Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots—A new collection method for remote settings

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(4), P. 2340 - 2352

Published: Jan. 29, 2024

Abstract BACKGROUND We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPS v enous ) for diagnosis monitoring neurodegenerative diseases in remote settings. METHODS In a discovery ( n = 154) validation cohort 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; phosphorylated tau (p‐tau181 p‐tau217) were measured paired DPS ethylenediaminetetraacetic acid samples with single‐molecule array. cohort, subset participants 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS All analytes correlated significantly, except Aβ42. GFAP, NfL, p‐tau181, p‐tau217 differed between CSF Aβ‐positive ‐negative individuals associated worsening cognition. DISCUSSION Our data suggest that measuring blood biomarkers related AD pathology extends utility blood‐based settings simplified sampling conditions, storage, logistics. Highlights A wide array detectable ). standard procedures cognitive status. good diagnostic accuracy discriminating findings show potential interchangeability sampling. may facilitate temperature‐independent measurement. Innovative tools help recognizing earliest changes AD.

Language: Английский

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Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: May 15, 2024

Abstract Alzheimer’s disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades research clinical investigation. This might be partly due a lack widely available cost-effective modalities for diagnosis prognosis. Recently, blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity precision assays measurement platforms. Several biomarkers have shown high potential accurately detecting pathophysiology. As result, there been considerable interest in applying these prognosis, as surrogate metrics investigate impact various covariates on pathophysiology accelerate therapeutic trials monitor treatment effects. However, standardization how blood samples collected, processed, stored analyzed reported can affect reproducibility measurements, potentially hindering toward their widespread use settings. To help address issues, we provide fundamental guidelines developed according recent findings sample handling measurements. These cover important considerations including study design, collection, processing, biobanking, measurement, result reporting. Furthermore, proposed include best practices appropriate procedures genetic ribonucleic acid analyses. While focus key AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau glial fibrillary acidic protein), anticipate that will generally applicable other types biomarkers. We also assist investigators planning executing research, enabling harmonization improve comparability across studies.

Language: Английский

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Effects of certain pre-analytical factors on the performance of plasma phospho-tau217

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Feb. 8, 2024

Pre-analytical factors can cause substantial variability in the measurements of cerebrospinal fluid (CSF) and plasma biomarkers Alzheimer's disease (AD). However, their effects on performance one most promising AD biomarkers, phosphorylated tau (p-tau)217, are not known. We included 50 amyloid-β positive (Aβ+) Aβ- participants from Swedish BioFINDER-1 study. Plasma CSF p-tau217 were measured using an immunoassay developed by Lilly Research Laboratories. examined effect four handling conditions, i.e., (1) thawing at room temperature (RT) with no centrifugation, (2) RT followed (3) ice (4) centrifugation. In addition, we also tested up to 3 freeze-thaw cycles associations AD-related pathologies Aβ42/Aβ40. whole cohort (combining Aβ+ participants), found significant correlations between both (Rrange, 0.614-0.717, p < 0.001) Aβ42/Aβ40 (Spearman Rrange, - 0.515 0.652, for each conditions. Correlations all conditions group 0.506-0.579, 0.001). this subgroup, only centrifuged samples (thawed RT, R = 0.394, 0.010; thawed ice, 0.406; 0.007). participants, again 0.007; 0.334; 0.022), seen any While accuracy identify individuals abnormal or status was high, AUCs analyzed without centrifugation numerically lower than other (CSF 0.845 vs 0.872-0.884; 0.866 0.908-0.924, pdiff > 0.11). P-tau217 concentration consistently higher non-centrifuged (p ≤ 0.021). There differences freeze-thawed once, twice, three times. Centrifugation improved p-tau217, but temperatures did have a impact. These results may inform future development standardized sample-handling protocols biomarkers.

Language: Английский

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Preanalytical stability of plasma biomarkers for Alzheimer's disease pathology

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2023, Volume and Issue: 15(2)

Published: April 1, 2023

Plasma tests have demonstrated high diagnostic accuracy for identifying Alzheimer's disease pathology. To facilitate the transition to clinical utility, we assessed whether plasma storage duration and temperature affect biomarker concentrations.

Language: Английский

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Differences in Alzheimer's disease blood biomarker stability: Implications for the use of tau/amyloid ratios

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(4)

Published: April 1, 2025

We compare the stability of phosphorylated tau (p-tau)217, amyloid beta (Aβ)42, Aβ40, Aβ42/40, and p-tau217/Aβ42 at different storage temperatures. Ten ethylenediaminetetraacetic acid-plasma sample aliquots stored frozen, refrigerated, ambient temperatures were tested various timepoints up to 30 days. The mean percent change from baseline was calculated. Aβ42 Aβ40 concentrations decreased by >15% after 6 hours temperature 24 while p-tau217 remained stable over 72 with < 10% deviation either temperature. Aβ42/40 ratio relatively constant as each analyte concentration concurrently, deviated time. All biomarkers days frozen. Differences in may lead altered results if samples are not handled properly during pre-analytical testing phase. Ideally, should be frozen promptly sent laboratory Plasma assessed. P-tau217 stable, but started decreasing differences led falsely increased ratios. Increases > 15% seen or 4°C.

Language: Английский

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Plasma P-Tau181 and Amyloid Markers in Alzheimer's Disease: A Method Comparison between Simoa and Lumipulse

SSRN Electronic Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Aim of the project was to evaluate technical and clinical validity plasma Lumipulse SIMOA p-tau, Aβ42 Aβ40 species their correlation with CSF core Alzheimer's Disease (AD) markers. One-hundred-thirty-three subjects, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) 50 controls were enrolled for study. showed high stability p-tau181, Aβ42, Aβ40, higher p-tau repeated freezing thaw cycles. p-tau181 levels detected by both techniques in AD compared NDD/controls exhibited a similar levels, whereas slightly lower methods. In comparison between markers, diagnostic accuracy (0.87; 0.81-0.94, vs 0.85; 0.78-0.93), best performance reached p-tau181/ ratio (ROC AUC 0.915, IC 0.86-0.97). The study thus confirmed construct identification pattern settings.

Language: Английский

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Plasma p-tau181 and amyloid markers in Alzheimer’s disease:a comparison between Lumipulse and SIMOA

Neurobiology of Aging, Journal Year: 2024, Volume and Issue: 143, P. 30 - 40

Published: Aug. 22, 2024

Aim of the project was to evaluate technical and clinical validity plasma Lumipulse p-tau, Aβ42 Aβ40 species their correlation with CSF core Alzheimer's Disease (AD) markers; a method comparison SIMOA also performed. One-hundred-thirthy-three participants, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) 50 controls were enrolled for study. showed high stability p-tau181, Aβ42, Aβ40, higher p-tau repeated freezing thaw cycles. p-tau181 levels detected by both techniques in AD compared NDD/controls exhibited similar levels, whereas slightly lower methods. In between markers, diagnostic accuracy (0.87; 95 %CI 0.81-0.94, vs 0.85; 0.78-0.93), best performance reached p-tau181/ ratio (ROC AUC 0.915, 0.86-0.97). The study thus confirmed construct identification pattern settings.

Language: Английский

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Effect of blood collection tube containing protease inhibitors on the pre‐analytical stability of Alzheimer's disease plasma biomarkers

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: May 30, 2024

Abstract The reliability of plasma biomarkers Alzheimer's disease (AD) can be compromised by protease‐induced degradation. This limit the feasibility conducting biomarker studies in environments that lack capacity for immediate processing and appropriate storage blood samples. We hypothesized collection tube supplementation with protease inhibitors improve stability at room temperatures (RT). In this study, we conducted a comparative analysis traditional ethylenediaminetetraacetic acid (EDTA) tubes versus BD™ P100 tubes, latter being coated inhibitor cocktail. six AD was evaluated over time under RT conditions. three experimental approaches. Approach 1, pooled samples underwent up to 96 h. 2, isolated upfront from whole collected into EDTA or were stored 0 h 24 before measurements. 3, paired followed isolating analyses. Biomarkers measured Single Molecule Array (Simoa) immunoprecipitation‐mass spectrometry (IP‐MS) assays. Both IP‐MS Simoa methods revealed use significantly improves Aβ42 Aβ40 across all However, Aβ42/Aβ40 ratio levels stabilized only assay 3. No significant differences observed p‐tau181, GFAP, NfL using either type any Supplementation could reduce degradation Aβ40, Aβ42/40 assay. These findings have crucial implications preanalytical procedures, particularly resource‐limited settings. image

Language: Английский

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The performance of plasma phosphorylated tau231 in detecting Alzheimer's disease: A systematic review with meta‐analysis

European Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 58(4), P. 3132 - 3149

Published: July 27, 2023

Abstract Cerebrospinal fluid (CSF) phosphorylated tau231 (P‐tau231) is associated with neuropathological outcomes of Alzheimer's disease (AD). The invasive access cerebrospinal has greatly stimulated interest in the identification blood‐based P‐tau231, and recent advent single‐molecule array assay for quantification plasma P‐tau231 may provide a turning point to evaluate usefulness as an AD‐related biomarker. Yet, literature, findings regard its diagnostic utility have been inconsistent, thus, we aimed statistically investigate potential context AD via meta‐analysis. Publications on were systematically retrieved from PubMed, EMBASE, Cochrane library Web Science databases. A total 10 studies covering 2007 participants included, conducted random‐effect or fixed‐effect meta‐analysis, sensitivity analysis publication bias using STATA SE 14.0 software. According our quantitative integration, increased cognitively unimpaired (CU) populations mild cognitive impairment showed significant changes pairwise comparisons AD, CU. Plasma level was significantly higher CU controls positive amyloid‐β (Aβ) status compared Aβ‐negative group. Additionally, excellent accuracy asymptomatic Aβ pathology verified by pooled value area under receiver operating characteristic curves (standard mean difference [95% confidence interval]: .75 [.69, .81], P < 0.00001). Overall, concentrations found relation early development progression AD.

Language: Английский

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Validating blood tests as a possible routine diagnostic assay of Alzheimer’s disease

Expert Review of Molecular Diagnostics, Journal Year: 2023, Volume and Issue: 23(12), P. 1153 - 1165

Published: Nov. 29, 2023

ABSTRACTIntroduction In recent years exciting developments in disease modifying treatments for Alzheimer's (AD) have made accurate and timely diagnosis of this a priority. Blood biomarkers (BBMs) amyloid pathology using improved immunoassay mass spectrometry techniques been an area intense research the last 10 are coming to fore, as real prospect be used clinical diagnostics disease.Areas covered The following review will update discuss blood that most useful diagnosing AD context necessary their implementation.Expert Opinion It is clear we now BBMs, technology measure them, capable detecting AD. challenge validate them across platforms populations incorporate into practice. important implementation comes with education, need give clinicians tools appropriate use interpretation. feasible BBMs screen populations, initially trial entry but also therapeutic intervention foreseeable future. We focus BBM on other pathologies ensure accelerate development therapeutics all neurodegenerative diseasesKEYWORDS: diseaseblood biomarkersImmunoassayDiagnosticsamyloidtauneurofilamentGFAPvalidationDisclaimerAs service authors researchers providing version accepted manuscript (AM). Copyediting, typesetting, resulting proofs undertaken before final publication Version Record (VoR). During production pre-press, errors may discovered which could affect content, legal disclaimers apply journal relate these versions also. Article highlightsAlzheimer's progressive disorder until recently there were no therapies available.There urgent fast, inexpensive diagnostic tests.Fluid possible measured cerebrospinal fluid number years.The super-sensitive mass-spectrometry methods allowing us blood.In order fully respect pre-analytical processing assay suitable labs.It within next few materials knowledge effectively see more cost-effective equitable access therapeutics.Declaration financial/other relationshipsH Zetterberg Wallenberg Scholar supported by grants from Swedish Research Council (#2022-01018 #2019-02397), European Union's Horizon Europe innovation programme under grant agreement No 101053962, State Support Clinical (#ALFGBG-71320), Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), Strategic Fund Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C), Bluefield Project, Olav Thon Foundation, Erling-Persson Family Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), 2020 Marie Skłodowska-Curie 860197 (MIRIADE), Union Joint Programme – Neurodegenerative Disease (JPND2021-00694), National Institute Health Care University College London Hospitals Biomedical Centre, UK Dementia at UCL (UKDRI-1003). H has served scientific advisory boards and/or consultant Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Wave, given lectures symposia sponsored Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, co-founder Brain Biomarker Solutions Gothenburg AB (BBS), part GU Ventures Incubator Program (outside submitted work). relevant affiliations or financial involvement any organization entity interest conflict subject matter discussed apart those disclosed.Reviewer disclosuresPeer reviewers relationships disclose.Author contributionsEleftheria Kodosaki wrote manuscript, reviewed manuscript. Henrik edited Amanda Heslegrave wrote, manuscript.Abbreviationsαsyn=alpha synucleinAPOE=apolipoprotein EAAIC=Alzheimer's International ConferenceAD=Alzheimer's diseaseALS=Amyotrophic Lateral SclerosisAPP=Amyloid precursor proteinAT(N)=amyloid, tau (neurodegeneration)AUC=Area Under CurveAβ=amyloid betaBBM=Blood BiomarkerBDNF=Brain derived neurotrophic factorBD-tau=Brain Derived tauBMI=Body indexcfDNA=cell-free DNACfH=complement factor HCh3L1=chitinase 3-like 1CNS=Central nervous systemCSF=cerebrospinal fluidCV=Coefficient VariationEDTA=Ethylenediaminetetraacetic acidELISA=enzyme-linked immunosorbent assayFDA=Food AdministrationFDG=FludeoxyglucoseFTD=Frontotemporal dementiaGFAP=Glial fibrillary acidic proteinIP-MS=immunoprecipitation spectrometrylncRNA=long non coding RNAMCI=Mild Cognitive ImpairmentmiRNA=micro RNAMS=Multiple sclerosisMSD=MesoScale DiscoveryMSp=Mass spectrometryNfL=neurofilament lightNIA-AA=National Aging AssociationPBS=Phosphate-buffered salinePET=positron emission tomographyp-tau=phosphorylated tauQC=Quality controlRT=Room temperatureSABB=Standardization BiomarkersSiMoA=single molecule arraySOP=Standard operating proceduressTREM2=soluble Triggered receptor expressed myeloid cells 2TBI=Traumatic InjuryTDP-43=TAR DNA-binding protein-43t-tau=total tauVILIP-1=Visinin-like protein 1WB=western blotFigure 1. Description typical (immunoassays Mass Spectrometry) detection quantification blood-based biomarkers. HRP=Horseradish peroxidase, Ag=antigen, SA=streptavidin, B=biotin, SGB=Streptavidin beta galactosidaseDisplay full sizeAdditional informationFundingThis paper was not funded.

Language: Английский

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