without cognitive impairment grouped by (AT) status using PET or CSF biomarkers. Data were analyzed June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 p-tau immunoassays), (ALZpath pTau217 assay). Main Outcomes Measures Accuracy detecting according baseline status. Results The 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] 282 males [35.9%]). High accuracy was observed identifying elevated (area under curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) (AUC, 0.93-0.97; 0.84-0.99) all These accuracies comparable determining signal. detection 3-range yielded reproducible results reduced confirmatory testing approximately 80%. Longitudinally, values showed an annual increase only Aβ-positive individuals, highest those positivity. Conclusions Relevance found that accurately identified biological AD, biomarkers, cut-offs It detected changes, including at preclinical stage.

Язык: Английский

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Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease

Nature Medicine, Год журнала: 2022, Номер unknown

Опубликована: Авг. 11, 2022

Abstract Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer’s disease are needed to facilitate the initial screening process of participants disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood is lacking. In ALFA+ cohort, all tested plasma (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed disease. However, p-tau231 reached abnormal levels lowest burden. Plasma p-tau217 had strongest association positron emission tomography (PET) retention early accumulating regions associated longitudinal increases PET uptake individuals without overt at baseline. summary, better capture earliest cerebral changes, before plaque present, promising enrich population for clinical

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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Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

JAMA Neurology, Год журнала: 2022, Номер 80(2), С. 188 - 188

Опубликована: Дек. 12, 2022

Importance The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies Alzheimer disease (AD): amyloid-β plaques and neurofibrillary tangles. Objective To determine whether cerebrospinal fluid (CSF) plasma p-tau preferentially reflect cerebral β-amyloidosis or tangle aggregation measured positron emission tomography (PET). Design, Setting, Participants This was a cross-sectional study 2 observational cohorts: Translational Biomarkers in Aging Dementia (TRIAD) study, data collected between October 2017 August 2021, Alzheimer’s Disease Neuroimaging Initiative (ADNI), September 2015 November 2019. TRIAD single-center ADNI multicenter study. Two independent subsamples were derived from TRIAD. first subsample comprised individuals assessed CSF (p-tau 181 , 217 231 235 ), [ 18 F]AZD4694 amyloid PET, F]MK6240 PET. second included An cohort F]florbetapir F]flortaucipir based on availability PET biomarker assessments within 9 months each other. Exclusion criteria history head trauma magnetic resonance imaging/PET safety contraindications. No participants who met eligibility excluded. Exposures Amyloid single molecule array (Simoa) assay enzyme-linked immunosorbent assay. Main Outcomes Measures Associations Results A total 609 (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) For all 4 phosphorylation sites CSF, significantly more closely associated amyloid-PET values than tau-PET difference, 13%; 95% CI, 3%-22%; P = .006; 11%; 3%-20%; .003; 15%; 5%-22%; < .001; 9%; 1%-19%; .02) . These results replicated (difference, 1%-22%; .02), 3%-24%; .009), 1%-21%; cohorts. Conclusions Relevance this cohorts suggest that abnormality as an early event AD pathogenesis accumulation highlights need for careful interpretation context amyloid/tau/neurodegeneration, A/T/(N), framework.

Язык: Английский

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Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape

Neuron, Год журнала: 2023, Номер 111(18), С. 2781 - 2799

Опубликована: Июнь 8, 2023

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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The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

European Journal of Nuclear Medicine and Molecular Imaging, Год журнала: 2021, Номер 48(7), С. 2140 - 2156

Опубликована: Март 6, 2021

Abstract Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included in systematic validation biomarkers. Methods A panel experts convened November 2019 at a two-day workshop Geneva. level maturity (fully achieved, partly preliminary evidence, not unsuccessful) was assessed based on methodology discussed fully during which also evaluated cerebrospinal fluid (CSF) positron emission tomography (PET) Results Plasma p-tau shown analytical validity (phase 2 primary aim 1) first evidence clinical 3 1), whereas Aβ remains to be partially achieved. Full partial achievement been assigned Aβ, respectively, their associations ante-mortem measures secondary 2). However, only exists influence covariates, assay comparison cut-off criteria. Conclusions Despite relative infancy biomarkers, CSF much already achieved phases 1 through – with having greater success detecting predicting progression. sufficient data about effect covariates biomarker measurement is lacking. No phase 4 (real-world performance) or 5 (assessment impact/cost) tested, thus

Язык: Английский

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CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Nature Aging, Год журнала: 2023, Номер 3(4), С. 391 - 401

Опубликована: Март 13, 2023

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations nine five nonphosphorylated species phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) ten sites. In we show that, in 750 individuals with a median age 71.2 years, CSF pT217/T217 predicted presence brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for positive PET (n 263), was more strongly correlated amount (Spearman's ρ 0.69) (ρ -0.42, P < 0.0001). two independent cohorts participants symptoms AD dementia 55 n 90), pT205/T205 were measures p-tau181 concentration. These findings suggest that represent improved pathology AD.

Язык: Английский

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