Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia

Bateman, Randall J.; Mattsson, Niklas; Palmqvist, Sebastian; Smith, Ruben; Beach, Thomas G.; Serrano, Geidy E.; Chai, Xiyun; Proctor, Nicholas K.; Eichenlaub, Udo; Zetterberg, Henrik; Blennow, Kaj; Reiman, Eric M.; Stomrud, Erik; Dage, Jeffrey L.; Hansson, Oskar

doi:10.1038/s41591-020-0755-1

Cited by 820 publications

(1,074 citation statements)

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“…Our < 65-year plasma NfL cut-offs (19.4 pg/mL, 21.5 pg/mL, 30.0 pg/mL) were substantially lower as to compared older cut-offs (38.0 pg/mL, 46.0 pg/mL, 54.8 pg/mL) and when this was applied, EOAD patients had the equivalent rate of abnormal plasma NfL as typical AD dementia -consistent with the reported literature on familial AD 56,57 . We also observed that age-related cut-offs may be more sensitive to neurodegeneration related to Aβ deposition, although it is clear that recent developments in plasma p-tau181 or p-tau217 would be a superior measure of Aβ and tau pathologies 10,11,14,15,51,58 . In individuals < 65 years, rates of abnormal plasma NfL were 3-fold higher in Aβ + controls as compared to Aβ-controls and also higher in MCI Aβ + than MCI Aβ-.…”

Section: Discussionmentioning

confidence: 75%

“…Individuals clinically classi ed as CU, SCD (Lund cohort only) and MCI were further categorized into Aβ-negative (Aβ-) or Aβ-positive (Aβ+). In the KCL cohort, Aβ cut-off values for assigning positivity were determined by CSF Aβ42, [ 11 46 . This determined that 103/376, 75/209 and 165/280 of CU, SCD and MCI individuals were Aβ+, respectively.…”

Section: Determination Of Amyloid-β Statusmentioning

confidence: 99%

“…Recent advances in ultrasensitive immunological assays [10][11][12][13][14][15] and immunoprecipitation mass spectrometry (IPMS) methods [16][17][18] have been developed to measure neurodegenerative biomarkers in blood. NfL can be quanti ed at femtomolar concentrations in plasma or serum, which has enabled the reliable detection of NfL not only in symptomatic patients but also in cognitively unimpaired (CU) individuals of all ages 19 .…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic value of plasma neurofilament light: A multicentre validation study

Ashton

Bateman

Khleifat

et al. 2020

Preprint

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Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fifteen neurodegenerative diseases from two multicenter cohorts: King’s College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We further demonstrate that plasma NfL is clinically useful in identifying, i) atypical parkinsonian disorders in patients with parkinsonism, ii) dementia in individuals with Down Syndrome, iii) detect cases of frontotemporal dementia among psychiatric disorders such as moderate and severe depression, iv) identify frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related plasma NfL cut-offs for disorders with a younger age of onset. Finally, our findings suggest that plasma NfL performs best when a concentration cut-off is applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

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Section: Discussionmentioning

confidence: 75%

Section: Determination Of Amyloid-β Statusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diagnostic value of plasma neurofilament light: A multicentre validation study

Ashton

Bateman

Khleifat

et al. 2020

Preprint

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“…These differences in disease trajectories are apparent from the cohort estimates in (Janelidze et al, 2020;Mielke et al, 2018;Palmqvist et al, 2019;Schindler et al, 2019), longitudinal evaluations in the context of trial-ready cohorts may greatly improve early diagnosis and expedite the execution of clinical trials in early AD.…”

Section: A Pet and Estimation Of Tfa+mentioning

confidence: 99%

Time between milestone events in the Alzheimer’s disease amyloid cascade

Insel

Donohue

Berron

et al. 2020

Preprint

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Objective: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease.Methods: In a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of A, tau, and decreases in cognition with respect to the time of A-positivity.Results: Small effect sizes of change in CSF A42 and regional A PET were estimated to occur several decades before A-positivity. Increases in CSF tau occurred 11-12 years before A-positivity. Temporoparietal tau PET showed increases 4-5 years before Apositivity. Subtle cognitive dysfunction was observed 7-9 years before A-positivity.Conclusions: Increases in tau and cognitive dysfunction occur years before the presence of significant A. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments. O. 2017. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun 8.

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“…plasma and serum) using ultrasensitive immunoassays [9][10][11][12][13] and mass spectrometry methods [14]. Plasma p-tau181 levels have been shown to be strongly associated with brain tau pathology, signi cantly elevated in AD, and differentiate AD from other neurodegenerative diseases [9][10][11][12][13]. However, to date the associations between plasma p-tau181 and AD-related brain metabolic dysfunction, a well-recognized pathophysiological process underlying AD, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Lussier¹,

Benedet²,

Therriault³

et al. 2020

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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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Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia

Cited by 820 publications

References 45 publications

Diagnostic value of plasma neurofilament light: A multicentre validation study

Diagnostic value of plasma neurofilament light: A multicentre validation study

Time between milestone events in the Alzheimer’s disease amyloid cascade

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

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