| 51. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury.
- 2023
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Ingår i: JAMA network open. - 2574-3805. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- 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.To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year.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.Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury.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).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).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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| 52. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.
- 2022
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:3, s. 1152-1165
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 53. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.
- 2024
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 20:1, s. 745-751
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Tidskriftsartikel (refereegranskat)abstract
- 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.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).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).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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| 54. |
- Gonzalez-Ortiz, Fernando, 1990, et al.
(författare)
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Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Staging amyloid-beta (Aβ) 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 Aβ 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 Aβ ("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 Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
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| 55. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Plasma phospho-tau in Alzheimer's disease: towards diagnostic and therapeutic trial applications
- 2023
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 18:1
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Forskningsöversikt (refereegranskat)abstract
- 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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| 56. |
- Gonzalez-Ortiz, Fernando, et al.
(författare)
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Preanalytical stability of plasma/serum brain-derived tau
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260. ; 19:10, s. 4764-4770
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONWe investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau). METHODSWe 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. RESULTSIn 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 similar to 40% 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 similar to 10% of the first-run concentrations for the remeasured values showed overlapping estimated trajectories without significant differences at any time point. DISCUSSIONBD-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. HighlightsBrain-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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| 57. |
- Grothe, Michel J., 1981, et al.
(författare)
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Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy.
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:12
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Tidskriftsartikel (refereegranskat)abstract
- To study cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.
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| 58. |
- Hill, E., et al.
(författare)
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A Validated Method to Prepare Stable Tau Oligomers
- 2023
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer US. ; 2551, s. 203-224
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Tidskriftsartikel (refereegranskat)abstract
- There is growing evidence that tau oligomers are a major pathological species in a number of tauopathies including Alzheimer's disease. However, it is still unclear what exact mechanisms underlie tau oligomer-mediated dysfunction. Studies of tau oligomers in vitro are limited by the high propensity for aggregation and consequent changes in the aggregation state of the produced tau samples over time. In this protocol, we provide a step-by-step description of a validated method for producing stable and structurally characterized oligomers of tau that can be used in biochemical, cellular, and animal model studies to evaluate mechanisms of action of tau in tauopathies. © 2023. Springer Science+Business Media, LLC, part of Springer Nature.
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| 59. |
- Hill, E., et al.
(författare)
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Functional Applications of Stable Tau Oligomers in Cell Biology and Electrophysiology Studies
- 2023
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer US. ; 2551, s. 147-161
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated tau protein plays a key role in the pathogenesis of neurodegenerative tauopathies including Alzheimer's disease. Soluble, low-molecular-weight tau oligomers are formed early in disease processes and are thought to have toxic functions that disrupt neuronal function. The dynamic and transient nature of tau oligomers complicates in vitro functional studies to explore the mechanistic links between oligomer formation and neurodegeneration. We have previously described a method of producing stable and structurally characterized oligomers that maintain their oligomeric conformation and prevent further aggregation. This method allows for the flexibility of stabilizing tau oligomers by specifically labelling cysteine residues with fluorescent or colorless maleimide conjugates. Here, we describe the functional applications of these preformed stable tau oligomers in cell biology and electrophysiological studies. These investigations allow real-time insights into the cellular uptake of exogenous tau oligomers and their functional effects in the recipient cells. © 2023. Springer Science+Business Media, LLC, part of Springer Nature.
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| 60. |
- Hill, E., et al.
(författare)
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Introduction of Tau Oligomers into Cortical Neurons Alters Action Potential Dynamics and Disrupts Synaptic Transmission and Plasticity
- 2019
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Ingår i: Eneuro. - : Society for Neuroscience. - 2373-2822. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Tau is a highly soluble microtubule-associated protein that acts within neurons to modify microtubule stability. However, abnormally phosphorylated tau dissociates from microtubules to form oligomers and fibrils which associate in the somatodendritic compartment. Although tau can form neurofibrillary tangles (NFTs), it is the soluble oligomers that appear to be the toxic species. There is, however, relatively little quantitative information on the concentration-dependent and time-dependent actions of soluble tau oligomers (oTau) on the electrophysiological and synaptic properties of neurons. Here, whole-cell patch clamp recording was used to introduce known concentrations of oligomeric full-length tau-441 into mouse hippocampal CA1 pyramidal and neocortical Layer V thick-tufted pyramidal cells. oTau increased input resistance, reduced action potential amplitude and slowed action potential rise and decay kinetics. oTau injected into presynaptic neurons induced the run-down of unitary EPSPs which was associated with increased short-term depression. In contrast, introduction of oTau into postsynaptic neurons had no effect on basal synaptic transmission, but markedly impaired the induction of long-term potentiation (LTP). Consistent with its effects on synaptic transmission and plasticity, oTau puncta could be observed in the soma, axon and in the distal dendrites of injected neurons.
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