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BACKGROUND: Large vessel occlusion acute ischemic stroke prognosis improved following the 2015 endovascular therapy (EVT) trials. Blood-based biomarkers may improve outcome prediction. We aimed to assess plasma brain-derived tau (BD-Tau) performance in predicting post-EVT large vessel occlusion acute ischemic stroke outcomes. METHODS: We included 2 temporally independent prospective cohorts of anterior circulation in patients with large vessel occlusion acute ischemic stroke who successfully recanalized post-EVT. We measured plasma BD-Tau, GFAP (glial-fibrillary-acidic-protein), NfL (neurofilament-light-chain), and total-Tau upon admission, immediately, 24 hours, and 72 hours post-EVT. Twenty-four-hour neuroimaging and 90-day functional outcomes were independently assessed using the Alberta Stroke Program Early Computed Tomography Score (good outcome: >7 or unchanged) and the modified Rankin Scale (favorable outcome <3 or unchanged), respectively. Based on the first cohort (derivation), we built a multivariable logistic regression model to predict a 90-day functional outcome. Model results were evaluated using the second cohort (evaluation). RESULTS: In the derivation cohort (n=78, mean age=72.9 years, 50% women), 62% of patients had a good 24-hour neuroimaging outcome, and 45% had a favorable 90-day functional outcome. GFAP admission-to-EVT rate-of-change was the best predictor for early neuroimaging outcome but not for 90-day functional outcome. At admission, BD-Tau levels presented the highest discriminative performance for 90-day functional outcomes (area under the curve, 0.76 [95% CI, 0.65-0.87]; P<0.001). The model incorporating age, admission BD-Tau, and 24-hour Alberta Stroke Program Early Computed Tomography Score achieved excellent discrimination of 90-day functional outcome (area under the curve, 0.89 [95% CI, 0.82-0.97]; P<0.001). The score's predictive performance was maintained in the evaluation cohort (n=66; area under the curve, 0.82 [95% CI, 0.71-0.92]; P<0.001). CONCLUSIONS: Admission plasma BD-Tau accurately predicted 90-day functional outcomes in patients with large vessel occlusion acute ischemic stroke after successful EVT. The proposed model may predict functional outcomes using objective measures, minimizing human-related biases and serving as a simplified prognostic tool for AIS.
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Biomarcadores , Accidente Cerebrovascular Isquémico , Proteínas tau , Humanos , Femenino , Masculino , Anciano , Proteínas tau/sangre , Pronóstico , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/terapia , Persona de Mediana Edad , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Prospectivos , Procedimientos Endovasculares/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/irrigación sanguínea , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/sangre , Isquemia Encefálica/terapia , Estudios de Cohortes , Proteína Ácida Fibrilar de la Glía/sangreRESUMEN
Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Proteínas tau , Encéfalo , BiomarcadoresRESUMEN
Alzheimer's disease (AD) represents a growing global health challenge, necessitating accurate and reliable diagnostic methodologies for timely intervention and management. Immunoassays, specifically designed to detect biomarkers associated with AD pathology, have emerged as pivotal tools in diagnostic development. Understanding of the established protocols ensures assay sensitivity, specificity, and reproducibility, thereby enhancing the clinical utility of these diagnostic tools. Here, we explore the considerations in immunoassay development, focusing on phosphorylated tau217 assays. Ultimately, a clear understanding of immunoassay development is paramount in advancing the precision and reliability of AD diagnostics, contributing to early detection, improved patient outcomes, and advancements in therapeutic interventions.
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Enfermedad de Alzheimer , Humanos , Reproducibilidad de los Resultados , Enfermedad de Alzheimer/diagnóstico , Plasma , Biomarcadores , Proteínas tau , Péptidos beta-AmiloidesRESUMEN
INTRODUCTION: Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. METHODS: We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). RESULTS: Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001). DISCUSSION: Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.
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Enfermedad de Alzheimer , Síndrome de Creutzfeldt-Jakob , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Encéfalo , Biomarcadores/líquido cefalorraquídeo , Diagnóstico Diferencial , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
INTRODUCTION: The 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. METHODS: We 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. RESULTS: N-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). DISCUSSION: Variable 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 (Aß) co-pathology. N-terminal p-tau181 and p-tau231 in Aß-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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Síndrome de Creutzfeldt-Jakob , Proteínas tau , Humanos , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Fosforilación , Persona de Mediana Edad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited. METHODS: We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaßeta Brain Research Center's Alzheimer's At-Risk Cohort [ß-AARC]). RESULTS: UGOT p-tau217 showed high accuracy (area under the curve [AUC] = 0.80-0.91) identifying amyloid beta (Aß) pathology, determined either by Aß positron emission tomography or CSF Aß42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aß42/40 ratio (AUC = 0.91). DISCUSSION: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Encéfalo , Biomarcadores/líquido cefalorraquídeoRESUMEN
INTRODUCTION: We investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau). METHODS: We evaluated (i) Cohort 1: paired EDTA plasma and serum from Alzheimer biomarker-positive older adults versus controls (n = 26); and (ii) Cohort 2: n = 79 acute ischemic stroke patients with 265 longitudinal samples across four time points. RESULTS: In Cohort 1, plasma and serum BD-tau were strongly correlated (rho = 0.96, p < 0.0001) with similar diagnostic performances (AUCs >99%) and correlations with CSF total-tau (rho = 0.93-0.94, p < 0.0001). However, absolute concentrations were â¼40% higher in plasma versus serum. In Cohort 2, first and repeated BD-tau measurements showed a near-perfect correlation (rho = 0.96, p < 0.0001), with no significant between-batch concentration differences. In longitudinal analyses, substituting â¼10% of the first-run concentrations for the remeasured values showed overlapping estimated trajectories without significant differences at any time point. DISCUSSION: BD-tau has equivalent diagnostic accuracies, but non-interchangeable absolute concentrations, in plasma versus serum. Furthermore, the analytical robustness is unaffected by batch-to-batch reagent variations. HIGHLIGHTS: Brain-derived tau (BD-tau) is a novel blood-based biomarker that quantifies tau protein of CNS origin. Effects of preanalytical handling procedures on the quality and reproducibility of BD-tau measures are unknown. In two cohorts of n = 105 participants, we compared BD-tau concentrations and diagnostic performances in paired plasma and serum samples, and evaluated impacts of batch-to-batch reagent variations. Paired plasma and serum showed equivalent diagnostic performances to separate amyloid-positive AD from amyloid-negative controls, indicating both can be used independently. Repeated measurements and longitudinal trajectories of plasma BD-tau were unaffected by batch-to-batch reagent variation.
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Enfermedad de Alzheimer , Accidente Cerebrovascular Isquémico , Humanos , Anciano , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Reproducibilidad de los Resultados , Encéfalo/metabolismo , BiomarcadoresRESUMEN
INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid-beta (Aß)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aß and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aß42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aß-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. HIGHLIGHTS: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aß42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden.
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Enfermedad de Alzheimer , Masculino , Femenino , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Proteína Ácida Fibrilar de la Glía , Plasma , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones , Proteínas tauRESUMEN
INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aß42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aß42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aß42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. HIGHLIGHTS: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Inmunoensayo , Proteínas tau , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismoRESUMEN
OBJECTIVES: To investigate whether circulating acute-phase brain-derived tau (BD-tau) is associated with functional outcome after ischemic stroke. METHODS: Plasma tau was measured by a novel assay that selectively quantifies BD-tau in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which includes adult cases with ischemic stroke and controls younger than 70 years, and in an independent cohort of adult cases of all ages (SAHLSIS2). Associations with unfavorable 3-month functional outcome (modified Rankin scale score >2) were analyzed by logistic regression. Various stratified and sensitivity analyses were performed, for example, by age, stroke severity, recanalization therapy, and etiologic subtype. RESULTS: This study included 454 and 364 cases from the SAHLSIS and SAHLSIS2, with a median age of 58 and 68 years, respectively. Higher acute BD-tau concentrations were significantly associated with increased odds of unfavorable outcome after adjustment for age, sex, day of blood draw, and stroke severity (NIH stroke scale score) in both cohorts (OR per doubling of BD-tau: 2.9 [95% CI 2.2-3.7], P = 1 × 10-15 and 1.8 [1.5-2.2], P = 7 × 10-9, respectively). The association was consistent in the different stratified and sensitivity analyses. DISCUSSION: BD-tau is a promising blood-based biomarker of ischemic stroke outcomes, and future studies in larger cohorts are warranted.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Adulto , Humanos , Persona de Mediana Edad , Anciano , Isquemia Encefálica/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , EncéfaloRESUMEN
BACKGROUND: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers. METHODS: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis. RESULTS: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01). CONCLUSION: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.
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Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aß (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. Setting: Longitudinal observational cohort. Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. Exposures: Plasma Aß 42/40 was measured using IP-MS; CSF Aß 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aß-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir. Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)?Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau.Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.
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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 tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Neuropatología , Plasma , Ovillos Neurofibrilares , Autopsia , Proteínas tau , Biomarcadores , Péptidos beta-AmiloidesRESUMEN
Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Biomarcadores/líquido cefalorraquídeo , AtrofiaRESUMEN
As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Neuropatología , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
Importance: Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples. Objectives: To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year. Design, Setting, and Participants: This prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021. Exposures: Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury. Main Outcomes and Measures: Associations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3). Results: Among the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, -22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, -6.4 to 23.0 pg/mL]; serum NfL, -5.4 pg/mL [95% CI, -99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL). Conclusions and Relevance: This study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.
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Lesiones Traumáticas del Encéfalo , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores , Encéfalo , Escala de Coma de Glasgow , Estudios Prospectivos , FemeninoRESUMEN
The evolution of infarcts varies widely among patients with acute ischemic stroke (IS) and influences treatment decisions. Neuroimaging is not applicable for frequent monitoring and there is no blood-based biomarker to track ongoing brain injury in acute IS. Here, we examined the utility of plasma brain-derived tau (BD-tau) as a biomarker for brain injury in acute IS. We conducted the prospective, observational Precision Medicine in Stroke [PROMISE] study with serial blood sampling upon hospital admission and at days 2, 3, and 7 in patients with acute ischemic stroke (IS) and for comparison, in patients with stroke mimics (SM). We determined the temporal course of plasma BD-tau, its relation to infarct size and admission imaging-based metrics of brain injury, and its value to predict functional outcome. Upon admission (median time-from-onset, 4.4h), BD-tau levels in IS patients correlated with ASPECTS (ρ=-0.21, P<.0001) and were predictive of final infarct volume (ρ=0.26, P<.0001). In contrast to SM patients, BD-tau levels in IS patients increased from admission (median, 2.9 pg/ml [IQR, 1.8-4.8]) to day 2 (median time-from-onset, 22.7h; median BD-tau, 5.0 pg/ml [IQR, 2.6-10.3]; P<.0001). The rate of change of BD-tau from admission to day 2 was significantly associated with collateral supply (R2=0.10, P<.0001) and infarct progression (ρ=0.58, P<.0001). At day 2, BD-tau was predictive of final infarct volume (ρ=0.59, P<.0001) and showed superior value for predicting the 90-day mRS score compared with final infarct volume. In conclusion, in 502 patients with acute IS, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome. Further research is needed to determine whether BD-tau assessments can inform decision-making in stroke care.
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INTRODUCTION: Detection of Alzheimer's disease (AD) pathophysiology among cognitively unimpaired individuals and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma p-tau217 is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited. METHODS: We employed a novel p-tau217 immunoassay (UGOT p-tau217) in four independent cohorts (n=308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (ß-AARC). RESULTS: UGOT p-tau217 showed high accuracy (AUC= 0.80-0.91) identifying Aß pathology, determined either by Aß positron emission tomography or CSF Aß42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aß42/40 ratio (AUC= 0.91). DISCUSSION: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum.
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BACKGROUND: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. METHODS: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. FINDINGS: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aß changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9-0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. INTERPRETATION: Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. FUNDING: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit.
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Enfermedad de Alzheimer , Síndrome de Down , Enfermedades Neurodegenerativas , Adulto , Humanos , Enfermedad de Alzheimer/metabolismo , Síndrome de Down/epidemiología , Estudios Longitudinales , Péptidos beta-Amiloides/metabolismo , Proteína Ácida Fibrilar de la Glía , Estudios de Cohortes , Biomarcadores , Proteínas tau/metabolismoRESUMEN
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 tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Thereafter, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a novel peripherally accessible biomarker of AD pathophysiology.