Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

Acta Neuropathologica, Год журнала: 2020, Номер 140(3), С. 267 - 278

Опубликована: Июль 27, 2020

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis Alzheimer's disease (AD). Nowadays, in vivo AD is greatly aided by both cerebrospinal fluid (CSF) positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation restricted high cost, limited accessibility invasiveness. We recently developed high-performance, ultrasensitive immunoassay quantification phosphorylated at threonine-181 (p-tau181) plasma, which identifies pathophysiology with accuracy. However, it unclear whether plasma p-tau181, measured years before death, can predict eventual AD, successfully discriminates from non-AD dementia pathologies. studied unique cohort 115 individuals longitudinal blood collections clinical evaluation 8, 4 2 prior to assessment death. results demonstrate that p-tau181 associates better neuropathology Braak staging than 8 post-mortem. Moreover, while all patients had during life, proved discriminate pathologies accuracy (AUC = 97.4%, 95% CI 94.1-100%) even Additionally, trajectory was assessed patients. found main increases occurred between death later plateauing. In contrast, controls exhibited minor, albeit significant, up until Overall, our study demonstrates predictive specific post-mortem examination. These data add further support use aid management primary care recruitment trials.

Язык: Английский

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Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease

EMBO Molecular Medicine, Год журнала: 2019, Номер 11(12)

Опубликована: Ноя. 11, 2019

Article11 November 2019Open Access Transparent process Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease Sebastian Palmqvist Corresponding Author [email protected] orcid.org/0000-0002-9267-1930 Clinical Memory Research Unit, Department of Sciences, Lund University, Lund, Sweden Neurology, Skåne University Hospital, Search for more papers by this author Philip S Insel Psychiatry, California, San Francisco, CA, USA Erik Stomrud Clinic, Malmö, Shorena Janelidze Henrik Zetterberg Psychiatry Neurochemistry, The Sahlgrenska Academy at the Gothenburg, Mölndal, Neurochemistry Laboratory, Neurodegenerative Disease, UCL Institute Queen Square, London, UK Dementia UCL, Britta Brix Euroimmun AG, Lübeck, Germany Udo Eichenlaub Roche Diagnostics GmbH, Penzberg, Jeffrey L Dage Eli Lilly Company, Indianapolis, IN, Xiyun Chai Kaj Blennow Niklas Mattsson orcid.org/0000-0002-8885-7724 Wallenberg Center Molecular Medicine, Oskar Hansson orcid.org/0000-0001-8467-7286 Information *,1,2, Insel1,3, Stomrud1,4, Janelidze1, Zetterberg5,6,7,8, Brix9, Eichenlaub10, Dage11, Chai11, Blennow5,6, Mattsson1,2,12 *,1,4 1Clinical 2Department 3Department 4Memory 5Department 6Clinical 7Department 8UK 9Euroimmun 10Roche 11Eli 12Wallenberg *Corresponding author. Tel: +46 46 177808; E-mail: 40-335036; Fax: 40-335657; EMBO Mol Med (2019)11:e11170https://doi.org/10.15252/emmm.201911170 ELECSYS, COBAS, COBAS E are registered trademarks Roche. All mentioned enjoy legal protection PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Failures (AD) drug trials highlight need further explore mechanisms alterations biomarkers during development AD. Using cross-sectional data from 377 participants BioFINDER study, we examined seven cerebrospinal (CSF) six relation β-amyloid (Aβ) PET uptake understand their evolution In CSF, Aβ42 changed first, closely followed Aβ42/Aβ40, phosphorylated-tau (P-tau), total-tau (T-tau). CSF neurogranin, YKL-40, neurofilament light increased after point Aβ positivity. findings were replicated using Aβ42, Aβ40, P-tau, T-tau assays five different manufacturers. Changes seen approximately simultaneously biomarkers. Overall, had smaller dynamic ranges, except P-tau which similar. conclusion, state-of-the-art biomarkers, identified first changes Aβ, soluble tau. Only became abnormal, neuroinflammation, synaptic dysfunction, neurodegeneration altered. These lend vivo support cascade hypotheses humans. Synopsis Analysis 13 key accumulation confirms hypothesis, presence other already prior threshold study examines tau, then markers dysfunction neurodegeneration. results T-tau. Introduction Continued failures clinical against presumably correct targets research all important what stage they occur become measurable (Honig et al, 2018; Jack Egan 2019; Knopman, Selkoe, 2019). pathogenesis AD is complex involves many mechanisms. According hallmark pathology abnormal that can start decades before dementia continues throughout course (Villemagne 2013). thought trigger or drive tau pathology, which, possibly together inflammatory mechanisms, may cause result cognitive impairment (Jack 2013; Sperling 2014). There now several that, extent, measure these pathogenic Examining these, especially earlier stages AD, would allow us better disease, essential identifying potential targets, designing trials, improving diagnostics work-up (Blennow 2010). By comparing also identify measuring blood instead samples. elderly, non-demented (Aβ42 Aβ40), (neurogranin), [total-tau (T-tau) chain (NfL)], glial activation neuroinflammation (YKL-40, measured only CSF). modeled as functions positron emission tomography (PET) signal measures amount accumulated fibrillar neocortex (used proxy time disease). We load significant occurred (change trajectory). Differences between change points map temporal Finally, T-tau, manufacturers compared assess generalizability results. Results Demographic shown Table 1. Of included participants, 242 cognitively unimpaired (CU) 135 mild (MCI). mixture modeling-derived cutoff < 0.736 SUVR, 151 (40%) Aβ-positive (Aβ+) 226 (60%) Aβ-negative (Aβ−). significantly Aβ+ Aβ− neurogranin. stratified positivity Variable Total population P-value N Age (years) 72.1 (5.4) 72.6 (5.0) 71.8 (5.6) 0.10 Sex (female) 50% 44% 54% 0.042 MMSE (0–30 points) 28.3 (1.6) 27.8 28.5 (1.5) <0.001 APOE ε4-positive 38% 66% 22% (SUVR)a 0.782 (0.23) 1.023 (0.18) 0.622 (0.05) Hippocampus volume/ICV 0.0045 (0.00069) 0.00425 (0.00062) 0.00468 (0.00068) (pg/ml) 1,321 (650) 818 (319) 1,657 (596) Aβ40 22,811 (82,293) 29,261 (129,856) 18,501 (5,362) 0.57 Aβ42/Aβ40 0.0717 (0.028) 0.0448 (0.0164) 0.0898 (0.0187) 256 (116) 319 (139) 215 (73.0) 22.8 (12.4) 30.0 (15.1) 17.9 (6.7) NfL 1,192 (948) 1,399 (1,133) 1,053 (847) Neurogranin 405 (213) 480 (253) 356 (164) YKL-40 194,090 (63,108) 205,273 (64,958) 186,618 (60,847) 0.003 Plasma 31.6 (4.9) 29.9 (4.7) 32.7 484 (72) 483 (73) 485 (71) 0.66 0.0657 (0.0082) 0.0622 (0.0078) 0.0680 (0.0077) 17.8 (5.3) 18.2 17.6 (5.5) 0.12 2.7 (4.6) 3.4 (3.2) 2.1 22.9 (17.0) 23.9 (11.2) 22.2 (19.9) 20,205 (10,655) 19,414 (10,961) 20,735 (10,437) 0.17 Values mean (SD) if not otherwise stated. Mann–Whitney was used compare groups. Bold P-values indicate statistical significance P 0.05. CU, unimpaired; ICV, intra cranial volume; MCI, impairment; MMSE, Mini-Mental State Examination; N, number participants; NfL, chain; phosphorylated-tau; SD, standard deviation, T-tau; total-tau. Early accumulating ROI composite reference region (see Materials Methods). function monotone spline models Fig 1A. Separate points, level, r2 value Appendix S1. Note fitted plasma, data. Initial declines both flat curve (i.e., no association increases SUVR) while continued decrease level when reached. concordance this, ratio started plateau, later drop (note increase be estimated given priori assumption monotonicity respect SUVR). Around 1.0 SUVR (after reached), Aβ42/40 flattened out did continue decline further. very similar greatest neurogranin showed modest range span, even (< 0.5 z-score). exhibited sigmoid trajectory subtle initial around same most marked span SUVRs (Fig 1A). Based on appearance, two established below As expected dependent variable, best model fits (r2 = 0.42) 0.55), poorer 0.30), 0.25), 0.11), 0.02), 0.02). Figure A, B. where acted (A) (B) separately, but selected direct comparisons 3. Individual actual Figs S1 S2. modeling statistics. Point (also referred change) vertical dashed lines. They defined 2 SE (derived 500 bootstrap samples) starting trajectory. missing 34 cases. To facilitate levels have been transformed z-scores based distribution present z-score 0 corresponds cohort). Download figure PowerPoint A (or "change point") error (SE) lines 1 95% CIs Aβ42/Aβ40. Later, seen, differences them overlapping CIs). latter just Slightly later, hippocampal volume seen. second last than changes. 2. CIsChange divided total intracranial added reference. splines 1B. models, (Appendix S2). Similar an initial, parallel line resulting 3A). contrast over entire (about vs. about CSF; 3A) overall lesser agreement (plasma r2: 0.07–0.12; 0.42–0.55; This true corresponding S2), 3B). Comparison A. Same 1A B Aβ42/40, panel easier comparison. Spline dataset there (n 343); i.e., 1B, slightly Data information: 2, S1), non-significant models. Compared wider CIs, indicating greater variability early phase and/or less rapid Comparisons comparative analysis performed subset complete available 352 n population). (Elecsys®, EUROIMMUN, INNOTEST, MSD), P-tau181, P-tau217), MSD) 4A–D. assays. No obtained any 5). 4. vendors A–D. (A), (B), (C), (D) assays, Significant some almost identical therefore partially hidden 5 overview points). sample whole 5. assaysSignificant 377) gave Elecsys® assay full dataset. Discussion individuals who 242) MCI 135), 7 6 (measured PET) onset dementia. found (which concurrently ratio). Overt (as hippocampus second, pronounced increase) neither nor 2). When 3). could confirm (Figs 4 conduct comparison accumulation, include (except plasma). Two recent studies rare autosomal dominant variant symptoms variable Dominantly Inherited Network (DIAN) (McDade Schindler Despite samples sequence changing shortly (neurogranin one diverge healthy controls). has recently demonstrated Disease Neuroimaging Initiative (ADNI) longitudinal estimate (Insel under review). agree current postulating initiating factor hitherto do 2) previous showing becomes (Palmqvist 2016, 2017; Vlassenko 2016). Further, might explanations higher (dichotomous) 2), reported previously (Janelidze Lewczuk Doecke 2018). Although difference stable 3A), supported (Schindler finding should interpreted cautiously since driven few barely (P 0.02; S1) 0.37; Even though supporting use isolation detect (Mattsson 2015, 2019b; 2017), probably provides reliable fibrils its specificity acts peptide can, example, account inter-individual concentrations pre-analytical handling lead false-positive false-negative 2016; 2017). phosphorylation state inflammation (YKL-40), (NfL T-tau) still stage, known pathological develop fairly long-lasting manifest ("Aβ positivity") required occur. well accordance work, brain hypometabolism accelerate reached However, complicate matters, must consider examining validity does it supposed measure) thus clearly affect It is, possible reflects neuronal reaction amyloidosis, rather neurofibrillary 2017b; Sato 2018), activity secretion variety intra-neuronal proteins event (Cirrito 2008; Li case peptides extracellular space without new taking place (other secretion). for, too clinically relevant (early point; overt (late hypothesis contradictory detected 16 years (Preische 2019), noticeable 2019a,b). addition validity, sensitivity (for detecting underlying pathology) For much sensitive find mechanism brain. want note order refers translate appears overlapped 2; S1). Nonetheless, considerable trajectories. considerably lower values ranges S2, B,

Язык: Английский

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

Molecular Psychiatry, Год журнала: 2020, Номер 26(2), С. 429 - 442

Опубликована: Окт. 26, 2020

Язык: Английский

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Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease

JAMA Neurology, Год журнала: 2020, Номер 78(2), С. 149 - 149

Опубликована: Ноя. 9, 2020

There is an urgent need for inexpensive and minimally invasive blood biomarkers Alzheimer disease (AD) that could be used to detect early changes.To assess how in the course of AD plasma levels tau phosphorylated at threonine 217 (P-tau217) start change compared with established cerebrospinal fluid (CSF) positron emission tomography (PET) pathology.This cohort study included cognitively healthy control individuals (n = 225) participants subjective cognitive decline 89) or mild impairment 176) from BioFINDER-2 study. Participants were enrolled 2 different hospitals Sweden January 2017 October 2019. All underwent P-tau217 assessments tau- amyloid-β (Aβ)-PET imaging. A subcohort 111 had 3 tau-PET scans.Changes preclinical prodromal changes CSF PET measures.Of 490 participants, 251 women (51.2%) mean (SD) age was 65.9 (13.1) years. Plasma increased unimpaired abnormal Aβ-PET but normal entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] 0.7 [IQR, 0.3-1.4 pg/mL]). Most who discordant positive negative (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: [5.3%]). Event-based modeling cross-sectional data predicted those impairment, both would before signal cortex, followed by more widespread cortical changes. When testing association global Aβ load nonlinear spline models, lower values measures. Among baseline tau-PET, rates longitudinal increase higher (median standardized uptake value ratio, 0.029 -0.006 0.041] -0.001 -0.021 0.020]; Mann-Whitney U, P .02).In this study, during stages when insoluble aggregates not yet detectable tau-PET. may hold promise as a biomarker brain pathology.

Язык: Английский

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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Science Advances, Год журнала: 2020, Номер 6(16)

Опубликована: Апрель 15, 2020

The links between β-amyloid (Aβ) and tau in Alzheimer's disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated (P-tau181 P-tau217) total-tau (T-tau), which over time, despite no detection insoluble aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau T-tau started to increase before the threshold for Amyloid PET positivity, while after positivity. Effects on were mediated by P-tau, high predicted rates. Individuals

Язык: Английский

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