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Biological Markers in Alzheimer's Disease

Published online by Cambridge University Press:  02 December 2014

Peter Bailey*
Affiliation:
Department of Medicine, Dalhousie University, Saint John Regional Hospital, Saint John, New Brunswick, Canada
*
Department of Medicine, Dalhousie University, Saint John Regional Hospital, Suite 5DN - 400 University Avenue, P.O. Box 2100, Saint John, New Brunswick, E2L 4L2, Canada.
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Abstract

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Biomarkers are required to improve our diagnostic sensitivity and specificity and to monitor the biological activity of the Alzheimer’s disease (AD) in terms of the burden of neural involvement and the tempo of disease progression. Biomarkers will initially supplement our more traditional neuropsychological and imaging markers but may eventually evolve into useful surrogate endpoints in AD research. These markers may also provide important mechanistic clues to the pharmacological action of anti-dementia compounds. At this point, the combination of elevated cerebrospinal fluid phosphorylated TAU (CSF p-TAU) proteins and low CSF A²1-42 are the only biomarkers with the sensitivity and specificity to serve as useful diagnostic biomarkers capable of distinguishing AD from other dementias in the early stages. Advances in non CSF tests is urgently required. Markers assessing the progression of disease do not necessarily require the same high disease specificity as diagnostic markers, but need to be sensitive to changes in disease state. At present, candidate markers fall under four main biological rationales: 1. Specific markers of AD neuropathology; 2. Non-specific markers of neural degeneration; 3. Markers of oxidative stress; 4. Markers of neural inflammation. It is foreseeable that a panel of such markers might prove advantageous. It will be important to develop “non-invasive “ markers utilizing readily obtainable tissue samples such as serum or urine to monitor disease progression (or hopefully regression). Repeated sampling would allow for comparison with traditional neuropsychological and imaging measures. The assays themselves will need to be reproducible, reliable and relatively inexpensive. Unfortunately, these biomarkers are in the formative stages of testing and results at present are inconclusive. To facilitate biomarker development in the future it would be highly advantageous to begin to collect and store biological specimens as an adjunct to current research in AD.

Résumé:

RÉSUMÉ:

Nous avons besoin de biomarqueurs pour améliorer la sensibilité et la spécificité du diagnostic et pour suivre l'activité biologique de la maladie d'Alzheimer (MA) en ce qui concerne le fardeau de l'atteinte neurologique et le rythme de progression de la maladie. Au début, les biomarqueurs serviront de supplément aux marqueurs traditionnels de neuropsychologie et d'imagerie, mais éventuellement ils pourraient devenir des critères d'évaluation de substitution dans la recherche sur la MA. Ces marqueurs pourraient également fournir des indices concernant les mécanismes d'action pharmacologique des médicaments anti-démence. Actuellement, la combinaison d'un taux élevé de protéines phosphorylées TAU dans le liquide céphalorachidien (LCR) et d'un taux bas d'Abl-42 dans le LCR sont les seuls biomarqueurs qui ont une sensibilité et une spécificité permettant de les utiliser comme biomarqueurs diagnostiques capables de distinguer la MA des autres démences aux stades précoces. Il est urgent de développer des tests autres que les tests sur le LCR. Les marqueurs pour évaluer la progression de la maladie ne doivent pas nécessairement posséder une spécificité aussi élevée que les marqueurs diagnostiques, mais ils doivent être sensibles au changement au cours de la maladie. Actuellement, les marqueurs candidats se classent en quatre groupes principaux au point de vue biologique : 1. Des marqueurs spécifiques de la neuropathologie de la MA; 2. Des marqueurs non spécifiques de la dégénérescence neuronale; 3. Des marqueurs du stress oxydatif; 4. Des marqueurs de l'inflammation neuronale. Il est probable qu'une batterie de ces marqueurs pourra s'avérer utile. Il sera important de développer des marqueurs non effractifs utilisant des échantillons de tissus faciles à obtenir, comme du sérum ou de l'urine, pour surveiller la progression de la maladie ou même sa régression. Un échantillonnage sérié permettrait de les comparer aux mesures traditionnelles de neuropsychologie ou d'imagerie. Les analyses devront être reproductibles, fiables et relativement peu coûteuses. Malheureusement, ces biomarqueurs sont encore en évaluation et les résultats sont non concluants. Il serait très avantageux de commencer à récolter et à conserver des spécimens biologiques dans le cadre de la recherche actuelle sur la MA pour faciliter le développement de biomarqueurs dans l'avenir.

Type
Original Articles
Copyright
Copyright © The Canadian Journal of Neurological 2007

References

1. Vandermeeren, M, Merken Vanmechelen, J, Six, A, van de Voorde, J, Martin, P, et al. Detection of TAU proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem. 1193;61:182834.CrossRefGoogle Scholar
2. Hansson, O, Zetterberg, H, Buchhave, P, Londos, E, Blennow, K, Minhhon, L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurology. Vol 5 (3)22834.Google Scholar
3. Andreasen, N, Sjogren, M, Blennow, K. CSF Markers for Alzheimer’s Disease: Total Tau, Phospho-tauand AB42. World J Biol Psychiatry 2003;4:14755.CrossRefGoogle Scholar
4. Blennow, K, Wallin, A, Agren, H, Spenger, C, Siegfried, I, Vanmechelan, . Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer’s disease. Mol Chem Neuropathology. 26:23145.CrossRefGoogle Scholar
5. Iqbal, K, Grundke-Iqbal, I. Mechanism of Alzheimer neurofibrillary degeneration and formation of tangles. Mol Psychiatry. 1997;2: 17880.CrossRefGoogle ScholarPubMed
6. Andreasen, N, Sjogren, M, Blennow, K. CSF Markers for Alzheimer’s Disease: Total Tau, Phospho-tau and AB42. World J Biol Psychiatry. 2003;4:14755.Google Scholar
7. Kohnken, R, Buerger, K, Zinkowski, R, Miller, C, Kerkman, D, DeBernardis, , et al. Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer’s disease patients. Neurosci Lett. 2000;287:18790.Google Scholar
8. Burger, K, Teipel, S, Zinkowski, R. CSF tau proteins phosphorylated at threonine 231 correlate with cognitive decline in MCI subjects. Neurology. 2002;59(4) 627.Google Scholar
9. Hampel, H, Burger, K, Kohnken, R, Teipel, SJ, Zinkowski, R, Moeller, H, et al. Tracking Alzheimer’s disease progression with cerebrospinal fluid tau protein phosphorylated at Threonine 231. Ann Neurol. 2001;49(4):5456.Google Scholar
10. Andreasen, N, Minthon, L, Clarberg, A, Daviidson, P, Vanmechelen, E, Vanderstichele, H, Winblad, B, et al. Sensitivity, specificity and stability of CSF tau in AD in a community -based sample. Neurology. 1999;53:148894.Google Scholar
11. Sjogren, M, Minthon, L, Davidsson, P, Graanerus, A, Clarberg, A, Vanderstichele, H, et al. CSF Levels of tau, b-amyloid-42 and GAP-43 in Frontotemporal dementia, other types of dementia and normal aging. J Neural Transm. 2000;107:56376.Google ScholarPubMed
12. Tamaoka, A, Sawamura, N, Fukushima, T, et al. Amyloid beta protein in cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci. 1997;141:658.CrossRefGoogle Scholar
13. Borron, B, DiLuca, M, Padovani, A. Predicting Alzheimer dementia in mild cognitive impairment patients. Are biomarkers useful? Eur J Pharmacol. Vol 545 (1): 7380.CrossRefGoogle Scholar
14. Mayeux, R, Tang, MX, Jacobs, DM, et al. Plasma amyloid betapeptide 1-42 and incipient Alzheimer’s disease. Ann Neuro. 1999;46:41216.Google Scholar
15. Mayeux, R, Honig, LS, Tang, MX, Manly, J, Stern, Y, Schupf, N, et al. Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology. 2003;61: 118590.CrossRefGoogle Scholar
16. Schoonenboom, NS, Pijnenburg, YA, Mulder, C, Rosso, SM, Van Elk, EJ, VanKanp, GJ, et al. Amyloid beta(1-42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease. Neurology. 2004;62:15804.Google Scholar
17. Maddalena, A, Papassotiropoulos, A, Muller-Tillmanns, B, Jung, HH, Hegi, T, Nitsch, RM, et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol. 2003;60:1202 CrossRefGoogle ScholarPubMed
18. Frank, RA, Galasko, D, Hampel, H, Hardy, J, Deleon, M, Mehta, P, et al. Biological markers for therapeutic trials in Alzheimer’s disease proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease Neurobiol Aging. 2004;24:52136.Google Scholar
19. Saez-Vaero, J, Fodero, LR, Sjogren, M, Andreasen, N, Amici, S, Gallai, V, et al. Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer’s disease. J Neurosci Res. 2003;72:5206.CrossRefGoogle Scholar
20. Rosengren, L, Karlsson, J, Karlsson, J, Persson, L, Wikkelso, C, Sjogren, M, et al. Neurofilament protein levels in CSF are increased in dementia. Neurology. 1999;52:10903.CrossRefGoogle ScholarPubMed
21. Davidsson, P, Puchades, M, Blennow, K. Identification of synaptic vesicle, pre-and postsynaptic proteins in human cerebrospinal fluid using liquid using liquid-phase isoelectric focusing. Electrophoresis. 1999;20:4317.Google Scholar
22. Brachova, L, Lue, lf, Schultz, J, Rashidy, T, Rogers, J. Association Cortex, cerebellum, and serum concentrations of C1q and factor B in Alzheimer’s Disease. Mol Brain Res. 1993;18:32934.Google Scholar
23. Webster, S, Rogers, J. Relative efficacies of amyloid beta peptide (AB) binding proteins in A beta aggregation. J Neurosci Res. 1996;46:5866.3.0.CO;2-E>CrossRefGoogle Scholar
24. Smyth, MD, Cribbs, D, Tenner, A, Shankle, W, Dick, M, Kesslak, J, et al. Decreased levels of C1q in cerebrospinal fluid of living Alzheimer’s patients correlate with disease state. Neurobiol Aging. 1994;15:60914.CrossRefGoogle ScholarPubMed
25. Kennard, ML, Feldman, H, Yamada, T, Jefferies, WA. Serum levels of iron binding protein p97 are elevated in Alzheimer’s disease. Nat Med. 1996;2:12305.CrossRefGoogle ScholarPubMed
26. Feldman, H, Gabathuler, R, Kennard, M, Nurinen, J, Levy, D, Foti, S, et al. Serum p97 levels as an aid to identifying Alzheimer’s disease. J Alzheimers Dis. 2001;3:50716.CrossRefGoogle ScholarPubMed
27. Kim, DK, Seo, M, Lim, S, Kim, J, Kim, J, Carroll, , et al. Serum melanotransferase, p97 as a biochemical marker of Alzheimer’s disease. Neuropsychopharmacology. 2001;25:8490.CrossRefGoogle ScholarPubMed
28. Lanzrein, A, Johnston, C, Perry, V, Jobst, K, King, E, Smith, A, et al. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer’s disease: IL-1beta, IL-6, Il-1 receptor antagonist, TNF-alpha, the soluble TNF receptors 1 and 11 and alpha-1-antichymotrypsin. Alzheimer Dis Assoc Disord. 1998;12:21517.Google Scholar
29. Matsubara, E, Hirai, S, Amari, M, Shoji, M, Yamaguchi, H, Okamoto, K, et al. Alpha 1-antichymotrypsin as a possible biochemical marker for Alzheimer-type dementia. Ann Neuro. 1990;28:5617.Google Scholar
30. Pirttila, T, Mehta, P, Frey, H, Wisneiwski, HM. Alpha 1-antichymotrypsinand IL-1 beta are not increased in CSF or serum in Alzheimer’s disease. Neurobiol Aging. 1994;15:3137.Google Scholar
31. Licastro, F, Pedrini, S, Caputo, L, Annoni, G, Davis, I, Ferri, C, et al. Increased serum IL-1, IL-6 and alpha 1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or markers from the brain? J Neuroimmunol. 2000;103:97102.Google Scholar
32. Giasson, B, Lee, VM, Ichiropoulos, H, Trojanowski, J. The relationship between oxidative stress and the pathological inclusions in Alzheimer’s disease and Parkinson’s disease. Free Rad Biol Med. 2002.Google Scholar
33. Practico, D, Clark, CM, Lee, V, Trojanowski, JQ. Increased 8, 12-isoiPF2·-VI in Alzheimer’s disease: correlation of a non-invasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:80912.Google Scholar
34. Tohgi, H, Abe, T, Yamazaki, K, Murata, T, Ishizaki, E, Isobe, C. Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer’s disease. Neurosci Lett. 1999;269:534.Google Scholar
35. Lovell, MA, Gabbita, SP, Markesbery, WR. Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem. 1999;72:7716.Google Scholar
36. Fassbender, K, Simons, M, Bergman, C, Stoick, M, Lutjohann, D, Kellar, P, et al. Simvinstatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA. 2001;98:585661.Google Scholar
37. Simons, M, Schwarzler, F, Lutjoohann, D, von Bergmann, K, Beyreuther, K, Dichgans, J, et al. Treatment with simvinstatin in normocholestestrolemic patients with Alzheimer’s disease: a 26 week randomized placebo-controlled double-blind trial. Ann Neurol. 2002;52:34650.CrossRefGoogle ScholarPubMed
38. Han, X, Holtzman, D, McKeel, DW, et al. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem. 2002;82:80918.CrossRefGoogle ScholarPubMed
39. Wallin, A, Blennow, K, Rosengren, LE. Glial fibrillary acidic protein in the cerebrospinal fluid of patients with dementia. Dementia. 1996;7:26772.Google Scholar
40. Takahashi, M, Stanton, E, Moreno, JI, Jackowski, G. Immunoassay for serum glutamine synthetase in serum: development, reference values and preliminary study in dementias. Clin Chem. 2002;48:3758.Google Scholar