Alzheimer disease

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: May 13, 2021

Language: Английский

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Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders

JAMA, Journal Year: 2020, Volume and Issue: 324(8), P. 772 - 772

Published: July 28, 2020

Importance

There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective

To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a biomarker AD.

Design, Setting, and Participants

Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD 47 without (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 2), cognitively unimpaired (n = 301) clinically diagnosed patients mild cognitive impairment (MCI) 178), dementia 121), other neurodegenerative diseases 99) (April 2017-September Colombian autosomal-dominant kindred 3), 365PSEN1E280A mutation carriers 257 noncarriers (December 2013-February 2017).

Exposures

Plasma P-tau217.

Main Outcomes Measures

Primary outcome was discriminative accuracy P-tau217 (clinical or neuropathological diagnosis). Secondary association pathology (determined using positron emission tomography [PET]).

Results

Mean age 83.5 (SD, 8.5) years 1, 69.1 10.3) 2, 35.8 10.7) 3; 38% were women 51% 57% 3. In antemortem differentiated neuropathologically defined from non-AD (area under curve [AUC], 0.89 [95% CI, 0.81-0.97]) significantly higher than P-tau181 neurofilament light chain (NfL) (AUC range, 0.50-0.72;P < .05). The 2 clinical vs (AUC, 0.96 0.93-0.98]) P-tau181, NfL, MRI measures 0.50-0.81;P .001) but not different compared cerebrospinal fluid (CSF) P-tau217, CSF tau-PET 0.90-0.99;P > .15). 3, levels greater amongPSEN1mutation carriers, noncarriers, approximately 25 older, which is 20 prior to estimated onset MCI among carriers. correlated tangles (Spearman ρ 0.64;P .001), 0.15;P .33), β-amyloid plaques 1. discriminated abnormal normal scans 0.93 0.91-0.96]) Aβ42:Aβ40 ratio, 0.67-0.90;P .05), its performance 0.96;P .22).

Conclusions Relevance

Among 1402 3 selected cohorts, diseases, established plasma- MRI-based biomarkers, key CSF- PET-based measures. Further research needed optimize assay, validate findings unselected diverse populations, determine potential role care.

Language: Английский

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Biomarkers for neurodegenerative diseases

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(6), P. 954 - 963

Published: June 1, 2021

Language: Английский

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Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 709 - 724

Published: Feb. 14, 2021

Abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise detecting Alzheimer’s disease (AD) pathophysiology. Tau at threonine 231 (p-tau231) is one such biomarker CSF but its usefulness as a blood currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the plasma p-tau231 which was validated four independent cohorts ( n = 588) different settings, including full AD continuum and non-AD neurodegenerative disorders. Plasma able to identify patients with differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults high accuracy (AUC 0.92–0.94). also distinguished disorders 0.93), well MCI 0.89). In neuropathology cohort, samples taken on avergae 4.2 years prior post-mortem very accurately identified comparison 0.99), this despite all being given dementia diagnosis during life. highly correlated p-tau231, pathology assessed by [ 18 F]MK-6240 positron emission tomography (PET), brain amyloidosis F]AZD469 PET. Remarkably, inflection point increasing function continuous PET standardized uptake value ratio, be earlier than standard thresholds positivity increase p-tau181. Furthermore, significantly increased quartiles 2–4, whereas p-tau217 p-tau181 only 3–4 4, respectively. Finally, differentiated individuals across entire Braak stage spectrum, staging 0 through I–II, not observed To conclude, novel assay identifies clinical stages equally p-tau181, increases earlier, already subtle deposition, threshold been attained, response early deposition. Thus, promising emerging potential facilitate trials vulnerable populations below apparent entorhinal

Language: Английский

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Diagnosis of Early Alzheimer’s Disease: Clinical Practice in 2021

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2021, Volume and Issue: unknown, P. 1 - 16

Published: Jan. 1, 2021

Alzheimer’s disease is a progressive, irreversible neurodegenerative impacting cognition, function, and behavior. progresses along continuum from preclinical disease, to mild cognitive and/or behavioral impairment then dementia. Recently, clinicians have been encouraged diagnose earlier, before patients progressed The early accurate detection of disease-associated symptoms underlying pathology by fundamental for the screening, diagnosis, subsequent management patients. It also enables their caregivers plan future make appropriate lifestyle changes that could help maintain quality life longer. Unfortunately, detecting early-stage in clinical practice can be challenging hindered several barriers including constraints on clinicians’ time, difficulty accurately diagnosing pathology, healthcare providers often dismiss as part normal aging process. As prevalence this continues grow, current model diagnosis patient will need evolve integrate care across disciplines continuum, beginning with primary care. This review summarizes importance establishing an related practical ‘how-to’ guidance considerations, tools used throughout diagnostic journey.

Language: Английский

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Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 20(9), P. 739 - 752

Published: Aug. 19, 2021

Language: Английский

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Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(6), P. 1034 - 1042

Published: May 24, 2021

Language: Английский

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Blood-based biomarkers for Alzheimer's disease: towards clinical implementation

The Lancet Neurology, Journal Year: 2021, Volume and Issue: 21(1), P. 66 - 77

Published: Nov. 25, 2021

Language: Английский

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

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(11)

Published: July 28, 2020

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

Language: Английский

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Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(12)

Published: Nov. 10, 2020

Article10 November 2020Open Access Transparent process Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of preclinical Alzheimer's continuum when only subtle changes Aβ pathology are detected Marc Suárez-Calvet orcid.org/0000-0002-2993-569X Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain IMIM (Hospital del Mar Medical Institute), Servei de Neurologia, Hospital Mar, Centro Investigación Biomédica en Red sFragilidad y Envejecimiento Saludable (CIBERFES), Madrid, SpainThese authors contributed equally to this work Search for more papers by author Thomas K Karikari Department Psychiatry and Neurochemistry, Institute Neuroscience Physiology, The Sahlgrenska Academy, University Gothenburg, SwedenThese Nicholas J Ashton orcid.org/0000-0002-6353-9316 Sweden Wallenberg Centre Molecular Translational Medicine, Academy Psychiatry, Psychology & Neuroscience, King's College London, Maurice Wohl Clinical Institute, UK NIHR Biomedical Mental Health Unit Dementia South London Maudsley NHS Juan Lantero Rodríguez Marta Milà-Alomà Universitat Pompeu Fabra, Domingo Gispert Bioingeniería, Biomateriales Nanomedicina, Gemma Salvadó Carolina Minguillon Karine Fauria Mahnaz Shekari Oriol Grau-Rivera Eider M Arenaza-Urquijo Aleix Sala-Vila Gonzalo Sánchez-Benavides José Maria González-de-Echávarri Gwendlyn Kollmorgen Roche Diagnostics GmbH, Penzberg, Germany Erik Stoops ADx NeuroSciences, Ghent, Belgium Eugeen Vanmechelen Henrik Zetterberg Neurochemistry Laboratory, Hospital, Mölndal, Neurodegenerative Disease, UCL Neurology, UCL, Kaj Blennow Corresponding Author [email protected] orcid.org/0000-0002-1890-4193 Luis Molinuevo orcid.org/0000-0003-0485-6001 ALFA Study StudyThe complete list collaborators can be found acknowledgements section. Information Suárez-Calvet1,2,3,4, Karikari5, Ashton5,6,7,8, Rodríguez5, Milà-Alomà1,2,4,9, Gispert1,2,9,10, Salvadó1,2, Minguillon1,2,4, Fauria1,4, Shekari1,2,9, Grau-Rivera1,2,3,4, Arenaza-Urquijo1,2,4, Sala-Vila1,2, Sánchez-Benavides1,2,4, González-de-Echávarri1,2, Kollmorgen11, Stoops12, Vanmechelen12, Zetterberg5,13,14,15, *,5,13, *,1,2,4,9, , Annabella Beteta, Raffaele Cacciaglia, Alba Cañas, Carme Deulofeu, Irene Cumplido, Ruth Dominguez, Emilio, Carles Falcon, Sherezade Fuentes, Laura Hernandez, Gema Huesa, Jordi Huguet, Paula Marne, Tania Menchón, Grégory Operto, Albina Polo, Sandra Pradas, Anna Soteras, Vilanova Natalia Vilor-Tejedor 1Barcelonaβeta 2IMIM 3Servei 4Centro 5Department 6Department 7Institute 8NIHR 9Universitat 10Centro 11Roche 12ADx 13Clinical 14Department 15UK *Corresponding author. Tel: +46 0313421000; E-mail: +34 933160990; EMBO Mol Med (2020)12:e12921https://doi.org/10.15252/emmm.202012921 PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract In disease (AD), phosphorylation brain its subsequent release into cerebrospinal fluid (CSF) blood is dynamic that during evolution. aim our study was characterize pattern (p-tau) stage continuum. We measured three novel CSF p-tau biomarkers, threonine-181 threonine-217 with an N-terminal partner antibody threonine-231 mid-region antibody. These were compared automated p-tau181 assay (Elecsys) as gold standard measure. demonstrate these increase prominently Alzheimer, amyloid-β (Aβ) detected, accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show plasma biomarker mildly but significantly increased stage. Our results support idea early neuronal metabolism likely response exposure, assays. SYNOPSIS This investigated them widely used Mid-ptau181. N-p-tau181, N-p-tau217 Mid-p-tau231 continuum, detected. Aβ-positive, individuals those Aβ-negative. Plasma N-p-tau181 suggest there probably emerging pathology. paper explained Problem Cerebrospinal one core (AD). Most assays target (Mid) fragment protein (Mid-p-tau181). Recently, new have been developed, targeting different sites (T181, T217, T231) fragments [N-terminal (N) vs. tau]. shown high accuracy detect AD. Results However, it less known whether change asymptomatic emerging. study, aimed characterizing performed head-to-head comparison following biomarkers: (a) Mid-p-tau181 (used reference biomarker), (b) (c) N-p-tau217, (d) (e) N-p-tau181. Furthermore, also increases stage, although milder. Impact which Therefore, they therapeutically very disease, soon arises. Introduction is, together 42 (Aβ42) total (t-tau), Overwhelming evidence indicates patients AD (both prodromal dementia stages) controls (Hansson et al, 2006; Shaw 2009; Mattsson Olsson 2016). correlates cognitive impairment better than Aβ-related (Gómez-Isla 1997; 2010; Nelson 2012; Roe 2013; Jack 2018; Aschenbrenner 2018). useful longitudinal studies may decrease late (Fagan 2014; McDade Sutphen Lleó 2019; Schindler 2019). excellent prognosis since finely predicts progression (CU) mild (MCI) and, eventually, (Roe Petersen Ferreira 2014). Bateman 2012). AD, aggregated neurofibrillary tangles (NFTs) aberrantly hyperphosphorylated several identified (Grundke-Iqbal 1986; Ksiezak-Reding 1988; Goedert 1988, 1989; Lee 1991, 2001). Yet, field, most common site (p-tau181) (Blennow 1995). fact, usually assumed term "p-tau" refers if not otherwise specified. Other residues p199, p212/p214, p217, p231, p231/p235 C-terminal p396/p404 (Ishiguro 1999; Kohnken 2000; Hu 2002; Buerger 2002b; Hampel 2004; Singer Meredith Russell 2016; Janelidze 2020b). A recent Dominantly Inherited Alzheimer Network (DIAN) cohort showed autosomal-dominant group sporadic (Barthélemy 2020c). Similarly, fragment, where commercially available targeted to. It known, however, contains mix both fragments, while considerably abundant (Meredith Barthélemy Sato Cicognola Chen Taking all account has key factor development tests p-tau. use antibodies allowed us others successfully measure plasma, detects discriminates other neurological diseases (Tatebe 2017; Mielke 2020; Thijssen 2020a). starts further (Karikari Besides p-tau181, strong data p-tau217, symptomatic discriminate healthy neurodegenerative (Barthelemy 2015; preprint: 2020a, 2020c; p-tau217 even two decades before PET Despite breakthrough developments understanding biomarker, specific subtle, incipient present. Studying particularly relevant their precede NFT Amid being developed (targeting sites, using platforms), important perform promising phosphorylations, such p-tau231, yet stages. For purpose, set ALFA+ (a CU individuals, some whom continuum) well-established Elecsys® [targeting (Lifke 2019)], herein assay. studied include (Fig EV1): forms containing epitope 6-18], well 6–18) Mid threonine-231). investigated, reliably how against neurofilament light (NfL), biomarker. tested hypothesis process, detectable. order ensure robustness, pathology, reflect aspects (i.e. soluble fibrillar aggregates, respectively) (Dubois Based on findings, propose model Click here expand figure. Figure EV1. Diagram Tau domains recognized combination study. longest form (2N4R), comprises 441 amino acids. depicted green, proline-rich (P) yellow four microtubule-binding (R) blue. shown. Details methods Abbreviations: Mid, mid-region; N, N-terminal; p-tau, Download figure PowerPoint Participants' characteristics effect age sex first consecutive 381 participants included Their demographic clinical features concentrations Table 1. Participants classified (A−; n = 250) (A+; 131) previously established cut-off value Aβ42/40 ratio 0.071 (Milà-Alomà 2020). A+ older, no differences education, global cognition [as Mini-Mental State Examination (MMSE)] distribution. As expected, had higher percentage APOE-ε4 carriers, PET-positive visual reads [18F]flutemetamol uptake PET, Centiloid (CL) scale. t-tau NfL (Table 1). status group. Total (n 381) A− 250, 65.6%) 131, 34.4%) P-value* Demographics, Age, years 61.2 (4.68) 60.6 (4.44) 62.3 (4.93) 0.0007* Female, (%) 232 (60.9) 155 (62.0) 77 (58.8) 0.541 Education, 13.4 (3.51) 13.5 (3.48) 13.2 (3.57) 0.467 201 (52.8) 102 (40.8) 99 (75.6) <0.0001* MMSE 29.1 (0.954) (0.935) 29.2 (0.993) 0.608 Centiloidsa 2.82 (16.8) −4.54 (6.37) 16.83 (21.1) (VR), (%)a (12.8) 3 (1.4) 39 (34.8) p-tau-related (pg/ml) 16.3 (7.69) 14.5 (5.23) 19.8 (10.1) 346 (216) 278 (97.7) 477 (304) 6.29 (6.41) 4.07 (2.28) 10.5 (9.07) 8.29 (6.08) 6.11 12.5 (8.46) 9.55 (3.

Language: Английский

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