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Erschienen in: Der Nervenarzt 11/2011

01.11.2011 | Leitthema

Die Zukunft der Biomarker in der Demenzdiagnostik

verfasst von: R. Zimmermann, Prof. Dr. J. Kornhuber, P. Lewczuk

Erschienen in: Der Nervenarzt | Ausgabe 11/2011

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Zusammenfassung

Die neurochemische Demenzdiagnostik (NDD) ist ein Routineinstrument in der Diagnostik neurodegenerativer Erkrankungen wie der Alzheimer-Erkrankung (Alzheimer’s disease, AD). Gegenwärtig werden zwei Biomarkergruppen verwendet, die im Liquor cerebrospinalis („cerebrospinal fluid“, CSF) gemessen werden. Es handelt sich um Amyloid-β-Peptide (Aβ) und Tau-Proteine einschließlich hyperphosphorylierte Formen (pTau). Aktuell geht die Entwicklung der NDD in folgende Richtungen: 1. Suche nach neuen Biomarkern mit verbesserter diagnostischer Leistung; 2. Suche nach Biomarkern im Blut; 3. Anwendung neuer Technologien zur ökonomischeren Handhabung der Patientenproben; 4. Optimierung der Bestimmung bereits verwendeter Biomarker (z. B. durch verbesserte Qualitätskontrolle und Vergleichbarkeit der Ergebnisse unterschiedlicher Labore). In diesem Artikel geben wir einen kurzen Überblick über die gegenwärtige Situation auf dem Gebiet der liquorbasierten NDD und fassen einige Hypothesen zur möglichen zukünftigen Entwicklung zusammen.
Literatur
1.
Zurück zum Zitat Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment 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 7:270–279PubMedCrossRef Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment 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 7:270–279PubMedCrossRef
2.
Zurück zum Zitat Andreasen N, Blennow K (2005) CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease. Clin Neurol Neurosurg 107:165–173PubMedCrossRef Andreasen N, Blennow K (2005) CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease. Clin Neurol Neurosurg 107:165–173PubMedCrossRef
3.
Zurück zum Zitat Andreasen N, Sjogren M, Blennow K (2003) CSF markers for Alzheimer’s disease: total tau, phospho-tau and Abeta42. World J Biol Psychiatry 4:147–155PubMedCrossRef Andreasen N, Sjogren M, Blennow K (2003) CSF markers for Alzheimer’s disease: total tau, phospho-tau and Abeta42. World J Biol Psychiatry 4:147–155PubMedCrossRef
4.
Zurück zum Zitat Barthel H, Gertz HJ, Dresel S et al (2011) Cerebral amyloid-beta PET with florbetaben (18 F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10:424–435PubMedCrossRef Barthel H, Gertz HJ, Dresel S et al (2011) Cerebral amyloid-beta PET with florbetaben (18 F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10:424–435PubMedCrossRef
5.
Zurück zum Zitat Blennow K (2004) Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 1:213–225PubMedCrossRef Blennow K (2004) Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 1:213–225PubMedCrossRef
6.
Zurück zum Zitat Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613PubMedCrossRef Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613PubMedCrossRef
7.
Zurück zum Zitat Carson RT, Vignali DA (1999) Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J Immunol Methods 227:41–52PubMedCrossRef Carson RT, Vignali DA (1999) Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J Immunol Methods 227:41–52PubMedCrossRef
8.
Zurück zum Zitat DeMattos RB, Bales KR, Cummins DJ et al (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 98:8850–8855PubMedCrossRef DeMattos RB, Bales KR, Cummins DJ et al (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 98:8850–8855PubMedCrossRef
9.
Zurück zum Zitat DeMattos RB, Bales KR, Cummins DJ et al (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267PubMedCrossRef DeMattos RB, Bales KR, Cummins DJ et al (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267PubMedCrossRef
10.
Zurück zum Zitat Di Luca M, Pastorino L, Bianchetti A et al (1998) Differential level of platelet amyloid beta precursor protein isoforms: an early marker for Alzheimer disease. Arch Neurol 55:1195–1200CrossRef Di Luca M, Pastorino L, Bianchetti A et al (1998) Differential level of platelet amyloid beta precursor protein isoforms: an early marker for Alzheimer disease. Arch Neurol 55:1195–1200CrossRef
11.
Zurück zum Zitat Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127PubMedCrossRef Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127PubMedCrossRef
12.
Zurück zum Zitat Dubois B, Feldman HH, Jacova C et al (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746PubMedCrossRef Dubois B, Feldman HH, Jacova C et al (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746PubMedCrossRef
13.
Zurück zum Zitat Felgenhauer K, Beuche W (1999) Labordiagnostik neurologischer Erkrankungen: Liquoranalytik und -zytologie, Diagnose- und Prozessmarker. Thieme, Stuttgart Felgenhauer K, Beuche W (1999) Labordiagnostik neurologischer Erkrankungen: Liquoranalytik und -zytologie, Diagnose- und Prozessmarker. Thieme, Stuttgart
14.
Zurück zum Zitat Funke SA, Birkmann E, Henke F et al (2007) Single particle detection of Abeta aggregates associated with Alzheimer’s disease. Biochem Biophys Res Commun 364:902–907PubMedCrossRef Funke SA, Birkmann E, Henke F et al (2007) Single particle detection of Abeta aggregates associated with Alzheimer’s disease. Biochem Biophys Res Commun 364:902–907PubMedCrossRef
15.
Zurück zum Zitat Gabelle A, Roche S, Geny C et al (2010) Correlations between soluble alpha/beta forms of amyloid precursor protein and Abeta38, 40, and 42 in human cerebrospinal fluid. Brain Res 1357:175–183PubMedCrossRef Gabelle A, Roche S, Geny C et al (2010) Correlations between soluble alpha/beta forms of amyloid precursor protein and Abeta38, 40, and 42 in human cerebrospinal fluid. Brain Res 1357:175–183PubMedCrossRef
16.
Zurück zum Zitat Graff-Radford NR, Crook JE, Lucas J et al (2007) Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 64:354–362PubMedCrossRef Graff-Radford NR, Crook JE, Lucas J et al (2007) Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 64:354–362PubMedCrossRef
17.
Zurück zum Zitat Hampel H, Buerger K, Zinkowski R et al (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 61:95–102PubMedCrossRef Hampel H, Buerger K, Zinkowski R et al (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 61:95–102PubMedCrossRef
18.
Zurück zum Zitat Kuo YM, Kokjohn TA, Watson MD et al (2000) Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol 156:797–805PubMedCrossRef Kuo YM, Kokjohn TA, Watson MD et al (2000) Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol 156:797–805PubMedCrossRef
19.
Zurück zum Zitat Lewczuk P, Beck G, Ganslandt O et al (2006) International quality control survey of neurochemical dementia diagnostics. Neurosci Lett 409:1–4PubMedCrossRef Lewczuk P, Beck G, Ganslandt O et al (2006) International quality control survey of neurochemical dementia diagnostics. Neurosci Lett 409:1–4PubMedCrossRef
20.
Zurück zum Zitat Lewczuk P, Esselmann H, Bibl M et al (2004) Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer’s disease: original data and review of the literature. J Mol Neurosci 23:115–122PubMedCrossRef Lewczuk P, Esselmann H, Bibl M et al (2004) Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer’s disease: original data and review of the literature. J Mol Neurosci 23:115–122PubMedCrossRef
21.
Zurück zum Zitat 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 25:273–281PubMedCrossRef 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 25:273–281PubMedCrossRef
22.
Zurück zum Zitat Lewczuk P, Kamrowski-Kruck H, Peters O et al (2010) Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer’s disease: a multicenter study. Mol Psychiatry 15:138–145PubMedCrossRef Lewczuk P, Kamrowski-Kruck H, Peters O et al (2010) Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer’s disease: a multicenter study. Mol Psychiatry 15:138–145PubMedCrossRef
23.
Zurück zum Zitat Lewczuk P, Kornhuber J, Vanderstichele H et al (2008) Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: a multicenter study. Neurobiol Aging 29:812–818PubMedCrossRef Lewczuk P, Kornhuber J, Vanderstichele H et al (2008) Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: a multicenter study. Neurobiol Aging 29:812–818PubMedCrossRef
24.
Zurück zum Zitat Lewczuk P, Kornhuber J, Vanmechelen E et al (2010) Amyloid beta peptides in plasma in early diagnosis of Alzheimer’s disease: A multicenter study with multiplexing. Exp Neurol 223:366–370PubMedCrossRef Lewczuk P, Kornhuber J, Vanmechelen E et al (2010) Amyloid beta peptides in plasma in early diagnosis of Alzheimer’s disease: A multicenter study with multiplexing. Exp Neurol 223:366–370PubMedCrossRef
25.
Zurück zum Zitat Mattsson N, Blennow K, Zetterberg H (2009) CSF biomarkers: pinpointing Alzheimer pathogenesis. Ann N Y Acad Sci 1180:28–35PubMedCrossRef Mattsson N, Blennow K, Zetterberg H (2009) CSF biomarkers: pinpointing Alzheimer pathogenesis. Ann N Y Acad Sci 1180:28–35PubMedCrossRef
26.
Zurück zum Zitat Mattsson N, Blennow K, Zetterberg H (2010) Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer’s disease: united we stand, divided we fall. Clin Chem Lab Med 48:603–607PubMedCrossRef Mattsson N, Blennow K, Zetterberg H (2010) Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer’s disease: united we stand, divided we fall. Clin Chem Lab Med 48:603–607PubMedCrossRef
27.
Zurück zum Zitat Mayeux R, Honig LS, Tang MX et al (2003) Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190PubMed Mayeux R, Honig LS, Tang MX et al (2003) Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190PubMed
28.
Zurück zum Zitat McKhann GM, Knopman DS, Chertkow H et al (2011) 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 7:263–269PubMedCrossRef McKhann GM, Knopman DS, Chertkow H et al (2011) 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 7:263–269PubMedCrossRef
29.
Zurück zum Zitat Olsson A, Vanderstichele H, Andreasen N et al (2005) Simultaneous measurement of beta-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51:336–345PubMedCrossRef Olsson A, Vanderstichele H, Andreasen N et al (2005) Simultaneous measurement of beta-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51:336–345PubMedCrossRef
30.
Zurück zum Zitat Preston SD, Steart PV, Wilkinson A et al (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117PubMedCrossRef Preston SD, Steart PV, Wilkinson A et al (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117PubMedCrossRef
31.
Zurück zum Zitat Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 310:173–186PubMedCrossRef Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 310:173–186PubMedCrossRef
32.
Zurück zum Zitat Riemenschneider M, Schmolke M, Lautenschlager N et al (2000) Cerebrospinal beta-amyloid ((1-42)) in early Alzheimer’s disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 284:85–88PubMedCrossRef Riemenschneider M, Schmolke M, Lautenschlager N et al (2000) Cerebrospinal beta-amyloid ((1-42)) in early Alzheimer’s disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 284:85–88PubMedCrossRef
33.
Zurück zum Zitat Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292PubMedCrossRef Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292PubMedCrossRef
34.
Zurück zum Zitat Sun X, Steffens DC, Au R et al (2008) Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch Gen Psychiatry 65:542–550PubMedCrossRef Sun X, Steffens DC, Au R et al (2008) Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch Gen Psychiatry 65:542–550PubMedCrossRef
35.
Zurück zum Zitat Oijen M van, Hofman A, Soares HD et al (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 5:655–660PubMedCrossRef Oijen M van, Hofman A, Soares HD et al (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 5:655–660PubMedCrossRef
36.
Zurück zum Zitat Verwey NA, Flier WM van der, Blennow K et al (2009) A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer’s disease. Ann Clin Biochem 46:235–240PubMedCrossRef Verwey NA, Flier WM van der, Blennow K et al (2009) A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer’s disease. Ann Clin Biochem 46:235–240PubMedCrossRef
37.
Zurück zum Zitat Vignali DA (2000) Multiplexed particle-based flow cytometric assays. J Immunol Methods 243:243–255PubMedCrossRef Vignali DA (2000) Multiplexed particle-based flow cytometric assays. J Immunol Methods 243:243–255PubMedCrossRef
38.
Zurück zum Zitat Wiltfang J, Esselmann H, Maler JM et al (2001) Molecular biology of Alzheimer’s dementia and its clinical relevance to early diagnosis and new therapeutic strategies. Gerontology 47:65–71PubMedCrossRef Wiltfang J, Esselmann H, Maler JM et al (2001) Molecular biology of Alzheimer’s dementia and its clinical relevance to early diagnosis and new therapeutic strategies. Gerontology 47:65–71PubMedCrossRef
39.
Zurück zum Zitat Zetterberg H, Wahlund LO, Blennow K (2003) Cerebrospinal fluid markers for prediction of Alzheimer’s disease. Neurosci Lett 352:67–69PubMedCrossRef Zetterberg H, Wahlund LO, Blennow K (2003) Cerebrospinal fluid markers for prediction of Alzheimer’s disease. Neurosci Lett 352:67–69PubMedCrossRef
Metadaten
Titel
Die Zukunft der Biomarker in der Demenzdiagnostik
verfasst von
R. Zimmermann
Prof. Dr. J. Kornhuber
P. Lewczuk
Publikationsdatum
01.11.2011
Verlag
Springer-Verlag
Erschienen in
Der Nervenarzt / Ausgabe 11/2011
Print ISSN: 0028-2804
Elektronische ISSN: 1433-0407
DOI
https://doi.org/10.1007/s00115-011-3348-x

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