Tau plasma levels in subjective cognitive decline: Results from the DELCODE study

Müller, Stephan; Preische, Oliver; Göpfert, Jens; Yañez, Viviana A. Carcamo; Joos, Thomas; Boecker, Henning; Düzel, Emrah; Falkai, Peter; Priller, Josef; Büerger, Katharina; Catak, Cihan; Janowitz, Daniel; Heneka, Michael T.; Brosseron, Frederic; Nestor, Peter J.; Peters, Oliver; Schipke, Carola G.; Schneider, Anja; Spottke, Annika; Fließbach, Klaus; Kilimann, Ingo; Teipel, Stefan J.; Wagner, Michael; Wiltfang, Jens; Jessen, Frank; Laske, Christoph

doi:10.1038/s41598-017-08779-0

Cited by 32 publications

(27 citation statements)

References 23 publications

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“…Mattson et al found that higher plasma t-tau was associated with AD dementia and showed a signi cant correlation with worse cognition, more atrophy and more hypometabolism during follow-up in the ADNI study [30]. However, in our study, plasma t-tau showed no signi cant correlation with cognitive function and can not re ect the levels of t-tau in CSF, which is also in line with some previous ndings [30,32].Besides, increasing evidence supports that plasma p-tau is a promising biomarker for AD, which can not only be associated with CSF p-tau but also correlates with amyloid PET uptake and discriminates AD dementia from non-AD neurodegenerative disease, partly re ecting AD pathology and disease severity [33][34]. In this study, due to the low concentration in the samples and methodology limitations, we did not measure p-tau in plasma.…”

Section: Discussionsupporting

confidence: 90%

Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

Jiao¹,

Liu²,

Guo³

et al. 2020

Preprint

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BackgroundRobust studies have focused on blood-based biomarkers for diagnosis of Alzheimer’s disease (AD), while the results were still controversary and failed verified in different cohorts. The aim of this study was to detect the levels of plasma amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) in patients with AD and cognitive normal (CN) subjects, and clarify their associations with Aβ, t-tau, and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as well as brain amyloid PET, and calculate the diagnostic efficiency of these characteristics regarding AD.Methods Plasma Aβ42, Aβ40, t-tau and NfL levels were detected by single-molecule array (Simoa) in 379 AD patients and 153 CN subjects. Additionally, lumbar puncture was conducted in 125 AD patients to detect Aβ42, Aβ40, t-tau, and p-tau levels. Brain amyloid PET was performed in 52 AD patients to identify brain amyloid deposition levels. Correlation analysis were performed between plasma biomarkers and typical biomarkers of AD, including CSF core biomarkers and amyloid PET burden. Finally, the diagnostic value of plasma biomarkers was further assessed by receiver operating characteristic (ROC) curve.ResultsCompared with the CN group, plasma Aβ42 and Aβ42/Aβ40 levels were significantly lower in AD patients, while Aβ40, t-tau and NfL levels were higher in AD patients. Among the AD patients, plasma Aβ42 was positively correlated with CSF Aβ42 (r = 0.195, p = 0.03) and Aβ42/Aβ40 (r = 0.208, p = 0.04). Moreover, plasma NfL was positively correlated with age, disease course and severity. The diagnostic model with combined plasma Aβ42, t-tau, and NfL levels controlled for age and APOE genotype showed the best performance to identify AD (area under the curve (AUC) = 0.88, sensitivity = 82.84%, specificity = 81.69%, cutoff value = 0.64).ConclusionsTrends revealed by core biomarkers were generally consistent in AD patients’ plasma and CSF. Combining plasma biomarkers can provide comparatively high AD diagnostic performance.

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Section: Discussionsupporting

confidence: 90%

Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

Jiao¹,

Liu²,

Guo³

et al. 2020

Preprint

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“…Soluble T-tau proteins were quantitatively measured using the Simoa Tau 2.0 reagent kit (Quanterix), which has been widely used in multiple published studies (see, for example [58][59][60] ). The LLOD and LLOQ are reported as 0.019 and 0.061 pg/mL, respectively.…”

Section: Preparation Of Samples For Mass Spectrometrymentioning

confidence: 99%

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Liu

Smith

Montonye

et al. 2020

Sci Rep

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Neurofibrillary tangles are a pathological hallmark of Alzheimer's disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. Δtau314, the C-terminallytruncated cleavage products, are soluble and present in human brain. In addition, levels of Δtau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Δtau314 proteins in cognitive deterioration. Here we show that (1) Δtau314 proteins are present in the inferior temporal gyrus of human brains; (2) Δtau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Δtau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Δtau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Δtau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Δtau314 production to cognitive deterioration.Tau is a soluble and unstructured protein, is enriched in neurons of the central nervous system (CNS), and plays an essential role in the formation and stabilization of microtubules to maintain normal neuronal structure and function 1,2 . In the human CNS, six isoforms of tau are generated by alternative splicing of exons 2, 3, or 10 of mRNA 3,4 . Tau is subjected to more than ten types of post-translational modifications (PTMs); under pathological conditions, the coordinated actions of multiple tau PTMs result in its dissociation from microtubules and intra-cellular aggregation to form neurofibrillary tangles (NFTs), a pathological hallmark of Alzheimer's disease (AD) (for review, see 5 ). As the burden of NFTs in a variety of brain regions correlate well with the severity of cognitive deficits of AD patients (for example, see 6-10 ), NFTs were assumed to be one of the major drivers of cognitive impairment. However, Gomez-Isla and colleagues observed that in the brain of individuals with AD, both the amount of neuron loss and the amount of NFTs in the disease-affected superior temporal sulcus correlate with the duration and severity of cognitive dysfunction, but the former exceeds the latter more than 7-fold. This suggests that neuronal loss, rather than NFTs, contributes directly to cognitive dysfunction in AD 11 . Further, several studies using tau transgenic mouse models have shown that synaptic function impairment and cognitive deficits

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“…Regarding tau specifically, a study has shown that increased CSF phosphorylated tau in healthy elderly could predict development of SCD at 3 years, but another study showed that while Aβ42 might decrease in SCD, T-tau and P-tau181 do not change significantly [ 15 , 17 ]. In another study, plasma tau in SCD did not differ from levels in healthy controls, and plasma levels did not correlate with CSF [ 16 ]. In the present study, we observed that core AD biomarkers were lower (Aβ42) or higher (T-tau, P-tau181) in SCD compared to controls, although maintaining a large overlap between the two groups, while N-224 could not distinguish between controls and SCD.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid N-224 tau helps discriminate Alzheimer’s disease from subjective cognitive decline and other dementias

et al. 2021

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Background Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer’s disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls. Methods Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (Aβ42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay. Results N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson’s disease (PD, p < 0.0001), Parkinson’s disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R2 = 0.318, β = 0.564, p ≤ 0.0001) and could accurately identify a pathological (< 24) MMSE score (p < 0.0001, AUC = 0.824). Conclusions N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.

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Tau plasma levels in subjective cognitive decline: Results from the DELCODE study

Cited by 32 publications

References 23 publications

Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Cerebrospinal fluid N-224 tau helps discriminate Alzheimer’s disease from subjective cognitive decline and other dementias

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