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Neue Biomarker für die Alzheimer-Krankheit in Liquor und Blut

New biomarkers for Alzheimer’s disease in cerebrospinal fluid and blood

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Zusammenfassung

Entsprechend der aktuellen Leitlinie „Demenzen“ werden die Demenzbiomarker Amyloid-β1–42 sowie die Tau-Proteine Gesamt-Tau und das phosphorylierte Tau-Epitop 181 für die liquorbasierte neurochemische Demenzdiagnostik empfohlen. Mehrere Studien weisen deutlich darauf hin, dass die Bestimmung des Amyloid-β42-zu-Amyloid-β40-Peptid-Quotienten der alleinigen Interpretation von Amyloid-β1–42 überlegen ist und daher in der klinischen Routine angewandt werden sollte. In den vergangenen Jahren wurden jedoch verschiedene weitere Biomarker, sowohl im lumbalen Liquor als auch im Blut, vorgestellt. Neben der liquorbasierten neurochemischen Demenzdiagnostik wurden zwischenzeitlich vielversprechende Ansätze zur Messung von Amyloid-β-Peptiden im Blut beschrieben, welche bereits aktuell in klinischen Therapiestudien für die blutbasierte Frühdiagnostik der Alzheimer-Demenz genutzt werden können und voraussichtlich nach weiterer Validierung und Assayoptimierung in naher Zukunft auch für die klinische Routinediagnostik zur Verfügung stehen werden.

Abstract

In accordance with the current German dementia guidelines, the dementia biomarkers amyloid beta 42, the tau peptides total tau and phosphorylated tau 181 are recommended for cerebrospinal fluid (CSF)-based diagnostics of dementia. Several studies have clearly shown that determination of the amyloid beta 42 to amyloid beta 40 peptide ratio is superior to the interpretation of amyloid beta 42 alone and should be implemented in the clinical work-up; however, in recent years different studies have presented many other innovative CSF and blood-based biomarkers. Besides CSF-based neurochemical diagnostics of dementia promising novel protocols for the detection of amyloid beta peptides in blood have meanwhile been published, which can currently be used in clinical studies for blood-based early diagnostics of Alzheimer’s dementia. Following further validation and assay optimization these blood assays should be available for routine diagnostics in the near future.

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Literatur

  1. Baiardi S, Abu‐Rumeileh S, Rossi M et al (2018) Antemortem CSF A β 42/A β 40 ratio predicts Alzheimer’s disease pathology better than A β 42 in rapidly progressive dementias. Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.697

    Article  PubMed  PubMed Central  Google Scholar 

  2. Baldeiras I, Santana I, Leitão MJ et al (2018) Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment. Alzheimers Res Ther 10:33. https://doi.org/10.1186/s13195-018-0362-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baldeiras I, Santana I, Leitão MJ et al (2019) Erlangen Score as a tool to predict progression from mild cognitive impairment to dementia in Alzheimer’s disease. Alzheimers Res Ther 11:2. https://doi.org/10.1186/s13195-018-0456-x

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bouter C, Vogelgsang J, Wiltfang J (2019) Comparison between amyloid-PET and CSF amyloid-β biomarkers in a clinical cohort with memory deficits. Clin Chim Acta 492:62–68. https://doi.org/10.1016/j.cca.2019.02.005

    Article  CAS  PubMed  Google Scholar 

  5. del Campo M, Mollenhauer B, Bertolotto A et al (2012) Recommendations to standardize preanalytical confounding factors in Alzheimer’s and Parkinson’s disease cerebrospinal fluid biomarkers: an update. Biomark Med 6:419–430. https://doi.org/10.2217/bmm.12.46

    Article  CAS  PubMed  Google Scholar 

  6. Deuschl G, Maier W (2016) S3-Leitlinie „Demenzen“. http://www.dgn.org/leitlinien (Erstellt: 25. Jan. 2016). Zugegriffen: 29. Nov. 2017

    Google Scholar 

  7. Dumurgier J, Schraen S, Gabelle A et al (2015) Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a multicentric study. Alzheimers Res Ther 7:1–9. https://doi.org/10.1186/s13195-015-0114-5

    Article  CAS  Google Scholar 

  8. Fourier A, Portelius E, Zetterberg H et al (2015) Pre-analytical and analytical factors influencing Alzheimer’s disease cerebrospinal fluid biomarkers variability. Clin Chim Acta. https://doi.org/10.1016/j.cca.2015.05.024

    Article  PubMed  Google Scholar 

  9. Gaiottino J, Norgren N, Dobson R et al (2013) Increased Neurofilament light chain blood levels in Neurodegenerative neurological diseases. PLoS ONE 8:1–9. https://doi.org/10.1371/journal.pone.0075091

    Article  CAS  Google Scholar 

  10. Gronewold J, Klafki H‑W, Baldelli E et al (2016) Factors responsible for plasma β‑Amyloid accumulation in chronic kidney disease. Mol Neurobiol 53:3136–3145. https://doi.org/10.1007/s12035-015-9218-y

    Article  CAS  PubMed  Google Scholar 

  11. Kaneko N, Nakamura A, Washimi Y et al (2014) Novel plasma biomarker surrogating cerebral amyloid deposition. Proc Japan Acad Ser B 90:353–364. https://doi.org/10.2183/pjab.90.353

    Article  CAS  Google Scholar 

  12. Kaneko N, Yamamoto R, Sato T‑A, Tanaka K (2014) Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Jpn Acad, Ser B, Phys Biol Sci 90:104–117. https://doi.org/10.2183/pjab.90.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim Y, Yoo YK, Kim HY et al (2019) Comparative analyses of plasma amyloid-β levels in heterogeneous and monomerized states by interdigitated microelectrode sensor system. Sci Adv 5:eaav1388. https://doi.org/10.1126/sciadv.aav1388

    Article  PubMed  PubMed Central  Google Scholar 

  14. Klafki HW, Wiltfang J, Staufenbiel M (1996) Electrophoretic separation of betaA4 peptides (1-40) and (1-42). Anal Biochem 237:24–29. https://doi.org/10.1006/abio.1996.0195

    Article  CAS  PubMed  Google Scholar 

  15. Kuhle J, Barro C, Andreasson U et al (2016) Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med 54:1655–1661. https://doi.org/10.1515/cclm-2015-1195

    Article  CAS  Google Scholar 

  16. Lewczuk P, Ermann N, Andreasson U et al (2018) Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease. Alzheimers Res Ther 10:71. https://doi.org/10.1186/s13195-018-0404-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lewczuk P, Esselmann H, Otto M et al (2004) Neurochemical diagnosis of Alzheimer’s dementia by CSF Abeta42, Abeta42/Abeta40 ratio and total tau. Neurobiol Aging 25:273–281. https://doi.org/10.1016/S0197-4580(03)00086-1

    Article  CAS  PubMed  Google Scholar 

  18. Lewczuk P, Matzen A, Blennow K et al (2016) Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to Amyloid PET in alzheimer’s disease. J Alzheimer’s Dis 55:813–822. https://doi.org/10.3233/JAD-160722

    Article  CAS  Google Scholar 

  19. Lewczuk P, Zimmermann R, Wiltfang J, Kornhuber J (2009) Neurochemical dementia diagnostics: a simple algorithm for interpretation of the CSF biomarkers. J Neural Transm 116:1163–1167. https://doi.org/10.1007/s00702-009-0277-y

    Article  CAS  PubMed  Google Scholar 

  20. Maler JM, Klafki HW, Paul S et al (2007) Urea-based two-dimensional electrophoresis of beta-amyloid peptides in human plasma: evidence for novel Aβ species. Proteomics 7:3815–3820. https://doi.org/10.1002/pmic.200700311

    Article  CAS  PubMed  Google Scholar 

  21. Mattsson N, Andreasson U, Zetterberg H, Blennow K (2017) Association of plasma Neurofilament light with Neurodegeneration in patients with alzheimer disease. Jama Neurol 74:557–566. https://doi.org/10.1001/jamaneurol.2016.6117

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mattsson N, Cullen NC, Andreasson U et al (2019) Association between longitudinal plasma Neurofilament light and Neurodegeneration in patients with alzheimer disease. Jama Neurol. https://doi.org/10.1001/jamaneurol.2019.0765

    Article  PubMed  PubMed Central  Google Scholar 

  23. Molinuevo JL, Ayton S, Batrla R et al (2018) Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol 136:821–853. https://doi.org/10.1007/s00401-018-1932-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nabers A, Hafermann H, Wiltfang J, Gerwert K (2019) Aβ and tau structure-based biomarkers for a blood- and CSF-based two-step recruitment strategy to identify patients with dementia due to Alzheimer’s disease. Alzheimer’s Dement Diagnosis Assess Dis Monit 11:257–263. https://doi.org/10.1016/j.dadm.2019.01.008

    Article  Google Scholar 

  25. Nabers A, Ollesch J, Schartner J et al (2016) Amyloid-β-secondary structure distribution in cerebrospinal fluid and blood measured by an immuno-infrared-sensor: a Biomarker candidate for alzheimer’s disease. Anal Chem 88:2755–2762. https://doi.org/10.1021/acs.analchem.5b04286

    Article  CAS  PubMed  Google Scholar 

  26. Nabers A, Perna L, Lange J et al (2018) Amyloid blood biomarker detects Alzheimer’s disease. Embo Mol Med e8763. https://doi.org/10.15252/emmm.201708763

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nakamura A, Kaneko N, Villemagne VL et al (2018) High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554:249–254. https://doi.org/10.1038/nature25456

    Article  CAS  PubMed  Google Scholar 

  28. Olsson B, Lautner R, Andreasson U et al (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15:673–684. https://doi.org/10.1016/S1474-4422(16)00070-3

    Article  CAS  PubMed  Google Scholar 

  29. Ovod V, Ramsey KN, Mawuenyega KG et al (2017) Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimer’s Dement 13:841–849. https://doi.org/10.1016/j.jalz.2017.06.2266

    Article  Google Scholar 

  30. Shahpasand-Kroner H, Klafki H, Bauer C et al (2018) 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 10:121. https://doi.org/10.1186/s13195-018-0448-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Teunissen CE, Chiu M‑J, Yang C‑C et al (2018) Plasma Amyloid-β (Aβ42) correlates with cerebrospinal fluid Aβ42 in alzheimer’s disease. J Alzheimer’s Dis 62:1857–1863. https://doi.org/10.3233/JAD-170784

    Article  Google Scholar 

  32. Verberk IMW, Slot RE, Verfaillie SCJ et al (2018) Plasma Amyloid as Prescreener for the earliest alzheimer pathological changes. Ann Neurol 84:648–658. https://doi.org/10.1002/ana.25334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vogelgsang J, Shahpasand-Kroner H, Vogelgsang R et al (2018) Multiplex immunoassay measurement of amyloid-β42 to amyloid-β40 ratio in plasma discriminates between dementia due to Alzheimer’s disease and dementia not due to Alzheimer’s disease. Exp Brain Res 236:1241–1250. https://doi.org/10.1007/s00221-018-5210-x

    Article  CAS  PubMed  Google Scholar 

  34. Vogelgsang J, Vukovich R, Wedekind D, Wiltfang J (2019) Higher level of mismatch in APOE ε 4 carriers for Amyloid-beta peptide alzheimer’s disease Biomarkers in cerebrospinal fluid. ASN Neuro 11:175909141984552. https://doi.org/10.1177/1759091419845524

    Article  Google Scholar 

  35. Vogelgsang J, Wedekind D, Bouter C et al (2018) Reproducability of alzheimer’s disease cerebrospinal fluid-Biomarker measurements under clinical routine conditions. J Alzheimers Dis 62:203–212. https://doi.org/10.3233/JAD-170793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wiltfang J, Esselmann H, Bibl M et al (2007) Amyloid beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in patients with low- and high-CSF A beta 40 load. J Neurochem 101:1053–1059. https://doi.org/10.1111/j.1471-4159.2006.04404.x

    Article  CAS  PubMed  Google Scholar 

  37. Zhao Y, Xin Y, Meng S et al (2019) Neurofilament light chain protein in neurodegenerative dementia: a systematic review and network meta-analysis. Neurosci Biobehav Rev 102:123–138. https://doi.org/10.1016/j.neubiorev.2019.04.014

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Universitätsmedizin Göttingen (UMG), Klinik für Psychiatrie und Psychotherapie, Georg-August-Universität, Von-Siebold-Str. 5, 37075, Göttingen, Deutschland

    Jonathan Vogelgsang &  Jens Wiltfang

  2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Deutschland

    Jens Wiltfang

  3. iBiMED, Medical Science Department, Universität Aveiro, Aveiro, Portugal

    Jens Wiltfang

Authors
  1. Jonathan Vogelgsang
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Correspondence to Jens Wiltfang.

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Interessenkonflikt

J. Wiltfang erhielt in den letzten 3 Jahren Berater- oder Vortragshonorare von Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim und Abbot. J. Wiltfang hat Patente mit Relevanz für die Demenzdiagnostik angemeldet: EP1270592B1, US 6,849,416, EP2095128B1 und EP3105589A1. J. Vogelgsang gibt an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Vogelgsang, J., Wiltfang, J. Neue Biomarker für die Alzheimer-Krankheit in Liquor und Blut. Nervenarzt 90, 907–913 (2019). https://doi.org/10.1007/s00115-019-0772-9

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  • DOI: https://doi.org/10.1007/s00115-019-0772-9

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