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Fortschr Neurol Psychiatr 2022; 90(07/08): 326-335
DOI: 10.1055/a-1839-6237
Übersichtsarbeit

Blutbasierte Biomarker zur Optimierung der Früh- und Differentialdiagnostik der Alzheimer-Demenz

Blood Based Biomarker for Optimization of Early and Differential Diagnosis of Alzheimer’s Dementia
Niels Hansen
1   Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin, Göttingen, Deutschland.
,
Carolin Rauter
1   Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin, Göttingen, Deutschland.
,
Jens Wiltfang
1   Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin, Göttingen, Deutschland.
2   Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Deutschland.
3   Neurosciences and Signaling Group, Biomedizinisches Institut (iBiMED), Abteilung für medizinische Wissenschaft, Universität Aveiro, Aveiro, Portugal.
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Zusammenfassung

Ziele der Studie Die Demenz bei Alzheimer-Krankheit ist eine globale Herausforderung. Studien weisen auf Blutbiomarker zur Diagnose der Alzheimer-Krankheit als eine minimal invasive, schnellere, kostengünstigere und daher zukunftsträchtige Methode hin. Ziel dieser Übersicht ist es, Studien zu vielversprechenden Biomarkern der Alzheimer-Krankheit darzustellen.

Methodik Für diese Übersichtsarbeit wurden aktuelle Studien zusammengestellt.

Ergebnisse Immunassays mit anschließender Massenspektrometrie und solche mit immunmagnetischer Reduktion sind aussichtsreiche Methoden für die Bestimmung von Amyloid-ß 42 (Aß42) und Amyloid-ß 40 (Aß40) für die Bildung der Ratio von Aß42/Aß40 zur blutbasierten Früh- und Differentialdiagnostik der Alzheimer-Krankheit. Die Amyloid-ß (Aß) Peptide im Blutplasma sind ein potentieller Marker der Aß-Pathologie, da sie mit der Aß-Pathologie im Gehirn korrelieren. Das mittels der Simoa Technologie bestimmte phosphorylierte Tau-Protein 181 (p-tau181), das phosphorylierte Tau Protein 231 (p-tau231) und das phosphorylierte Tau Protein 217 (p-tau217) im Blut sind vielversprechend hinsichtlich einer möglichen Optimierung der Früh- und Differentialdiagnostik der Alzheimer-Krankheit und sind Marker einer Tau-Pathologie im Gehirn. Die Neurofilamente Leichtketten (Nfl) und das saure Gliafaserprotein (GFAP) sind als Zusatzmarker hilfreich, um eine axonale und astrogliale Hirnschädigung bei Alzheimer-Krankheit zu beurteilen. GFAP im Blut könnte vor allem als Zusatzmarker zur Frühdiagnostik und Prädiktion des Verlaufs der Alzheimer-Krankheit sinnvoll sein.

Schlussfolgerungen Blutbasierte Biomarker sind ein wichtiger Schritt in Richtung einer weniger invasiven und kostengünstigeren Diagnostik der Alzheimer-Krankheit. Die Ratio Aß42/Aß40, das p-tau181, das p-tau217, das p-tau231, die Nfl und das GFAP sind vielversprechende Blutbiomarker unter Beachtung der AT(N) Klassifikation der Alzheimer-Krankheit. Hochdurchsatzfähige Methoden sollten in großen Kohorten und Metanalysen evaluiert werden. Zudem sollten Konsensus Kriterien mit einheitlichen Protokollen mit Normwerten zur Messung dieser Biomarker erstellt werden. Die Etablierung der AT(N) Klassifikation der Alzheimer-Krankheit im Blut ist unter Berücksichtigung ethischer Gesichtspunkte sowie des Alzheimer Phänotyps ein wichtiger Baustein für die Implementierung einer minimal-invasiven Präzisionsmedizin.

Abstract

Aim Dementia in Alzheimer´s disease is a global challenge. There is growing evidence that investigating blood biomarkers to diagnose Alzheimer´s disease is a promising fast, minimally invasive, and less costly method. The aim of this study was to review available studies on promising biomarkers for Alzheimer´s disease.

Method The latest studies were collated for this review.

Results Immunoassays followed by mass spectrometry and immunomagnetic reduction were reported to be highly relevant methods for detecting amyloid-ß 42 (Aß42) and amyloid-ß 40 (Aß40) to calculate the Aß42/Aß40 ratio, thereby improving the early diagnosis of Alzheimer´s disease. Amyloid-ß (Aß) peptides in blood plasma were considered as potential markers, as they correlated with the brain’s Aß pathology. Phosphorylated tau protein 181 (p-tau181), phosphorylated tau protein 217 (p-tau217) and phosphorylated tau protein 231 (p-tau231) in blood samples assessed via Simoa technology served as parameters for the early and differential diagnosis of AD, and were markers of tau pathology in the brain. Neurofilament light chain (Nfl) and glial fibrillary acid protein (GFAP) were additional markers possibly facilitating the assessment of axonal and astroglial brain damage in Alzheimer´s disease. GFAP in blood was useful as an additional marker to detect early and to predict the time course of Alzheimer´s disease.

Conclusions Determining blood biomarkers represents less invasive and less costly diagnostics for Alzheimer´s disease. The investigation of blood biomarkers such as the Aß42/Aß40 ratio, p-tau217, p-tau231, Nfl and GFAP have been promising in establishing the AT(N) classification for Alzheimer´s disease. High-throughput methods should be evaluated in large patient cohort studies and via meta-analyses of studies. Consensus criteria with standard protocols for measuring these biomarkers while considering ethical issues and Alzheimer´s phenotype should unify normative values from different laboratories. The AT(N) classification of Alzheimer´s disease in blood would be a key element towards the implementation of minimally-invasive precision medicine.

Schlüsselwörter

Alzheimer Demenz - Blut - Biomarker - Diagnose

Key words

Alzheimer´s dementia - blood - biomarker - diagnosis


Publikationsverlauf

Eingereicht: 01. Dezember 2021

Angenommen: 26. April 2022

Artikel online veröffentlicht:
20. Juli 2022

© 2022. Thieme. All rights reserved.

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  • Literatur

  • 1 Alagaratnam J, von Widekind S, De Francesco D. et al. Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis. BMJ Neurol Open 2021; 3: e000143
    CrossrefPubMedGoogle Scholar
  • 2 Alcolea D, Delaby C, Muñoz L. et al. Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias. J Neurol Neurosurg Psychiatry 2021; 92: 1206-1214
    CrossrefPubMedGoogle Scholar
  • 3 Ashton NJ, Pascoal TA, Karikari TK. et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 2021; 141: 709-724
    CrossrefPubMedGoogle Scholar
  • 4 Benedet AL, Milà-Alomà M, Vrillon A. et al. Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer’s and Families (ALFA) study, and BioCogBank Paris Lariboisière cohort. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum.JAMA Neurol 2021; e213671
    PubMedGoogle Scholar
  • 5 Casanova R, Varma S, Simpson B, Kim M, An Y. Blood metabolite markers of preclinical Alzheimer’s disease in two longitudinally followed cohorts of older individuals. Alzheimer’s & Dementia 2016; 12: 815-822
    CrossrefPubMedGoogle Scholar
  • 6 Chatterjee P, Pedrini S, Ashton NJ. et al. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement 2021; DOI: 10.1002/alz.12447.. Online ahead of print.PMID: 34494715
    CrossrefPubMedGoogle Scholar
  • 7 Cheng Y, Tian DY, Wang YJ. Peripheral clearance of brain-derived Aβ in Alzheimer’s disease: pathophysiology and therapeutic perspectives. Transl Neurodegener 2020; 9: 16 DOI: 10.1186/s40035-020-00195-1.
    CrossrefPubMedGoogle Scholar
  • 8 Cicognola C, Janelidze S, Hertze J. et al. Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment. Alzheimers Res Ther 2021; 13: 68
    CrossrefPubMedGoogle Scholar
  • 9 Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S. et al. Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol 2021; 20: 484-496 DOI: 10.1016/S1474-4422(21)00066-1.
    CrossrefPubMedGoogle Scholar
  • 10 Dumurgier J, Sabia S. [Epidemiology of Alzheimer’s disease: latest trends]. Rev Prat 2020; 70: 149-151
    PubMedGoogle Scholar
  • 11 Haberstroh J, Tesky VA, Pantel J. Einwilligungsfähigkeit von Menschen mit Demenz. Einblicke in die S2k-AWMF Leitlinie 108-001. Insights into the S2k AWMF guidlines 108-001. Zeitschrift für Gerontologie und Geriatrie 54: 167-175
    CrossrefPubMedGoogle Scholar
  • 12 Hampel H, Hardy J, Blennow K. et al. The Amyloid-beta Pathway in Alzheimer’s Disease. Mol Psychiatry 2021; DOI: 10.1038/s41380-021-01249-0.
    CrossrefPubMedGoogle Scholar
  • 13 Hansson O, Cullen N, Zetterberg H. Alzheimer’s Disease Neuroimaging Initiative, et al. Plasma phosphorylated tau181 and neurodegeneration in Alzheimer’s disease. Ann Clin Transl Neurol 2021; 8: 259-265 DOI: 10.1002/acn3.51253..
    CrossrefPubMedGoogle Scholar
  • 14 Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992; 256(5054):184-5
    PubMed
  • 15 Huynh K, Lim WLF, Giles C. et al. Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease. Nat Commun 2020; 11: 5698 DOI: 10.1038/s41467-020-19473-7.
    CrossrefPubMedGoogle Scholar
  • 16 Fagan AM, Henson RL, Li Y, Boerwinkle AH. et al. Alzheimer’s Biomarker Consortium–Down Syndrome; Dominantly Inherited Alzheimer Network. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study. Lancet Neurol 2021; Aug 20 (08) 615-626 DOI: 10.1016/S1474-4422(21)00139-3.
    CrossrefPubMedGoogle Scholar
  • 17 Islam MR, Kaurani L, Berulava T. et al. A microRNA signature that correlates with cognition and is a target against cognitive decline EMBO Mol Med 2021; 13: e13659
    PubMed
  • 18 Jack CR, Bennett DA, Blennow K. et al. Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14: 535-562
    Google Scholar
  • 19 Janelidze S, Mattsson N, Palmqvist S. et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med 2020; 26: 379-386 DOI: 10.1038/s41591-020-0755-1..
    CrossrefPubMedGoogle Scholar
  • 20 Janelidze S, Teunissen CE, Zetterberg H. et al. Head-to-Head Comparison of 8 Plasma Amyloid-beta 42/40 Assays in Alzheimer Disease. JAMA Neurol 2021; 78: 1375-1382
    CrossrefPubMedGoogle Scholar
  • 21 Janelidze S, Stomrud E, Palmqvist S. et al. Plasma beta-amyloid in Alzheimer’s disease and vascular disease. Sci Rep 2016; 6: 26801
    CrossrefPubMedGoogle Scholar
  • 22 Kaddurah-Daouk R, Kristal BS, Weinshilboum RM. Metabolomics: A Global Biochemical Approach to Drug Response and Disease. Annual Review of Pharmacology and Toxicology 2008; 48: 653-683
    CrossrefPubMedGoogle Scholar
  • 23 Kaddurah-Daouk R, Krishnan KR. Metabolomics: A Global Biochemical Approach to the Study of Central Nervous System Diseases. Neuropsychopharmacology 2009; 34: 173-186
    CrossrefPubMedGoogle Scholar
  • 24 Kaneko N, Nakamura A, Washimi Y. et al. Novel plasma biomarker surrogating cerebral amyloid deposition. Proc Jpn Acad Ser B Phys Biol Sci 2014; 90: 353-64
    CrossrefPubMedGoogle Scholar
  • 25 Karikari TK, Benedet AL, Ashton NJ. et al. Alzheimer’s Disease Neuroimaging Initiative. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry 2021; 26: 429-442
    CrossrefPubMedGoogle Scholar
  • 26 Kim K, Kim MJ, Kim DW. et al. Clinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma. Nat Commun 2020; 11 (119) DOI: 10.1038/s41467-019-13901-z.PMID:. 31913282
    CrossrefPubMedGoogle Scholar
  • 27 Klafki HW, Rieper P, Matzen A. et al. Development and Technical Validation of an Immunoassay for the Detection of APP669-711 (Aβ-3-40) in Biological Samples. Int J Mol Sci 2020; 21: 6564
    CrossrefPubMedGoogle Scholar
  • 28 Koychev I, Jansen K, Dette A. et al. Blood-Based ATN Biomarkers of Alzheimer’s Disease: A Meta-Analysis. J Alzheimers Dis 2021; 79: 177-195
    CrossrefPubMedGoogle Scholar
  • 29 Lantero Rodriguez J, Karikari TK, Suárez-Calvet M. et al. 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 Neuropathol 2020; 140: 267-278
    CrossrefPubMedGoogle Scholar
  • 30 Lemercier P, Vergallo A, Lista S. et al. INSIGHT-preAD study group and the Alzheimer Precision Medicine Initiative (APMI). Association of plasma Abeta40/Abeta42 ratio and brain Abeta accumulation: testing a whole-brain PLS-VIP approach in individuals at risk of Alzheimer’s disease. Neurobiol Aging 2021; 107: 57-69
    CrossrefPubMedGoogle Scholar
  • 31 Li Y, Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Weiner MW, Shaw LM, Masters CL, Fowler CJ, Trojanowski JQ, Korecka M, Martins RN, Janelidze S, Hansson O, Bateman RJ. Validation of Plasma Amyloid-beta 42/40 for Detecting Alzheimer Disease Amyloid Plaque. Neurology. 2022 Feb 15;98(7):e688-e699 DOI: 10.1212/WNL.0000000000013211..
    CrossrefPubMed
  • 32 Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR. 2014; Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine 20: 415-418
    CrossrefPubMedGoogle Scholar
  • 33 McKhann GM, Knopman DS, Chertkow H. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263-9 DOI: 10.1016/j.jalz.2011.03.005..
    CrossrefPubMedGoogle Scholar
  • 34 Monllor P, Giraldo E, Badia MC. et al. Serum Levels of Clusterin, PKR, and RAGE Correlate with Amyloid Burden in Alzheimer’s Disease J Alzheimers Dis 2021; 80: 1067-1077
    PubMed
  • 35 Moscoso A, Grothe MJ. et al. Alzheimer’s Disease Neuroimaging InitiativeLongitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease JAMA Neurol 2021; 78: 396-406
    PubMed
  • 36 Nabers A, Perna L, Lange J. et al. Amyloid blood biomarker detects Alzheimer’s disease EMBO Mol Med 2018; 10: e8763
    PubMed
  • 37 Nakamura A, Kaneko N, Villemagne VL. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease Nature 2018; 554: 249-254
    PubMed
  • 38 O’Connor A, Karikari TK, Poole T. et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry 2020; DOI: 10.1038/s41380-020-0838-x.
    CrossrefPubMedGoogle Scholar
  • 39 Palmqvist S, Janelidze S, Stomrud E. et al. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status. JAMA Neurol 2019; 76: 1060-1069
    CrossrefPubMedGoogle Scholar
  • 40 Palmqvist S, Janelidze S, Quiroz YT. et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.JAMA 2020; 324: 772-781
    PubMed
  • 41 Palmqvist S, Tideman P, Cullen N. et al. Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 2021; 27 (06) 1034-1042
    CrossrefPubMedGoogle Scholar
  • 42 Pannee J, Törnqvist U, Westerlund A. et al. The amyloid-beta degradation pattern in plasma--a possible tool for clinical trials in Alzheimer’s disease. Neurosci Lett 2014; 573: 7-12 DOI: 10.1016/j.neulet.2014.04.041..
    CrossrefPubMedGoogle Scholar
  • 43 Pase MP, Beiser AS, Himali JJ. et al. Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol 2019; 76: 598-606 DOI: 10.1001/jamaneurol.2018.4666.
    CrossrefPubMedGoogle Scholar
  • 44 Pereira JB, Janelidze S, Stomrud E. et al. Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain 2021; 144: 2826-2836 DOI: 10.1093/brain/awab163.
    CrossrefPubMedGoogle Scholar
  • 45 Pereira JB, Janelidze S, Smith R. et al. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain 2021b:awab223 DOI: 10.1093/brain/awab223..
    CrossrefPubMedGoogle Scholar
  • 46 Raket LL, Kühnel L, Schmidt E. et al. Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer’s disease. Alzheimers Dement (Amst) 2020; 12: e12099
    PubMedGoogle Scholar
  • 47 Shahpasand-Kroner H, Klafki HW, Bauer C. et al. A two-step immunoassay for the simultaneous assessment of Aβ38, Aβ40 and Aβ42 in human blood plasma supports the Aβ42/Aβ40 ratio as a promising biomarker candidate of Alzheimer’s disease. Alzheimers Res Ther 2018; 10: 121
    CrossrefPubMedGoogle Scholar
  • 48 Simrén J, Ashton NJ, Blennow K. et al. Blood neurofilament light in remote settings: Alternative protocols to support sample collection in challenging pre-analytical conditions. Alzheimers Dement (Amst) 2021b 13: e12145
    CrossrefPubMedGoogle Scholar
  • 49 Simrén J, Leuzy A, Karikari TK, Hye A, Lessa Benedet A, Lantero-Rodriguez J. et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer´s disease. Alzheimers Dementia 2021; 17: 1145-1156
    CrossrefPubMedGoogle Scholar
  • 50 Soares Martins T, Marçalo R, Ferreira M. et al. Exosomal Aβ-Binding Proteins Identified by “In Silico” Analysis Represent Putative Blood-Derived Biomarker Candidates for Alzheimer´s Disease. Int J Mol Sci 2021; 22: 3933
    CrossrefPubMedGoogle Scholar
  • 51 Swarbrick S, Wragg N, Ghosh S, Stolzing A. Systematic Review of miRNA as Biomarkers in Alzheimer’s Disease 2019; 56: 6156-6167
    PubMed
  • 52 Thijssen EH, La Joie R, Wolf A. et al. Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 2020; 26: 387-397
    CrossrefPubMedGoogle Scholar
  • 53 Thijssen EH, La Joie R, Strom A. et al. Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol 2021; 20: 739-752
    CrossrefPubMedGoogle Scholar
  • 54 Toombs J, Zetterberg H. In the blood: biomarkers for amyloid pathology and neurodegeneration in Alzheimer’s disease. Brain Commun 2020; 2: fcaa054 DOI: 10.1093/braincomms/fcaa054..
    CrossrefPubMedGoogle Scholar
  • 55 Tromp D, Dufour A, Lithfous S. et al. Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studiesAgeing Res Rev 2015; 24: 232-62
    PubMed
  • 56 Trushina E, Mielke MM. Recent advances in the application of metabolomics to Alzheimer’s Disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2014; 1842 (08) 1232-1239 DOI: 10.1016/j.bbadis.2013.06.014.
    CrossrefPubMedGoogle Scholar
  • 57 Villain N, Dubois B. Alzheimer’s Disease Including Focal Presentations. Semin Neurol 2019; 39: 213-226
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 58 Walter M, Wiltfang J, Vogelgsang J. Pre-Analytical sampling and storage conditions of amyloid-ß peptides in venous and capillary blood. J Alzheimer Dis 2020; 78: 529-535 DOI: 10.3233/JAD-200777.
    CrossrefPubMedGoogle Scholar
  • 59 Weston PSJ, Poole T, Ryan NS. et al. Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration. Neurology. 2017; 89: 2167-2175
    CrossrefPubMedGoogle Scholar
  • 60 Yang CC, Chiu MJ, Chen TF. et al. Assay of Plasma Phosphorylated Tau Protein (Threonine 181) and Total Tau Protein in Early-Stage Alzheimer’s Disease J Alzheimers Dis 2018; 61: 1323-1332
    PubMed
  • 61 Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener 2021; 16: 10
    CrossrefPubMedGoogle Scholar
  • 62 Zetterberg H, Mörtberg E, Song L. et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 2011; 6: e28263
    CrossrefPubMedGoogle Scholar