Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Karikari, Thomas K.; Benedet, Andréa Lessa; Ashton, Nicholas J.; Lantero‐Rodriguez, Juan; Snellman, Anniina; Suárez‐Calvet, Marc; Saha-Chaudhuri, Paramita; Lussier, Firoza Z; Kvartsberg, Hlin; Moscoso, Alexis; Pascoal, Tharick A.; Andréasson, Ulf; Schöll, Michael; Rosa‐Neto, Pedro; Blennow, Kaj; Zetterberg, Henrik

doi:10.1101/2020.07.15.20154237

Cited by 50 publications

(107 citation statements)

References 43 publications

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“…We found that plasma p-tau181 was higher in males and in APOE ε4 carriers, which to our knowledge is a nding that has not been yet described. We also observed plasma p-tau181 to be signi cantly associated with older age, fewer years of education, elevated global cortical composite measure of Aβ-PET, and worse performance on cognitive scores, which, with the exception of education, concur with earlier studies on plasma p-tau181 [9][10][11][12]28]. As previously described, in our cross-sectional analyses, plasma p-tau181 was correlated with CSF p-tau181.…”

Section: Discussionsupporting

confidence: 92%

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Lussier¹,

Benedet²,

Therriault³

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) biomarkers are primarily evaluated through MRI, PET, and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible, and minimally invasive tools with diagnostic and prognostic value for AD. Most recently, plasma phosphorylated tau181 (p-tau181) has shown excellent performance. The relationship between plasma p-tau181 and cerebral metabolic dysfunction assessed by [18F]FDG PET in AD is still unknown.MethodsThis study was performed on a total of 892 individuals (297 cognitively unimpaired; 595 cognitively impaired) from the ADNI cohort. Plasma p-tau181 was assessed using single molecular array (Simoa) technology and metabolic dysfunction was indexed by [18F]FDG PET. Cross-sectional associations between plasma and CSF p-tau181 and [18F]FDG were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by Aβ status. Associations between baseline plasma p-tau181 and longitudinal rate of brain metabolic decline were also assessed in a subset (n=389) of individuals using correlations and voxelwise regression models.ResultsPlasma p-tau181 was elevated in Aβ+ and cognitively impaired individuals as well as in APOE ε4 carriers, and was significantly associated with age, worse cognitive performance, and CSF p-tau181. Cross-sectional analyses showed strong associations between plasma p-tau181 and [18F]FDG PET in Aβ+ and cognitively impaired individuals. Voxelwise longitudinal analyses showed that baseline plasma p-tau181 concentrations were significantly associated with annual rates of metabolic decline only in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes.ConclusionsThe associations between plasma p-tau181 and reduced brain metabolism, primarily in cognitively impaired and in Aβ+ individuals, supports the use of plasma p-tau181 as a simple, low-cost, minimally invasive, and accessible tool to both assess current and predict future metabolic dysfunction associated with AD, comparatively to PET, MRI, and CSF methods.

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Section: Discussionsupporting

confidence: 92%

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Lussier¹,

Benedet²,

Therriault³

et al. 2020

Preprint

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“…We observed a signi cant contribution of plasma p-tau181 independently of APOE ε4 in this model. Previous studies investigating the association of plasma p-tau181 with AD, either did not consider the APOE genotype (13,12); or they did not consider the effects of this factor independently of p-tau181 (10,9). Considering the APOE ε4 genotype as a covariate, we found that plasma p-tau181 additionally contributes to improve the prediction of AD in patients with cognitive impairment.…”

Section: Associations Of Plasma Nfl and P-tau181 With Disease Severitcontrasting

confidence: 56%

“…Plasma p-tau181 has been recently reported to be increased in both clinically diagnosed (9) and biomarker con rmed AD dementia (10), and to correlate with CSF tau levels and amyloid PET measurements (11,12). Furthermore, it may predict disease progression and cognitive decline in cognitively unimpaired participants and MCI patients (13).…”

Section: Introductionmentioning

confidence: 98%

Plasma Neurofilament Light and Phosphorylated Tau 181 as Biomarkers of Alzheimer’s Disease Pathology and Clinical Disease Progression

Clark

Lewczuk

Kornhuber

et al. 2020

Preprint

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Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology (CSF β-amyloid 1-42 (Aβ1-42), Aβ1-42 /Aβ1-40, total-tau (tau), and p-tau181) were measured in participants with normal cognition (CN, n=91) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI, n=127). Clinical and neuropsychological evaluations were performed at inclusion and follow-up visits at 18 and 36 months, to measure decline in global cognition and progression of disease severity. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with the presence of cerebral AD pathology (a priori defined by a CSF p-tau181/Aβ1-42 > 0.0779), single CSF biomarkers, and clinical measures of disease progression. Results: Plasma NfL levels were higher in CN participants with an AD CSF profile, and in CI participants when compared to CN non-AD participants, while p-tau181 plasma levels were higher in CI patients with AD when compared to the other participants. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF biomarkers in CI participants. Compared to a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients (AUC 0.861, p-value = 0.048) while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants (AUC 0.838, p-value = 0.032). Using a plasma p-tau181 cutoff of 9.68 pg/ml the models reached a sensitivity of 0.80 and specificity of 0.79 for AD prediction, and of 0.88 and 0.69 for the prediction of cognitive decline.Conclusion: Plasma NfL may be useful as a marker of neuronal injury, although it is not specific for AD. P-tau181 can serve, in a memory clinic setting, as a blood-based biomarker of both cerebral AD pathology and cognitive decline. The predictive performance of both markers depends on the presence of cognitive impairment.

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“…Nine studies that used Simoa or MSD methods were included for the analysis of normal range of plasma ptau181. Six publications, reporting seven cohorts, were retrieved using the Simoa technology [45,[84][85][86][87][88], including 1424 healthy subjects. The ES for plasma ptau181 levels in healthy populations was 11.18 pg/ml (95% CI 9.68-12.68, I 2 = 95.9%, P < 0.0001, Fig.…”

Section: Study Inclusions and Quality Assessmentmentioning

confidence: 99%

Ultrasensitive assays for detection of plasma tau and phosphorylated tau 181 in Alzheimer’s disease: a systematic review and meta-analysis

Ding

Zhang

Jiang

et al. 2021

Transl Neurodegener

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A lack of convenient and reliable biomarkers for diagnosis and prognosis is a common challenge for neurodegenerative diseases such as Alzheimer’s disease (AD). Recent advancement in ultrasensitive protein assays has allowed the quantification of tau and phosphorylated tau proteins in peripheral plasma. Here we identified 66 eligible studies reporting quantification of plasma tau and phosphorylated tau 181 (ptau181) using four ultrasensitive methods. Meta-analysis of these studies confirmed that the AD patients had significantly higher plasma tau and ptau181 levels compared with controls, and that the plasma tau and ptau181 could predict AD with high-accuracy area under curve of the Receiver Operating Characteristic. Therefore, plasma tau and plasma ptau181 can be considered as biomarkers for AD diagnosis.

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Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Cited by 50 publications

References 43 publications

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Plasma Levels of Phosphorylated Tau 181 Are Associated With Cerebral Metabolic Dysfunction in Cognitively Impaired Individuals

Plasma Neurofilament Light and Phosphorylated Tau 181 as Biomarkers of Alzheimer’s Disease Pathology and Clinical Disease Progression

Ultrasensitive assays for detection of plasma tau and phosphorylated tau 181 in Alzheimer’s disease: a systematic review and meta-analysis

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