Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers

Experimental & Molecular Medicine, Journal Year: 2019, Volume and Issue: 51(5), P. 1 - 10

Published: May 1, 2019

Current technological advancements in clinical and research settings have permitted a more intensive comprehensive understanding of Alzheimer's disease (AD). This development knowledge regarding AD pathogenesis has been implemented to produce disease-modifying drugs. The potential for accessible effective therapeutic methods generated need detecting this neurodegenerative disorder during early stages progression because such remedial effects are profound when the initial, prolonged prodromal pathogenesis. aggregation amyloid-β (Aβ) tau isoforms characteristic AD; thus, they considered core candidate biomarkers. However, attempting establish reliability Aβ as biomarkers culminated an amalgamation contradictory results theories biomarker concentrations necessary accurate diagnosis. In review, we consider capabilities limitations fluid collected from cerebrospinal fluid, blood, oral, ocular, olfactory secretions diagnostic tools AD, along with impact integration these settings. Furthermore, evolution criteria novel findings discussed. review is summary reflection ongoing concerted efforts tool implement them procedures. Markers body fluids could help clinicians diagnose before cognitive decline appears. After numerous setbacks treating advanced Alzheimer's, researchers eager identify biological indicators that facilitate earlier detection interception. A by YoungSoo Kim colleagues at Yonsei University South Korea, explores promise 'fluid biomarkers,' which enables diagnosis using (CSF), samples. Shifts CSF levels amyloid beta tau, two proteins central pathology, can reliably monitor at-risk individuals. Although collection unpleasant patients, it remains promising than where current data relatively inconclusive. investigations discover safer, cheaper, reliable shift treatment alleviation prevention introduced.

Language: Английский

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Clinical aspects of Alzheimer's disease

Clinical Biochemistry, Journal Year: 2019, Volume and Issue: 72, P. 3 - 6

Published: April 26, 2019

Language: Английский

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Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer’s disease (MCI and dementia) in primary care: a review and synthesis

Journal of Internal Medicine, Journal Year: 2021, Volume and Issue: 290(2), P. 310 - 334

Published: Jan. 18, 2021

Abstract The critical role of primary care clinicians (PCCs) in Alzheimer’s disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms disease‐modifying therapies (DMTs) emerge. Our understanding AD has grown substantially: no longer conceptualized a late‐in‐life syndrome cognitive functional impairments, we now recognize that pathology builds silently for decades before impairment is detectable. Clinically, first manifests subtly mild (MCI) due to progressing dementia. Emerging optimism improved outcomes stems from focus on preventive interventions midlife timely, biomarker‐confirmed at early signs deficits (i.e. MCI dementia). A timely particularly important optimizing patient enabling the appropriate use anticipated DMTs. An accelerating challenge PCCs specialists will be respond innovations diagnostics therapy system not currently well positioned do so. To overcome these challenges, collaborate closely navigate optimize dynamically evolving face opportunities. In spirit this collaboration, summarize here some prominent influential models inform our current AD. We also advocate accurate biomarker‐defined) doing so, consider issues related detecting emerging biomarkers clinic.

Language: Английский

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Amyloid blood biomarker detects Alzheimer's disease

EMBO Molecular Medicine, Journal Year: 2018, Volume and Issue: 10(5)

Published: April 6, 2018

Research Article6 April 2018Open Access Source DataTransparent process Amyloid blood biomarker detects Alzheimer's disease Andreas Nabers Department of Biophysics, Ruhr-University Bochum, Germany Search for more papers by this author Laura Perna Division Clinical Epidemiology and Aging Research, German Cancer Center (DKFZ), Heidelberg, Julia Lange Ute Mons Jonas Schartner Jörn Güldenhaupt Kai-Uwe Saum Shorena Janelidze Sciences, Lund University, Lund, Sweden Bernd Holleczek Saarland Registry, Saarbrücken, Dan Rujescu Psychiatry, Psychotherapy Psychosomatics, University Halle, Oskar Hansson orcid.org/0000-0001-8467-7286 Memory Clinic, Skåne Hospital, Malmö, Klaus Gerwert Corresponding Author [email protected] orcid.org/0000-0001-8759-5964 GermanyCorrection added online on 5 May 2018 after first publication: the affiliation corresponding has been corrected. Hermann Brenner Network (NAR), Information Nabers1,‡, Perna2,‡, Lange1, Mons2, Schartner1, Güldenhaupt1, Saum2, Janelidze3, Holleczek4, Rujescu5, Hansson3,6, *,1 Brenner2,7 1Department 2Division 3Department 4Saarland 5Department 6Memory 7Network ‡These authors contributed equally to work *Corresponding author. Tel: +49 234 32 24462; E-mail: EMBO Mol Med (2018)10:e8763https://doi.org/10.15252/emmm.201708763 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 (AD) is currently incurable, but there general agreement that minimally invasive screening in preclinical stages would be crucial future therapy. Diagnostic tools detection AD are either like cerebrospinal fluid (CSF) biomarkers or expensive such as positron emission tomography (PET) scanning. Here, we determine secondary structure change amyloid-β (Aβ) human blood. This used amyloid indicates prodromal correlates with CSF PET imaging cross-sectional BioFINDER cohort. In further population-based longitudinal cohort (ESTHER), detected several years before clinical diagnosis baseline samples positive likelihood ratio 7.9; is, those who were diagnosed over 7.9 times likely test positive. assay may open avenues early funnel tests. Synopsis Determination distribution plasma an immuno-IR-sensor scanning markers patients, potentials accurate, simple, detection. The can directly determined sensitive amide I band. Prodromal cases (BioFINDER study) showed significant correlations between frequency shift results values. Early identification (Esther) yielded 71% sensitivity, 91% specificity, LR+ 7.9–8 symptoms appeared, study. routine minimal-invasive, low-cost pre-select individuals which should undergo lumbar puncture Introduction brain disorder whose hallmarks plaques neurofibrillary tangles (Blennow et al, 2006; Zhao 2012; Wang Mandelkow, 2016). It believed up 15–20 prior (Bateman Rowe 2013), peptides alters its folds from "healthy" disordered α-helical "pathological" β-sheet-enriched structures (Sarroukh 2011). Such aggregate form soluble toxic oligomers, seeds, finally macroscopically visible plaques, thought contribute neurodegeneration (Cavallucci Jucker Walker, 2013). Hence, research diagnostic criteria recommend use amyloidosis (McKhann 2011; Sperling Jack Established Aβ-binding ligands (PET), costly time-consuming technique, assays measure Aβ42, total-tau (ttau) phosphor-tau (ptau) fluid, require procedure 2015). Recently, developed immuno-infrared-sensor (WO 2015121339 A1) monitored Aβ peptides. sensor antibody-based (immuno) method extract all spectroscopically senses extracted infrared (Fig 1A; 2016a,b). As compared established ELISA tests detection, immuno-infrared-assay does not absolute concentration relative measure. Thus, measurements principal robust against fluctuations caused biological variances. Figure 1. Schematic overview immuno-infrared-sensor, read-out, ESTHER study design simultaneously monitors caught monoclonal antibodies (mAb) covalently attached surface (schematic simplified representation; mAb A8978 raised middle epitope (aa13–28) Aβ). If marker band (amide I) dominated monomeric isoforms, patients non-AD (blue). β-sheet isoforms enriched (red), signal shifted below threshold (1,642 cm−1), indicating AD. Plasma (BioFINDER) measured differentiate 37 healthy elderly people (all negative) 36 (MCI) positive). record participants within comprised cognitive testing, assessment, other measures, 3 Tesla MRI, genetics, epidemiology [18F]-flutemetamol Nested case–control based January 2016. Baseline year 2000–2002 same way = disease; VD vascular dementia; MD mixed dementia investigated. Other forms include frontotemporal dementias. GPs practitioners; yr year; FU follow-up. number randomly selected controls reflects original design; sample sizes depicted brackets. Download figure PowerPoint We reliable severe (Nabers 2016a). expected, at these overall structures. specifically extracts under physiological conditions independent respective structure. read-out structure-sensitive absorbance band, average (see Fig 1A). conformations, comprising diverse oligomeric (pre-) fibrillary species, downshifted small elucidated large background difference spectroscopy (Garczarek Gerwert, An experimentally separates species unfolded (schematically shown summary, if maximum position shifts threshold, it AD, because towards species. previous 2016a) included neurochemical (such Aβ(40), Aβ(42), Aβ(42/40), phospho-tau, total-tau), was applied 141 moderate-to-severe stages. study, sensitivity 94% specificity 88% analyses. However, even interesting 75%, analyses demonstrated could Results Since structural proposed take place onset, here, investigated whether downshift also serve identify order answer questions, studied altered during From prospective Swedish non-demented mild impairment had abnormal scans, well cognitively normal scans 1B). design, 40 versus planned, four three samples, respectively, insufficient performance, thus, analysis possible. All collected subjects analysed using (samples blinded). significantly lower (P < 0.001) control group 2A). 2. maxima recorded diamonds 1,642 cm−1 (solid horizontal line) (MCI (PET positive), BioFINDER; ESTHER) (control negative), contr., ESTHER). (for see A) VD, controls. Only threshold. Therefore, provide differential diagnosis. groups differed 0.0001) (ESTHER). Data information: box plots, 25/50/75% quantiles lines, observed minimum/maximum values (×), square, ± standard deviation whiskers. Significant differences indicated P-values (two-sided nonparametric Kruskal–Wallis variance test) asterisks: *P 0.05, **P 0.01, ***P 0.001. state, less enrichment expected very state. Using cm−1, differentiated 69% 86%. AUC 0.78 (0.68–0.88, 95% CI) calculated differentiation 3A). shows able individuals. performance good 88%. might improved optimised antibody preliminary experiments have shown. 3. ROC curve data set curves PET-positive (n 36) vs. PET-negative 37) 65) 247) (red) (ESTHER, Germany) obtained variation 1,630.5 1,660.5 cm−1. 0.80 (0.76–0.84, achieved cut-off (threshold) limit negativity (black) 86% (red). (BioFINDER, Sweden) Aβ(40) (blue), Aβ(42) Aβ(42/40) (orange), ttau (green) ptau (pink). presented. available figure. [emmm201708763-sup-0003-SDataFig3.xls] Further, levels study: (P-value 4 × 10−4, rs 0.401), 0.407), 8 −0.382), phospho-tau 0.146, −0.172). standardised uptake value (SUVR) cortical composite region correlated IR-marker −0.397397; EV1). illustrates correlation image subject. Click here expand EV1. Correlation (BioFINDER)Summary Spearman rank coefficients (rs) their positions EDTA plasma, SUVR 18F imaging. 4. deposition depicts transaxial coronal sections (BioFINDER). scan non-specific binding radioligand white matter. patient's EDTA-blood presented below. correlate each (rs −0.397, P-value 10−4) patient clearly increased [18F]-flutemetamol. demographic 73 summarised Appendix Table S2. our scans. than 3B), prevents employment stand-alone instrument, allow two-stage combination and/or Moreover, become that, ideally, focus complementary tau filaments, second hallmark (Wang Particularly, preselect additional state/preclinical (ESTHER) next step, diagnoses population. older adults (ESTHER started 2000–2002. nested approach embedded (Saum 2015) 970 methods details), identified 195 follow-up, approximately many without These matched 70), (VD; n 85) (MD; 40) age, sex educational level 1b). For excluded 70 haemolytic 19 whom suspected confirmed medical records seven purported later reported. left 167 (65 66 MD) 707 (247 311 149 Aβ-analyses (Appendix S1). representative designed research; hence, necessarily supported nor present (2000–2002), Diagnoses made follow-up At stages, accurate assessment (Beach Martinelli 2014). Specifically, mean time collection listed detail S3. Also, carriage APOE e4 risk allele much common (45.8% 21.7%. 0.0002) S1) prevalence estimates reported studies [pooled allele: 53.0% (44.9–61.2) (Ward 2012)]. Mean ages 68.7 68.5 years. majority women (61.5% 62.4%, respectively) low (9 less) school education (86.2% 83.8%, respectively). total fraction subject assayed them blind manner. Values detect downward 1,641 (median cm−1) seen almost exclusively 2B). suggest β-folding appear stage dementias VD. Nevertheless, exclude some misclassification results, discriminate validated another additionally To knowledge, test, differentiates date. A receiver operator characteristics (ROC) characterised quality discrimination AD/AD (22 false positives out 247 controls). accuracy indicators (sensitivity, AUC) slightly higher confidence interval estimate evidence prescreening ratios appropriate measures. (LR+) result occurs about eight frequently develop do (Jaeschke 1994) Discussion seem confirm preselection two-step diagnostics suggested above set-up, high immuno-infrared-assay, increase specificity. diagnostics, 77% expense up-shifting 1,644 80% preselected 30% true negative wrongly false-negative will long no treatment implications subjects. Focusing great advantage targeting molecular pathomechanism transition, known initiate 20 manifestation us overcome shortcomings non-brain-specific markers. lack clear understanding relationship earliest possibility being influenced comorbidities among (Fiandaca 2014, 2015; Henriksen 2014; Mapstone O'Bryant 2017). finding appears lead deeper insights into pathophysiology, damaged blood–brain barrier generation cells outside and, possibly, comorbidity diseases diabetes. factors play role pathophysiology scope manuscript address issue detail. limitation β-misfolding persons absent patients; negatives intrinsic (Yang Fiandaca Jansen tests—either misfolding Aβ42 decrease (Ovod 2017; Nakamura 2018)—and demonstrate direct link alterations burden peripheral effect. encouraging initial eventually part trials therapeutics (Sevigny 2016) already important step forward hard identify. today available, tested both receive utility future, immuno-infrared-test needs multicentre especially NIH-ADNI. need operating procedures guarantee constant m

Language: Английский

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Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1–42), pTau and tTau CSF immunoassays

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Dec. 13, 2019

Abstract We evaluated the performance of CSF biomarkers for predicting risk clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. samples from two multicentre longitudinal studies (ADNI, n = 619; BioFINDER, 431) were analysed. Aβ(1–42), tTau pTau concentrations measured using Elecsys immunoassays, tTau/Aβ(1–42) pTau/Aβ(1–42) ratios calculated. Patients classified as biomarker (BM)-positive or BM-negative at baseline. Ability predict AD/dementia was assessed pre-established cut-offs Aβ(1–42) ratios; determined. BM-positive showed greater than patients, demonstrated by decreases MMSE scores (all biomarkers: –2.10 –0.70). Risk higher (HR: 1.67 11.48). Performance Tau/Aβ(1–42) superior single biomarkers, consistent even when derived a different cohort. Optimal approximately 27 pg/mL 300 both BioFINDER ADNI. are robust may support AD diagnosis practice.

Language: Английский

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Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(6), P. 1128 - 1140

Published: Sept. 27, 2021

Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels these markers.

Language: Английский

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Advances in the development of new biomarkers for Alzheimer’s disease

Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)

Published: April 21, 2022

Alzheimer's disease (AD) is a complex, heterogeneous, progressive and the most common type of neurodegenerative dementia. The prevalence AD expected to increase as population ages, placing an additional burden on national healthcare systems. There large need for new diagnostic tests that can detect at early stage with high specificity relatively low cost. development modern analytical tools has made it possible determine several biomarkers specificity, including pathogenic proteins, markers synaptic dysfunction, inflammation in blood. considerable potential using microRNA (miRNA) AD, studies based miRNA panels suggest could potentially be determined accuracy individual patients. Studies retina improved methods visualization fundus are also showing promising results diagnosis disease. This review focuses recent developments blood, plasma, ocular AD.

Language: Английский

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Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2019, Volume and Issue: 15(6), P. 764 - 775

Published: May 18, 2019

Abstract Introduction Blood‐based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large‐scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials management. Methods We investigated whether plasma concentrations the Aβ 1–40 /Aβ 1–42 ratio, assessed using single‐molecule array (Simoa) immunoassay, may predict positron emission tomography status in a longitudinal monocentric cohort (N = 276) older individuals with subjective memory complaints. performed hypothesis‐driven investigation followed by no‐a‐priori hypothesis study machine learning. Results The receiver operating characteristic curve learning showed balanced accuracy 76.5% 81%, respectively, ratio. is not affected apolipoprotein E ( APOE ) ε4 allele, sex, or age. Discussion Our results encourage an independent validation confirm indication that via Simoa, improve future standard care trial design.

Language: Английский

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Retinal imaging in Alzheimer's and neurodegenerative diseases

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(1), P. 103 - 111

Published: Oct. 8, 2020

Abstract In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Association & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Dementia ) convened an interdisciplinary discussion in 2019 identify path expedite development capable identifying biological changes associated with AD, tracking progression severity over time. As different modalities provide types structural and/or functional information, reflected these their respective strengths weaknesses. Discussion further importance defining context use help guide biomarkers. Moving from use, ultimately clinical evaluation, this article outlines ongoing today brain including future directions area study.

Language: Английский

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Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aβ42/Aβ40 and p‐tau

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(2), P. 283 - 293

Published: June 20, 2021

We studied usefulness of combining blood amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain Aβ deposition in different stages early Alzheimer's disease (AD).Plasma biomarkers were measured using mass spectrometry (Aβ42/Aβ40) immunoassays (p-tau217 NfL) cognitively unimpaired individuals (CU, N = 591) patients with mild cognitive impairment (MCI, 304) from two independent cohorts (BioFINDER-1, BioFINDER-2).In CU, a combination plasma Aβ42/Aβ40 p-tau217 detected status area under the curve (AUC) 0.83 0.86. In MCI, models including alone or had similar AUCs (0.86-0.88); however, latter showed improved model fit. The implemented an online application providing individualized risk assessments (https://brainapps.shinyapps.io/PredictABplasma/).A discriminated relatively high accuracy, whereas strongest associations pathology MCI but not CU.

Language: Английский

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