Neurochemische Frühdiagnostik und klinische Neuroproteomik demenzieller Erkrankungen

J. Wiltfang; M. Bibl; M. Maler; H.-W. Klafki; H. Esselmann; J. Kornhuber; P. Lewczuk

doi:10.1055/s-0038-1626936

Nervenheilkunde, Inhaltsverzeichnis

Nervenheilkunde 2007; 26(10): 853-860
DOI: 10.1055/s-0038-1626936

Arbeiten zum Schwerpunkt - Theme Articles

Schattauer GmbH

Neurochemische Frühdiagnostik und klinische Neuroproteomik demenzieller Erkrankungen

Neurochemical early diagnostic and clinical neuroproteomik in dementia diseases

Authors

J. Wiltfang

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg
M. Bibl

²Klinik für Psychiatrie und Psychotherapie der Rheinischen Kliniken Essen, Universität Duisburg-Essen
M. Maler

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg
H.-W. Klafki

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg
H. Esselmann

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg
J. Kornhuber

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg
P. Lewczuk

¹Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Universität Erlangen-Nürnberg

Abstract

Zusammenfassung

Die vorliegende Arbeit soll eine Übersicht über das sich schnell entwickelnde Gebiet der Neurochemischen Demenzdiagnostik (NDD) geben, wobei der Schwerpunkt auf Anwendungen liegen soll, die zwischenzeitlich bereits Eingang in die Routinediagnostik gefunden haben oder wo dies bald zu erwarten ist. Demenzbiomarker, die in unabhängigen größeren Studien multizentrisch an mehreren tausend Patienten und Probanden validiert wurden, liegen bisher nur für folgende Parameter im lumbalen Liquor vor (liquorbasierte neurochemische Demenzdiagnostik, LiquorNDD): beta-Amyloidpeptide, Gesamt-Tau und hyperphosphorylierte Tau-Proteine (phospho-Tau). Diese Studien belegen eindrucksvoll, dass die CSF-NDD zwischenzeitlich eine hohe Relevanz für die verbesserte Frühund Differenzialdiagnostik demenzieller Erkrankungen erlangt hat und für die Alzheimer-Demenz eine prädiktive Diagnostik bietet.

Summary

This article summarises the current achievements in neurochemical dementia diagnostics (NDD) with special emphasis on applications which have already been introduced into routine diagnostics or which are expected to be introduced shortly. Based on independent multi center studies with several thousands of patients the following neurochemical dementia markers have been validated in cerebrospinal fluid (CSF-NDD): beta-amyloid peptides, total tau and hyperphosphorylated tau proteins (phospho-tau). These studies clearly show that CSF-NDD is of high clinical relevance for the improved early and differential diagnosis of dementias and that it also does offer a diagnostic tool for the predictive diagnosis of incipient Alzheimer’s dementia.

Schlüsselwörter

Alzheimer-Demenz - Liquor zerebrospinalis - Biomarker - Tau-Protein - Amyloidpeptid - beta-Amyloidpeptid - klinische Neurochemie

Keywords

Alzheimer’s Dementia - cerebrospinal fluid - biomarkers - tau - amyloid - beta-amyloid peptides - clinical neurochemistry

Volltext

Referenzen

Literatur
1 Andreasen N. et al. Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 1999; 53: 1488-1494.
2 Andreasen N. et al. Evaluation of CSF-tau and CSF-Aß42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58: 373-379.
3 Arai H. et al. CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000; 166: 201-203.
4 Arai H. et al. Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol 1995; 38: 649-652.
5 Bibl M. et al. CSF amyloid-beta-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain 2006; 129: 1177-1187.
6 Bibl M. et al. CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies. J Neural Transm 2006; 113: 1771-1778.
7 Bibl M. et al. Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias. Mol Psychiatry. 2007 in Druck.
8 Bibl M. et al. Reduced CSF carboxyterminally truncated Abeta peptides in frontotemporal lobe degenerations. J Neural Transm 2007; 114: 621-628.
9 Blennow K, Vanmechelen E, Hampel H. CSF total tau, Aß42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001; 24: 87-97.
10 Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer’s Disease. Neuro RX 2004; 01: 213-255.
11 Blennow K, Wallin A, Hager O. Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol Scand 1993; 88: 221-223.
12 Blomberg M. et al. Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele epsilon 4 during 14 months follow-up. Neurosci Lett 1996; 214: 163-166.
13 Buee L. et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33: 95-130.
14 Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry 2002; 180: 135-139.
15 Citron M. et al. Evidence that the 42– and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. Proc Natl Acad Sci USA 1996; 93: 13170-13175.
16 De Jong D. et al. Cerebrospinal Fluid Amyloid b42/Phosphorylated Tau Ratio Discriminates Between Alzheimer’s Disease and Vascular Dementia. J Gerontol A Biol Sci Med Sci 2006; 61: 755-758.
17 De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003; 38: 9-12.
18 Farrer LA. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama 1997; 278: 1349-1356.
19 Ferri CP. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: 2112-2117.
20 Galasko D. et al. High cerebrospinal fluid tau and low amyloid b42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998; 55: 937-945.
21 Golombowski S. et al. Dependence of cerebrospinal fluid Tau protein levels on apolipoprotein E4 allele frequency in patients with Alzheimer’s disease. Neurosci Lett 1997; 225: 213-215.
22 Grundke-Iqbal I. et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913-4917.
23 Haass C. Take five--BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid betapeptide generation. Embo J 2004; 23: 483-488.
24 Hampel H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004; 61: 95-102.
25 Henkel AW. et al. Immune complexes of auto-antibodies against Abeta1-42 peptides patrol cerebrospinal fluid of non-Alzheimer’s patients. Mol Psychiatry 2007; 12: 601-610.
26 Hesse C. et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001; 297: 187-190.
27 Hu YY. et al. Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer’s disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 2002; 160: 1269-1278.
28 Hulstaert F. et al. Improved discrimination of AD patients using b-amyloid₍₁–₄₂₎ and tau levels in CSF. Neurology 1999; 52: 1555-1562.
29 Ida N. et al. Analysis of heterogeneous bA4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay. J Biol Chem 1996; 271: 22908-22914.
30 Iqbal K. et al. Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion. J Mol Neurosci 2002; 19: 95-99.
31 Iqbal K. et al. Defective brain microtubule assembly in Alzheimer’s disease. Lancet 1986; 02: 421-426.
32 Itoh N. et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer’s disease. Ann Neurol 2001; 50: 150-156.
33 Kanai M. et al. Longitudinal study of cerebrospinal fluid levels of tau, A beta1–40, and A beta1–42(43) in Alzheimer’s disease: a study in Japan. Ann Neurol 1998; 44: 17-26.
34 Kang J. et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733-736.
35 Klafk H. et al. The carboxyl termini of beta-amyloid peptides 1–40 and 1–42 are generated by distinct gamma-secretase activities. J Biol Chem 1996; 271: 28655-28659.
36 Klafki HW. et al. Therapeutic approaches to Alzheimer’s disease. Brain 2006; 129: 2840-2855.
37 Knopman D. Pharmacotheraphy for Alzheimer’s disease. Curr Neurol Neurosci Rep 2001; 01: 428-434.
38 Lammich S. et al. Expression of the Alzheimer protease BACE1 is suppressed via its 5’-untranslated region. EMBO Rep 2004; 05: 620-625.
39 Lewczuk P. et al. 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 2004; 23: 115-122.
40 Lewczuk P. et al. Neurochemical diagnosis of Alzheimer’s dementia by CSF Aß42, Aß42/Aß40 ratio and total tau. Neurobiol Aging 2004; 25: 273-281.
41 Mawal-Dewan M. et al. The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases. J Biol Chem 1994; 269: 30981-30987.
42 Maddalena A. et al. Cerebrospinal Fluid Amyloid b42/Phosphorylated Tau Ratio Discriminates Between Alzheimer’s Disease and Vascular Dementia. Arch Neurol 2003; 60: 1202-1206.
43 Mayeux R. Evaluation and use of diagnostic tests in Alzheimer’s disease. Neurobiol Aging 1998; 19: 139-143.
44 Mayeux R. et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. N Engl J Med 1998; 338: 506-511.
45 Motter R. et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995; 38: 643-648.
46 Mulder C. et al. Genetic and biochemical markers for Alzheimer’s disease: recent developments. Ann Clin Biochem 2000; 37: 593-607.
47 Otto M. et al. Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 1997; 225: 210-212.
48 Panegyres PK. The amyloid precursor protein gene: a neuropeptide gene with diverse functions in the central nervous system. Neuropeptides 1997; 31: 523-535.
49 Parnetti L. et al. CSF phosphorylated tau is a possible marker for discriminating Alzheimer’s disease from dementia with Lewy bodies. Phospho-Tau International Study Group. Neurol Sci 2001; 22: 77-78.
50 Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001; 310: 173-186.
51 Riemenschneider M. et al. Cerebrospinal betaamyloid₍₁–₄₂₎ in early Alzheimer’s disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 2000; 284: 85-88.
52 Rosner H. et al. Developmental expression of tau proteins in the chicken and rat brain: rapid downregulation of a paired helical filament epitope in the rat cerebral cortex coincides with the transition from immature to adult tau isoforms. Int J Dev Neurosci 1995; 13: 607-617.
53 Schoonenboom NS. et al. Amyloid beta (1–42) and phosphorylated tau in CSF as markers for earlyonset Alzheimer disease. Neurology 2004; 62: 1580-1584.
54 Shahani N, Brandt R. Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002; 59: 1668-1680.
55 Sjögren M. et al. Low cerebrospinal fluid b-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment. Neurosci Lett 2001; 314: 33-36.
56 Strittmatter WJ. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 1977-1981.
57 Strittmatter WJ. et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 8098-8102.
58 Sunderland T. et al. Decreased beta-amyloid1–42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. Jama 2003; 289: 2094-2103.
59 The Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”. The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Neurobiol Aging 1998; 19: 109-116.
60 Vanmechelen E. et al. CSF-Phospho-tau (181P) as a Promising Marker for Discriminating Alzheimer’s Disease from Dementia with Lewy Bodies. In Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics. Iqbal K, Sisodia SS, Winblad B. (eds.) Chichester: John Wiley and Sons Ltd; 2001: 285-291.
61 Vassar R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-741.
62 Wiltfang J. et al. Amyloid beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in patients with lowand high-CSF A beta 40 load. J Neurochem 2007; 101: 1053-1059.
63 Wiltfang J. et al. Highly conserved and diseasespecific patterns of carboxyterminally truncated Aß peptides 1–37/38/39 in addition to 1-40/42 in Alzheimer’s disease and in patients with chronic neuroinflammation. J Neurochem 2002; 81: 481-496.
64 Wiltfang J. et al. Elevation of b-amyloid peptide 2–42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem 2001; 27: 42645-42657.
65 Wiltfang J. et al. Molecular biology of Alzheimer’s dementia and its clinical relevance to early diagnosis and new therapeutic strategies. Gerontology 2001; 47: 65-71.
66 Wiltfang J. et al. β-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Ann Neurol 2003; 54: 263-267.
67 Wiltfang J. et al. Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry 2005; 06: 69-84.
68 Wiltfang J. et al. Isoform pattern of 14–3–3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 1999; 73: 2485-2490.
69 Zerr I. et al. Detection of 14–3–3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 1998; 43: 32-40.