| 1. |
- Kac, Przemyslaw R., et al.
(författare)
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Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
- 2023
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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 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.
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| 2. |
- Kac, Przemyslaw R., 1995, et al.
(författare)
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Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)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 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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| 3. |
- Karikari, Thomas, et al.
(författare)
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Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:5, s. 755-767
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N-terminal and mid-region p-tau181 and p-tau217 fragments are available, but head-to-head comparison in clinical settings is lacking.N-terminal-directed p-tau217 (N-p-tau217), N-terminal-directed p-tau181 (N-p-tau181), and standard mid-region p-tau181 (Mid-p-tau181) biomarkers in CSF were evaluated in three cohorts (n=503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ).CSF N-p-tau217 and N-p-tau181 had better concordance (88.2%) than either with Mid-p-tau181 (79.7%-82.7%). N-p-tau217 and N-p-tau181 were significantly increased in early mild cognitive impairment (MCI)-AD (A+T-N-) without changes in Mid-p-tau181 until AD-dementia. N-p-tau217 and N-p-tau181 identified Aβ pathophysiology (area under the curve [AUC]=94.8%-97.1%) and distinguished MCI-AD from non-AD MCI (AUC=82.6%-90.5%) signficantly better than Mid-p-tau181 (AUC=91.2% and 70.6%, respectively). P-tau biomarkers equally differentiated AD from non-AD dementia (AUC=99.1%-99.8%).N-p-tau217 and N-p-tau181 could improve diagnostic accuracy in prodromal-AD and clinical trial recruitment as both identify Aβ pathophysiology and differentiate early MCI-AD better than Mid-p-tau181.
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| 4. |
- Snellman, Anniina, et al.
(författare)
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N-terminal and mid-region tau fragments as fluid biomarkers in neurological diseases.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:8, s. 2834-2848
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Tidskriftsartikel (refereegranskat)abstract
- Brain-derived tau secreted into CSF and blood consists of different N-terminal and mid-domain fragments, which may have a differential temporal course and thus, biomarker potential across the Alzheimer's disease continuum or in other neurological diseases. While current clinically validated total-tau (t-tau) assays target mid-domain epitopes, comparison of these assays with new biomarkers targeting N-terminal epitopes using the same analytical platform may be important to increase the understanding of tau pathophysiology. We developed three t-tau immunoassays targeting specific N-terminal (NTA and NTB t-tau) or mid-region (MR t-tau) epitopes, using single molecule array technology. After analytical validation, the diagnostic performance of these biomarkers was evaluated in CSF and compared with the Innotest t-tau (and as proof of concept, with N-p-tau181 and N-p-tau217) in three clinical cohorts (n = 342 total). The cohorts included participants across the Alzheimer's disease continuum (n = 276), other dementia (n = 22), Creutzfeldt-Jakob disease (n = 24), acute neurological disorders (n = 18) and progressive supranuclear palsy (n = 22). Furthermore, we evaluated all three new t-tau biomarkers in plasma (n = 44) and replicated promising findings with NTA t-tau in another clinical cohort (n = 50). In CSF, all t-tau biomarkers were increased in Alzheimer's disease compared with controls (P < 0.0001) and correlated with each other (rs = 0.53-0.95). NTA and NTB t-tau, but not other t-tau assays, distinguished amyloid-positive and amyloid-negative mild cognitive impairment with high accuracies (AUCs 84% and 82%, P < 0.001) matching N-p-tau217 (AUC 83%; DeLong test P = 0.93 and 0.88). All t-tau assays were excellent in differentiating Alzheimer's disease from other dementias (P < 0.001, AUCs 89-100%). In Creutzfeldt-Jakob disease and acute neurological disorders, N-terminal t-tau biomarkers had significantly higher fold changes versus controls in CSF (45-133-fold increase) than Innotest or MR t-tau (11-42-fold increase, P < 0.0001 for all). In progressive supranuclear palsy, CSF concentrations of all t-tau biomarkers were similar to those in controls. Plasma NTA t-tau concentrations were increased in Alzheimer's disease compared with controls in two independent cohorts (P = 0.0056 and 0.0033) while Quanterix t-tau performed poorly (P = 0.55 and 0.44). Taken together, N-terminal-directed CSF t-tau biomarkers increase ahead of standard t-tau alternatives in the Alzheimer's disease continuum, increase to higher degrees in Creutzfeldt-Jakob disease and acute neurological diseases and show better potential than Quanterix t-tau as Alzheimer's disease blood biomarkers. For progressive supranuclear palsy, other tau biomarkers should still be investigated.
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