Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

Janelidze, Shorena; Stomrud, Erik; Smith, Ruben; Palmqvist, Sebastian; Mattsson, Niklas; Airey, David; Proctor, Nicholas K.; Chai, Xiyun; Shcherbinin, Sergey; Sims, John R.; Triana‐Baltzer, Gallen; Theunis, Clara; Slemmon, Randy; Mercken, Marc; Kolb, Hartmuth C.; Dage, Jeffrey L.; Hansson, Oskar

doi:10.1038/s41467-020-15436-0

Cited by 263 publications

(211 citation statements)

References 63 publications

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“…Plasma measures of p-tau-181 have been reported to significantly increase in AD particularly at symptomatic stages, detecting AD with good accuracy (Mielke et al, 2018;Janelidze et al, 2020a;Thijssen et al, 2020). Our results suggest that, as reported in CSF (Barthélemy et al, 2020a;Barthélemy et al, 2020b;Janelidze et al, 2020b), p-tau-217 in plasma would be more accurate than p-tau-181 for detecting abnormal CNS tau metabolism.…”

Section: Plasma Tau Is Truncated Similar To Csf Profilessupporting

confidence: 75%

“…phosphorylation measures on threonine 217 (p-tau-217) are closely associated with amyloidosis, improving identification of amyloidosis at the asymptomatic stage (Barthélemy et al, 2015, 2017Preprint, 2018. CSF hyperphosphorylation of p-tau-T217 is more accurate than other sites, such as T181 (Barthélemy et al, 2020b;Janelidze et al, 2020b) and T205 (Barthélemy et al, 2020a), to detect the presence of amyloid plaques. Phosphorylation occupancy on T217 is also lower intracellularly than extracellularly in CSF (Barthélemy et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease

Barthélemy

Horie

Sato

et al. 2020

Journal of Experimental Medicine

273

292

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Highly sensitive and specific plasma biomarkers for Alzheimer’s disease (AD) have the potential to improve diagnostic accuracy in the clinic and facilitate research studies including enrollment in prevention and treatment trials. We recently reported CSF tau hyperphosphorylation, especially on T217, is an accurate predictor of β-amyloidosis at asymptomatic and symptomatic stages. In the current study, we determine by mass spectrometry the potential utility of plasma p-tau isoforms to detect AD pathology and investigate CSF and plasma tau isoforms’ profile relationships. Plasma tau was truncated as previously described in CSF. CSF and plasma measures of p-tau-217 and p-tau-181 were correlated. No correlation was found between CSF and plasma on total-tau levels and pS202 measures. We found p-tau-217 and p-tau-181 were highly specific for amyloid plaque pathology in the discovery cohort (n = 36, AUROC = 0.99 and 0.98 respectively). In the validation cohort (n = 92), p-tau-217 measures were still specific to amyloid status (AUROC = 0.92), and p-tau-181 measures were less specific (AUROC = 0.75).

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Section: Plasma Tau Is Truncated Similar To Csf Profilessupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease

Barthélemy

Horie

Sato

et al. 2020

Journal of Experimental Medicine

273

292

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“…PET ligands speci c for NFTs in the AD brain recently have been developed, yet limitations including high costs, need for specialized instrumentation, and lack of binding to different tau strains (77,78) suggests that uid biomarkers, especially those obtained by minimally invasive procedures, such as a blood test, may be complementary or even advantageous to imaging biomarkers. A recent example is plasma pT217-tau, which recently has been shown to distinguish AD from other neurodegenerative diseases with high sensitivity and speci city (79,80). Here, we used neuronal exosomes enriched from the serum to test total tau concentration as an outcome measure for the treatment.…”

Section: Discussionmentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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“…Given the function of CSF as an essential route for the long-range trafficking of factors across the CNS, CSF has been also explored as a potential source for biomarkers providing information allowing for early detection and diagnosis of distinct pathological conditions such as neurodegenerative diseases or various types of brain cancer [39,40].…”

Section: Csf-an Intrinsic Component Of Cns Environmentmentioning

confidence: 99%

Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS

Kaiser

Bryja

2020

IJMS

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Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment—in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP–CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions.

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Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

Cited by 263 publications

References 63 publications

Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease

Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS

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