Neurochemische Demenzdiagnostik – Quo vadis?

Zusammenfassung

Die vorliegende Arbeit soll eine Übersicht über innovative diagnostische Ansätze der Neurochemischen Demenzdiagnostik (NDD) geben. Eine verbesserte Früh- und Differenzialdiagnostik demenzieller Erkrankungen ist unter dem Aspekt sich entwickelnder kausal orientierter Therapiestrategien für die Alzheimer-Demenz (AD) von Bedeutung. Dies betrifft insbesondere Patienten mit leichter kognitiver Beeinträchtigung, wo ein AD-typisches Demenzbiomarkerprofil die drohende AD bereits mindestens vier bis sieben Jahre vor Ausbruch des Demenzstadiums anzeigen kann. Ebenso besteht Bedarf an zusätzlichen Demenzbiomarkern für die verbesserte Differenzialdiagnostik anderer Frühstadien neurodegenerativer Demenzerkrankungen, wie frontotemporale Demenzen, Demenz mit Lewy-Körperchen und Parkinson-Demenz, oder aber für Demenzbiomarker, die eng mit dem Schweregrad der Demenz im Verlauf korrelieren. Bezüglich neuerer Forschungsansätze werden wir auch erste Ansätze einer blutbasierten NDD diskutieren und innovative methodische Ansätze der multiparametischen Diagnostik (Multiplex Assays) vorstellen.

Summary

This article focuses on innovative diagnostic applications in the field of neurochemical dementia diagnostics (NDD). Most importantly, the chance of reliable predictive dementia diagnostics by NDD will support the most effective use of forthcoming preventive therapeutic strategies. Here, CSFNDD is promising to identify patients with mild cognitive impairment (MCI) at high risk for incipient Alzheimer’s dementia (AD), who present with the AD-indicative neurochemical dementia marker pattern already 4 to7 years prior to the clinical manifestation of AD. There is additional demand for novel neurochemical dementia markers for improved early and differential diagnosis of other dementias like Fronto-temporal Lobe Degeneration (FTLD), Lewy- Body-Dementia, and Parkinson-Disease-Dementia as well as markers which correlate with the progression of dementia.

Finally we will discuss new approaches in blood-based NDD and give an overview of multiparametric neurochemical dementia diagnostics (multiplex assays).

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

• 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-Ab42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58: 373-379.
• 3 Andreasen N. et al. Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts development of Alzheimer’s disease in patients with mild cognitive impairment. Acta Neurol Scand Suppl 2003; 179: 47-51.
• 4 Bibl M. et al. Blood-based neurochemical diagnosis of vascular dementia: a pilot study. J Neurochem. 2007 im Druck.
• 5 Bibl M. et al. Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer’s disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 2004; 25: 2912-2918.
• 6 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.
• 7 Bibl M. et al. Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias. Mol Psychiatry. 2007 im 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, Wallin A, Hager O. Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol Scand 1993; 88: 221-223.
• 10 Bullock R. New drugs for Alzheimer’s disease and other dementias. Br J Psychiatry 2002; 180: 135-139.
• 11 Carson RT, Vignali DA. Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J Immunol Methods 1999; 227: 41-52.
• 12 DeMattos RB. et al. Peripheral anti-Ab antibody alters CNS and plasma Ab clearance and decreases brain Ab burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98: 8850-8855.
• 13 DeMattos RB. et al. Brain to plasma amyloid-b efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002; 295: 2264-2267.
• 14 Dermaut B. et al. A novel presenilin 1 mutation associated with Pick’s disease but not beta-amyloid plaques. Ann Neurol 2004; 55: 617-626.
• 15 Di Luca M. et al. Differential level of platelet amyloidb precursor protein isoforms: an early marker for Alzheimer disease. Arch Neurol 1998; 55: 1195-1200.
• 16 Felgenhauer K, Beuche W. Labordiagnostik neurologischer Erkrankungen: Liquoranalytik und -zytologie, Diagnose- und Processmarker. Stuttgart: Thieme; 1999
• 17 Graff-Radford NR. et al. Association of low plasma abeta42/abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 2007; 64: 354-362.
• 18 Hansson O. et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a followup study. Lancet Neurol 2006; 05: 228-234.
• 19 Höglund K. et al. Prediction of Alzheimer´s disease using a CSF pattern of C-terminally truncated beta-amyloid peptides. Neurodegenerative Diseases. 2007 in Druck.
• 20 Klafki HW. et al. Therapeutic approaches to Alzheimer’s disease. Brain 2006; 129: 2840-2855.
• 21 Knopman D. Pharmacotheraphy for Alzheimer’s disease. Curr Neurol Neurosci Rep 2001; 01: 428-434.
• 22 Kuo YM. et al. Elevated Ab42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbPP metabolism. Am J Pathol 2000; 156: 797-805.
• 23 Lewczuk P. et al. Effect of sample collection tubes on cerebrospinal fluid concentrations of Tau proteins and amyloid b peptides. Clin Chem 2006; 52: 332-334.
• 24 Lewczuk P. et al. Electrophoretic separation of amyloid beta peptides in plasma. Electrophoresis 2004; 25: 3336-3343.
• 25 Lewczuk P. et al. Multiplexed quantification of dementia biomarkers in the CSF of patients with early dementias and MCI: A multicenter study. Neurobiol Aging. 2007 im Druck.
• 26 Lewczuk P, Kornhuber J, Wiltfang J. The German Competence Net Dementias: Standard operating procedures for the neurochemical dementia diagnostics. J Neural Transm 2006; 113: 1075-1080.
• 27 Maler J. et al. Urea-based two-dimensional electrophoresis of beta-amyloid peptides in human plasma: evidence for novel Aβ species Proteomics. 2007 im Druck.
• 28 Mayeux R. et al. Plasma Ab40 and Ab42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 2003; 61: 1185-1190.
• 29 Olsson A. et al. Simultaneous measurement of beta-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 2005; 51: 336-345.
• 30 Petersen R. et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 303-308.
• 31 Preston SD. et al. 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 2003; 29: 106-117.
• 32 Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001; 310: 173-186.
• 33 Schoonenboom NS. et al. Effects of processing and storage conditions on amyloid beta (1–42) and tau concentrations in cerebrospinal fluid: implications for use in clinical practice. Clin Chem 2005; 51: 189-195.
• 34 van Oijen M. et al. Plasma Abeta(1–40) and Abeta(1–42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 2006; 05: 655-660.
• 35 Vanderstichele H. et al. Amino-Truncated b-Amyloid42 Peptides in Cerebrospinal Fluid and Prediction of Progression of Mild Cognitive Impairment. Clin Chem 2005; 51: 1650-1660.
• 36 Vignali DA. Multiplexed particle-based flow cytometric assays. J Immunol Methods 2000; 243: 243-255.
• 37 Wiltfang J. et al. Highly conserved and diseasespecific patterns of carboxyterminally truncated Ab 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.
• 38 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; 276: 42645-42657.
• 39 Zekanowski C. et al. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol 2006; 200: 82-88.
• 40 Zetterberg H, Wahlund LO, Blennow K. Cerebrospinal fluid markers for prediction of Alzheimer’s disease. Neurosci Lett 2003; 352: 67-69.
• 41 Wiltfang J et al. Publikation in Vorbereitung.