Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(5)

Опубликована: Март 13, 2023

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates not yet fully determined. To investigate and compare independent associations between multiple (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, NfL) neuropathologic measures of amyloid tau, we included 105 participants from the Arizona Study Aging Neurodegenerative Disorders (AZSAND) with antemortem samples a postmortem exam, 48 whom had longitudinal p-tau217 p-tau181. When simultaneously including plaque tangle loads, Aβ42/40 ratio p-tau231 were only associated plaques (ρAβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 0.28[0.10, 0.43]), GFAP was tangles (ρGFAP 0.39[0.17, 0.57]), p-tau181 both (ρp-tau217 0.40[0.21, 0.56], ρp-tau181 0.36[0.15, 0.50]) 0.52[0.34, 0.66]; 0.36[0.17, 0.52]). A model combining showed highest accuracy predicting presence change (ADNC, AUC[95%CI] 0.89[0.82, 0.96]) load (R2 0.55), while alone optimal 0.45). Our results suggest that high-performing assays might be an combination to assess Alzheimer's-related pathology in vivo.

Язык: Английский

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CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Nature Aging, Год журнала: 2023, Номер 3(4), С. 391 - 401

Опубликована: Март 13, 2023

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations nine five nonphosphorylated species phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) ten sites. In we show that, in 750 individuals with a median age 71.2 years, CSF pT217/T217 predicted presence brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for positive PET (n 263), was more strongly correlated amount (Spearman's ρ 0.69) (ρ -0.42, P < 0.0001). two independent cohorts participants symptoms AD dementia 55 n 90), pT205/T205 were measures p-tau181 concentration. These findings suggest that represent improved pathology AD.

Язык: Английский

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The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer’s disease: a literature review

Alzheimer s Research & Therapy, Год журнала: 2022, Номер 14(1)

Опубликована: Дек. 27, 2022

Abstract The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark Alzheimer’s disease (AD). Detection Aβ pathology essential for AD diagnosis and identifying recruiting research participants clinical trials evaluating disease-modifying therapies. Currently, diagnoses are usually made by assessments, although detection with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used specialty clinics. These measures aggregation, e.g. plaques, protofibrils, oligomers, medically invasive often only available at specialized medical centers not covered insurance, PET costly. Therefore, major goal recent years has been to identify blood-based biomarkers that accurately detect cost-effective, minimally procedures. To assess performance plasma assays predicting burden central nervous system (CNS), this review compares twenty-one different manuscripts measurements 42 40 amino acid-long (Aβ42 Aβ40) predict CNS status. Methodologies quantitate Aβ42 peptides blood via immunoassay immunoprecipitation-mass spectrometry (IP-MS) were considered, their ability distinguish amyloidosis compared CSF as reference standards was evaluated. Recent studies indicate some IP-MS perform well precisely measuring detecting aggregates.

Язык: Английский

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Equivalence of plasma p‐tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2023, Номер 19(11), С. 4967 - 4977

Опубликована: Апрель 20, 2023

Abstract INTRODUCTION Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established needed. METHODS We assessed the diagnostic performance of p‐tau 181 , 217 and 231 in plasma CSF 174 individuals evaluated by dementia specialists amyloid‐PET tau‐PET. Receiver operating characteristic (ROC) analyses to identify tau‐PET positivity. RESULTS had lower dynamic ranges effect sizes compared p‐tau. (AUC = 76%) 82%) assessments performed inferior 87%) 95%) However, 91%) indistinguishable from 94%) DISCUSSION equivalent biomarker‐defined AD. Our results suggest that may help reduce need invasive lumbar punctures without compromising accuracy identification Highlights diagnosis AD, suggesting increased accessibility is not offset accuracy. mean fold‐changes between negative positive groups than CSF. greater when differentiating groups. worse AD diagnosis.

Язык: Английский

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Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care

JAMA, Год журнала: 2024, Номер 332(15), С. 1245 - 1245

Опубликована: Июль 28, 2024

Importance An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. Objective To prospectively evaluate a clinically available AD in primary care secondary using predefined biomarker cutoff values. Design, Setting, Participants There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who examined between February 2020 January 2024 Sweden. The values had been established an independent cohort applied (n = 307) 300); 1 plasma sample per patient was analyzed as part single batch each cohort. then evaluated 208) 398); sent analysis within 2 weeks collection. Exposure Blood tests based on analyses by mass spectrometry determine ratio phosphorylated tau 217 (p-tau217) non–p-tau217 (expressed percentage p-tau217) alone when combined with amyloid-β 42 40 (Aβ42:Aβ40) (the amyloid probability score [APS2]). Main Outcomes Measures outcome pathology (determined abnormal cerebrospinal fluid Aβ42:Aβ40 p-tau217). positive predictive value (PPV), negative (NPV), accuracy, area under curve (AUC) calculated. Results mean age 74.2 years (SD, 8.3 years), 48% women, 23% subjective decline, 44% mild impairment, 33% dementia. In both assessments, 50% pathology. When samples cohort, AUC 0.97 (95% CI, 0.95-0.99) APS2 used, PPV 91% 87%-96%), NPV 92% 87%-96%); 0.96 0.94-0.98) 88% 83%-93%), 87% 82%-93%). (biweekly) 81%-94%), 90% 84%-96%); 0.95-0.98) 87%-95%), 87%-95%). accuracy high 4 cohorts (range, 88%-92%). Primary physicians 61% 53%-69%) identifying after examination, testing, computed tomographic scan vs 86%-96%) APS2. Dementia specialists 73% 68%-79%) 88%-95%) overall population, (90% [95% 88%-92%]) not different from p-tau217 88%-91%]). Conclusions Relevance among individuals Future studies should how use these biomarkers influences care.

Язык: Английский

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Mitigating the Associations of Kidney Dysfunction With Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios

JAMA Neurology, Год журнала: 2023, Номер 80(5), С. 516 - 516

Опубликована: Март 29, 2023

Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup Alzheimer (AD).To investigate associations CKD ratios p-tau217 p-tau181 to corresponding unphosphorylated peptides AD.This cross-sectional study included patients mild cognitive impairment (cohort 1; enrollment 2000-2005) replication cohort 2 from Swedish BioFINDER-2 study, including both cognitively unimpaired individuals those (enrollment 2017-2022). All participants were memory clinics Sweden had assessments status established within 6 months collection.P-tau217 (Tau212-221 Tau181-190), (pT217/T217 pT181/T181) as well estimated glomerular filtration rate (eGFR) an indicator CKD.Associations between plasma-soluble p-tau CKD.A total 141 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) 332 (172 160 individuals; mean 69.8 [9.4] 169 [50.9%] included. Higher eGFR was levels p-tau217, Tau212-221, Tau181-190 1: R range, -0.24 -0.59; P < .004; 2: -0.18 -0.53; .02) -0.44 -0.50; .001). However, did not correlate pT217/T217 ratio R, -0.11; = .19; -0.02; .78), correlations significantly attenuated (difference: -0.14 [95% CI, -0.22 -0.007]; For pT217/T217, fold increases amyloid-β positive (Aβ+) compared Aβ- groups ranged 2.31 (95% 1.86-2.77) 4.61 3.39-5.83) 1.26 0.98-1.55) 1.27 0.94-1.59) clearly higher than without CKD, ranging 0.05 -0.28 0.38) 0.72 0.25-1.19) 0.09 -0.08 0.26) 0.36 0.19-0.52) individuals.In this soluble tau, but for considerably lower association Aβ positivity. Importantly, ratios, especially less forms alone therefore are likely more accurately reflect AD-related pathological changes.

Язык: Английский

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Predicting amyloid PET and tau PET stages with plasma biomarkers

Brain, Год журнала: 2023, Номер 146(5), С. 2029 - 2044

Опубликована: Фев. 15, 2023

Abstract Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid tau PET has face validity; however, this would be more practical plasma biomarkers. Our objectives were, first, to examine approaches and, second, prediction stages Participants (n = 1136) were enrolled in either Mayo Clinic Study Aging or Research Center; had a concurrent PET, blood draw; met criteria cognitively unimpaired 864), mild cognitive impairment 148) syndrome dementia 124). The latter two groups combined into impaired group 272). We used multinomial regression models estimate discrimination [concordance (C) statistics] among three (low, intermediate, high), four (Braak 0, 1–2, 3–4, 5–6) stage (none/low versus intermediate/high severity) as predictors separately within individuals. Plasma analytes, p-tau181, Aβ1–42 Aβ1–40 (analysed Aβ42/Aβ40 ratio), glial fibrillary acidic protein neurofilament light chain measured on HD-X Simoa Quanterix platform. p-tau217 was also subset 355) participants Lilly Meso Scale Discovery assay. Models all analytes along risk factors (age, sex APOE) most often provided best (C 0.78–0.82). p-tau181 similar 0.72–0.85 C 0.73–0.86). Discriminating proxy from none/low neuropathological change excellent but not better than only 0.88 0.87 0.91 0.90 impaired). outperformed assay discriminating high intermediate 0.85 0.74) did improve over model 0.83). can discriminate between surrogate accuracy acceptable range. Combinations are single many predictions exception that alone usually performed equivalently combinations discrimination.

Язык: Английский

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Acceptable performance of blood biomarker tests of amyloid pathology — recommendations from the Global CEO Initiative on Alzheimer’s Disease

Nature Reviews Neurology, Год журнала: 2024, Номер 20(7), С. 426 - 439

Опубликована: Июнь 12, 2024

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need biomarker confirmation of amyloid pathology. Blood (BBM) tests pathology are more acceptable, accessible and scalable than PET or cerebrospinal fluid (CSF) tests, but highly variable levels performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider minimum acceptable performance clinical use. Amyloid status was identified as reference standard. For use triaging test before subsequent confirmatory such CSF recommends that sensitivity ≥90% with specificity ≥85% primary care ≥75–85% secondary depending availability follow-up testing. without should equivalent — ~90%. Importantly, predictive values all vary according pre-test probability must be interpreted complete context. Use meet these standards could enable people receive an accurate timely diagnosis potentially benefit from new treatments. blood offer test. This Consensus Statement provides recommendations

Язык: Английский

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Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies

JAMA Neurology, Год журнала: 2023, Номер 81(1), С. 69 - 69

Опубликована: Дек. 4, 2023

Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who most likely benefit from these therapies. Blood-based biomarkers might reduce the need use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this.

Язык: Английский

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Plasma Biomarkers of Alzheimer’s Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice

Journal of Alzheimer s Disease Reports, Год журнала: 2023, Номер 7(1), С. 355 - 380

Опубликована: Апрель 25, 2023

Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in determination of biomarkers Alzheimer's disease (AD). Despite significant variability, many studies established in-house cut-off values for most promising available biomarkers. We first reviewed used laboratory methods to measure AD Next, we review focused on diagnostic performance these identify cases, predict cognitive decline pre-clinical differentiate cases from other dementia. summarized data published until January 2023. A combination Aβ42/40 ratio, age, APOE status showed best diagnosing brain amyloidosis a liquid chromatography-mass (LC-MS) assay. Plasma p-tau217 has shown distinguishing Aβ-PET+ Aβ-PET-even cognitively unimpaired individuals. also different each biomarker when available. Recently developed undeniable importance research, improved analytical performance. Some extensively clinical trials are now clinically Nonetheless, several challenges remain their widespread use practice.

Язык: Английский

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