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Published in: Current Geriatrics Reports 2/2012

01-06-2012 | Biomarkers in the Classification of Biological Health and Disease Aging (Y Shen, Section Editor)

The Analytical Aspects and Regulatory Challenges of Biomarker Discovery: Examples from the Field of Neurodegeneration

Authors: Robert L. Martone, Richard Snyder, Arron S. L. Xu, Rachel Y. Reams

Published in: Current Geriatrics Reports | Issue 2/2012

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Abstract

Drug discovery is guided by theories regarding disease pathogenesis, and biomarkers are the essential analytical tools used to translate those theories into clinical experiments. Biomarkers can be used to expedite clinical trials by permitting selection of the most uniform and responsive patient population, by reporting on target engagement of a particular therapeutic mechanism, and by permitting measurement of biochemical or physiological correlates of disease mechanism with end points that may be more sensitive, immediate, or statistically robust than phenotypic or behavioral changes. Biomarker discovery necessarily begins with an analytically validated assay for an analyte, which is later qualified by demonstrating its utility in some context of disease and therapeutic state. Ultimately, just as with the drug discovery process as a whole, successful biomarker discovery and development depends upon a clear understanding of the disease process. This article reviews the challenges of biomarker discovery with an emphasis on fluid biomarkers in neurodegeneration.
Literature
1.
go back to reference Day M, Rutkowski JL, Feuerstein GZ. Translational medicine–a paradigm shift in modern drug discovery and development: the role of biomarkers. Adv Exp Med Biol. 2009;655:1–12.PubMedCrossRef Day M, Rutkowski JL, Feuerstein GZ. Translational medicine–a paradigm shift in modern drug discovery and development: the role of biomarkers. Adv Exp Med Biol. 2009;655:1–12.PubMedCrossRef
2.
go back to reference Soares HD. The use of mechanistic biomarkers for evaluating investigational CNS compounds in early drug development. Curr Opin Investig Drugs. 2010;11:795–801.PubMed Soares HD. The use of mechanistic biomarkers for evaluating investigational CNS compounds in early drug development. Curr Opin Investig Drugs. 2010;11:795–801.PubMed
3.
go back to reference Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23:213–27.PubMedCrossRef Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23:213–27.PubMedCrossRef
4.
go back to reference Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010;23:228–42.PubMedCrossRef Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010;23:228–42.PubMedCrossRef
5.
go back to reference Shi M, Caudle WM, Zhang J. Biomarker discovery in neurodegenerative diseases: a proteomic approach. Neurobiol Dis. 2009;35:157–64.PubMedCrossRef Shi M, Caudle WM, Zhang J. Biomarker discovery in neurodegenerative diseases: a proteomic approach. Neurobiol Dis. 2009;35:157–64.PubMedCrossRef
6.
go back to reference Bahl JM, Jensen SS, Larsen MR, Heegaard NH. Characterization of the human cerebrospinal fluid phosphoproteome by titanium dioxide affinity chromatography and mass spectrometry. Anal Chem. 2008;80:6308–16.PubMedCrossRef Bahl JM, Jensen SS, Larsen MR, Heegaard NH. Characterization of the human cerebrospinal fluid phosphoproteome by titanium dioxide affinity chromatography and mass spectrometry. Anal Chem. 2008;80:6308–16.PubMedCrossRef
7.
go back to reference Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol. 2008;129:526–9.PubMedCrossRef Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol. 2008;129:526–9.PubMedCrossRef
8.
go back to reference Calciano MA, Zhou W, Snyder PJ, Einstein R. Drug treatment of Alzheimer’s disease patients leads to expression changes in peripheral blood cells. Alzheimers Dement. 2010;6:386–93.PubMedCrossRef Calciano MA, Zhou W, Snyder PJ, Einstein R. Drug treatment of Alzheimer’s disease patients leads to expression changes in peripheral blood cells. Alzheimers Dement. 2010;6:386–93.PubMedCrossRef
9.
go back to reference Nalls MA, Plagnol V, Hernandez DG, et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377:641–9.PubMedCrossRef Nalls MA, Plagnol V, Hernandez DG, et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377:641–9.PubMedCrossRef
10.
go back to reference • Etheridge A, Lee I, Hood L, et al. Extracellular microRNA: a new source of biomarkers. Mutat Res 2011;717:85–90. This paper describes important new biomarker targets and methodologies, which will have a significant impact on future biomarker and drug discovery research.PubMedCrossRef • Etheridge A, Lee I, Hood L, et al. Extracellular microRNA: a new source of biomarkers. Mutat Res 2011;717:85–90. This paper describes important new biomarker targets and methodologies, which will have a significant impact on future biomarker and drug discovery research.PubMedCrossRef
11.
go back to reference Cogswell JP, Ward J, Taylor IA, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis. 2008;14:27–41.PubMed Cogswell JP, Ward J, Taylor IA, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis. 2008;14:27–41.PubMed
12.
go back to reference • Fehlbaum-Beurdeley P, Jarrige-Le Prado AC, Pallares D, et al. Toward an Alzheimer’s disease diagnosis via high-resolution blood gene expression. Alzheimers Dement 2010;6: 25–38. This paper describes important new biomarker targets and methodologies which will have a significant impact on future biomarker and drug discovery research. PubMedCrossRef • Fehlbaum-Beurdeley P, Jarrige-Le Prado AC, Pallares D, et al. Toward an Alzheimer’s disease diagnosis via high-resolution blood gene expression. Alzheimers Dement 2010;6: 25–38. This paper describes important new biomarker targets and methodologies which will have a significant impact on future biomarker and drug discovery research. PubMedCrossRef
13.
go back to reference Ikemura M, Saito Y, Sengoku R, et al. Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol. 2008;67:945–53.PubMedCrossRef Ikemura M, Saito Y, Sengoku R, et al. Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol. 2008;67:945–53.PubMedCrossRef
14.
go back to reference Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One. 2010;5:e12728.PubMedCrossRef Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One. 2010;5:e12728.PubMedCrossRef
15.
go back to reference Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol. 2010;119:703–13.PubMedCrossRef Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol. 2010;119:703–13.PubMedCrossRef
16.
17.
go back to reference Waterton JC, Pylkkanen L. Qualification of imaging biomarkers for oncology drug development. Eur J Cancer. 2012;48:409–15.PubMedCrossRef Waterton JC, Pylkkanen L. Qualification of imaging biomarkers for oncology drug development. Eur J Cancer. 2012;48:409–15.PubMedCrossRef
18.
go back to reference Bansal S, DeStefano A. Key elements of bioanalytical method validation for small molecules. AAPS J. 2007;9:E109–14.PubMedCrossRef Bansal S, DeStefano A. Key elements of bioanalytical method validation for small molecules. AAPS J. 2007;9:E109–14.PubMedCrossRef
19.
go back to reference Kelley M, DeSilva B. Key elements of bioanalytical method validation for macromolecules. AAPS J. 2007;9:E156–63.PubMedCrossRef Kelley M, DeSilva B. Key elements of bioanalytical method validation for macromolecules. AAPS J. 2007;9:E156–63.PubMedCrossRef
20.
go back to reference Viswanathan CT, Bansal S, Booth B, et al. Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Pharm Res. 2007;24:1962–73.PubMedCrossRef Viswanathan CT, Bansal S, Booth B, et al. Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Pharm Res. 2007;24:1962–73.PubMedCrossRef
21.
go back to reference Nowatzke W, Woolf E. Best practices during bioanalytical method validation for the characterization of assay reagents and the evaluation of analyte stability in assay standards, quality controls, and study samples. AAPS J. 2007;9:E117–22.PubMedCrossRef Nowatzke W, Woolf E. Best practices during bioanalytical method validation for the characterization of assay reagents and the evaluation of analyte stability in assay standards, quality controls, and study samples. AAPS J. 2007;9:E117–22.PubMedCrossRef
23.
go back to reference Findlay JW, Smith WC, Lee JW, et al. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. J Pharm Biomed Anal. 2000;21:1249–73.PubMedCrossRef Findlay JW, Smith WC, Lee JW, et al. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. J Pharm Biomed Anal. 2000;21:1249–73.PubMedCrossRef
24.
go back to reference Valentin MA, Ma S, Zhao A, et al. Validation of immunoassay for protein biomarkers: bioanalytical study plan implementation to support pre-clinical and clinical studies. J Pharm Biomed Anal. 2011;55:869–77.PubMedCrossRef Valentin MA, Ma S, Zhao A, et al. Validation of immunoassay for protein biomarkers: bioanalytical study plan implementation to support pre-clinical and clinical studies. J Pharm Biomed Anal. 2011;55:869–77.PubMedCrossRef
25.
go back to reference DeSilva B, Smith W, Weiner R, et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm Res. 2003;20:1885–900.PubMedCrossRef DeSilva B, Smith W, Weiner R, et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm Res. 2003;20:1885–900.PubMedCrossRef
26.
go back to reference Rhyne PW, Wong OT, Zhang YJ, Weiner RS. Electrochemiluminescence in bioanalysis. Bioanalysis. 2009;1:919–35.PubMedCrossRef Rhyne PW, Wong OT, Zhang YJ, Weiner RS. Electrochemiluminescence in bioanalysis. Bioanalysis. 2009;1:919–35.PubMedCrossRef
27.
go back to reference Guglielmo-Viret V, Attree O, Blanco-Gros V, Thullier P. Comparison of electrochemiluminescence assay and ELISA for the detection of Clostridium botulinum type B neurotoxin. J Immunol Methods. 2005;301:164–72.PubMedCrossRef Guglielmo-Viret V, Attree O, Blanco-Gros V, Thullier P. Comparison of electrochemiluminescence assay and ELISA for the detection of Clostridium botulinum type B neurotoxin. J Immunol Methods. 2005;301:164–72.PubMedCrossRef
28.
go back to reference Mikulskis A, Yeung D, Subramanyam M, Amaravadi L. Solution ELISA as a platform of choice for development of robust, drug tolerant immunogenicity assays in support of drug development. J Immunol Methods. 2011;365:38–49.PubMedCrossRef Mikulskis A, Yeung D, Subramanyam M, Amaravadi L. Solution ELISA as a platform of choice for development of robust, drug tolerant immunogenicity assays in support of drug development. J Immunol Methods. 2011;365:38–49.PubMedCrossRef
29.
go back to reference Eglen RM, Reisine T, Roby P, et al. The use of AlphaScreen technology in HTS: current status. Curr Chem Genomics. 2008;1:2–10.PubMedCrossRef Eglen RM, Reisine T, Roby P, et al. The use of AlphaScreen technology in HTS: current status. Curr Chem Genomics. 2008;1:2–10.PubMedCrossRef
30.
go back to reference Gubala V, Le Guevel X, Nooney R, et al. A comparison of mono and multivalent linkers and their effect on the colloidal stability of nanoparticle and immunoassays performance. Talanta. 2010;81:1833–9.PubMedCrossRef Gubala V, Le Guevel X, Nooney R, et al. A comparison of mono and multivalent linkers and their effect on the colloidal stability of nanoparticle and immunoassays performance. Talanta. 2010;81:1833–9.PubMedCrossRef
31.
go back to reference Darmanis S, Nong RY, Hammond M, et al. Sensitive plasma protein analysis by microparticle-based proximity ligation assays. Mol Cell Proteomics. 2010;9:327–35.PubMedCrossRef Darmanis S, Nong RY, Hammond M, et al. Sensitive plasma protein analysis by microparticle-based proximity ligation assays. Mol Cell Proteomics. 2010;9:327–35.PubMedCrossRef
32.
go back to reference Glickman JF, Wu X, Mercuri R, et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen. 2002;7:3–10.PubMedCrossRef Glickman JF, Wu X, Mercuri R, et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen. 2002;7:3–10.PubMedCrossRef
33.
go back to reference Soderstrom CI, Spriggs FP, Song W, Burrell S. Comparison of four distinct detection platforms using multiple ligand binding assay formats. J Immunol Methods. 2011;371:106–13.PubMedCrossRef Soderstrom CI, Spriggs FP, Song W, Burrell S. Comparison of four distinct detection platforms using multiple ligand binding assay formats. J Immunol Methods. 2011;371:106–13.PubMedCrossRef
34.
go back to reference Morris JC, Selkoe DJ. Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview. Neurobiol Aging. 2011;32 Suppl 1:S1–3.PubMedCrossRef Morris JC, Selkoe DJ. Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview. Neurobiol Aging. 2011;32 Suppl 1:S1–3.PubMedCrossRef
35.
go back to reference Gao CM, Yam AY, Wang X, et al. Abeta40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer’s disease. PLoS One. 2010;5:e15725.PubMedCrossRef Gao CM, Yam AY, Wang X, et al. Abeta40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer’s disease. PLoS One. 2010;5:e15725.PubMedCrossRef
36.
go back to reference Xia W, Yang T, Shankar G, et al. A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol. 2009;66:190–9.PubMedCrossRef Xia W, Yang T, Shankar G, et al. A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol. 2009;66:190–9.PubMedCrossRef
37.
go back to reference Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-beta (Abeta): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286:38825–32.PubMedCrossRef Jawhar S, Wirths O, Bayer TA. Pyroglutamate amyloid-beta (Abeta): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286:38825–32.PubMedCrossRef
38.
go back to reference Bjerke M, Portelius E, Minthon L, et al. Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Int J Alzheimers Dis 2010, 2010, Article ID 986310. Bjerke M, Portelius E, Minthon L, et al. Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Int J Alzheimers Dis 2010, 2010, Article ID 986310.
39.
go back to reference Lewczuk P, Beck G, Esselmann H, et al. Effect of sample collection tubes on cerebrospinal fluid concentrations of tau proteins and amyloid beta peptides. Clin Chem. 2006;52:332–4.PubMedCrossRef Lewczuk P, Beck G, Esselmann H, et al. Effect of sample collection tubes on cerebrospinal fluid concentrations of tau proteins and amyloid beta peptides. Clin Chem. 2006;52:332–4.PubMedCrossRef
40.
go back to reference Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology. 2007;68:666–9.PubMedCrossRef Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology. 2007;68:666–9.PubMedCrossRef
41.
go back to reference Vogelgesang S, Jedlitschky G, Brenn A, Walker LC. The role of the ATP-binding cassette transporter P-glycoprotein in the transport of beta-amyloid across the blood–brain barrier. Curr Pharm Des. 2011;17:2778–86.PubMedCrossRef Vogelgesang S, Jedlitschky G, Brenn A, Walker LC. The role of the ATP-binding cassette transporter P-glycoprotein in the transport of beta-amyloid across the blood–brain barrier. Curr Pharm Des. 2011;17:2778–86.PubMedCrossRef
42.
go back to reference Silverberg GD, Messier AA, Miller MC, et al. Amyloid efflux transporter expression at the blood–brain barrier declines in normal aging. J Neuropathol Exp Neurol. 2010;69:1034–43.PubMedCrossRef Silverberg GD, Messier AA, Miller MC, et al. Amyloid efflux transporter expression at the blood–brain barrier declines in normal aging. J Neuropathol Exp Neurol. 2010;69:1034–43.PubMedCrossRef
43.
go back to reference Fujiyoshi M, Tachikawa M, Ohtsuki S, et al. Amyloid-beta peptide(1–40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. J Neurochem. 2011;118:407–15.PubMedCrossRef Fujiyoshi M, Tachikawa M, Ohtsuki S, et al. Amyloid-beta peptide(1–40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. J Neurochem. 2011;118:407–15.PubMedCrossRef
44.
go back to reference Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.PubMedCrossRef Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.PubMedCrossRef
45.
go back to reference Buchhave P, Minthon L, Zetterberg H, et al. Cerebrospinal Fluid Levels of beta-Amyloid 1–42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Arch Gen Psychiatry. 2012;69:98–106.PubMedCrossRef Buchhave P, Minthon L, Zetterberg H, et al. Cerebrospinal Fluid Levels of beta-Amyloid 1–42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Arch Gen Psychiatry. 2012;69:98–106.PubMedCrossRef
46.
go back to reference Bateman RJ, Munsell LY, Morris JC, et al. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006;12:856–61.PubMedCrossRef Bateman RJ, Munsell LY, Morris JC, et al. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006;12:856–61.PubMedCrossRef
47.
go back to reference Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009;66:48–54.PubMedCrossRef Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009;66:48–54.PubMedCrossRef
48.
go back to reference Imbimbo BP, Peretto I. Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer’s disease. Curr Opin Investig Drugs. 2009;10:721–30.PubMed Imbimbo BP, Peretto I. Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer’s disease. Curr Opin Investig Drugs. 2009;10:721–30.PubMed
49.
go back to reference Galimberti D, Scarpini E. Genetics and biology of Alzheimer’s disease and frontotemporal lobar degeneration. Int J Clin Exp Med. 2010;3:129–43.PubMedCrossRef Galimberti D, Scarpini E. Genetics and biology of Alzheimer’s disease and frontotemporal lobar degeneration. Int J Clin Exp Med. 2010;3:129–43.PubMedCrossRef
50.
go back to reference Kim W, Lee S, Hall GF. Secretion of human tau fragments resembling CSF-tau in Alzheimer’s disease is modulated by the presence of the exon 2 insert. FEBS Lett. 2010;584:3085–8.PubMedCrossRef Kim W, Lee S, Hall GF. Secretion of human tau fragments resembling CSF-tau in Alzheimer’s disease is modulated by the presence of the exon 2 insert. FEBS Lett. 2010;584:3085–8.PubMedCrossRef
51.
go back to reference Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7.PubMedCrossRef Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7.PubMedCrossRef
52.
go back to reference Kovacech B, Novak M. Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer’s disease. Curr Alzheimer Res. 2010;7:708–16.PubMedCrossRef Kovacech B, Novak M. Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer’s disease. Curr Alzheimer Res. 2010;7:708–16.PubMedCrossRef
53.
go back to reference Portelius E, Hansson SF, Tran AJ, et al. Characterization of tau in cerebrospinal fluid using mass spectrometry. J Proteome Res. 2008;7:2114–20.PubMedCrossRef Portelius E, Hansson SF, Tran AJ, et al. Characterization of tau in cerebrospinal fluid using mass spectrometry. J Proteome Res. 2008;7:2114–20.PubMedCrossRef
54.
go back to reference Fagan AM, Shaw LM, Xiong C, et al. Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of {beta}-Amyloid 1–42, Total tau, and P-tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology. Arch Neurol. 2011;68:1137–44.PubMedCrossRef Fagan AM, Shaw LM, Xiong C, et al. Comparison of Analytical Platforms for Cerebrospinal Fluid Measures of {beta}-Amyloid 1–42, Total tau, and P-tau181 for Identifying Alzheimer Disease Amyloid Plaque Pathology. Arch Neurol. 2011;68:1137–44.PubMedCrossRef
55.
go back to reference Verwey NA, van der Flier WM, Blennow K, et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer’s disease. Ann Clin Biochem. 2009;46:235–40.PubMedCrossRef Verwey NA, van der Flier WM, Blennow K, et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer’s disease. Ann Clin Biochem. 2009;46:235–40.PubMedCrossRef
56.
go back to reference Mattsson N, Andreasson U, Persson S, et al. The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011;7:386–95. e386.PubMedCrossRef Mattsson N, Andreasson U, Persson S, et al. The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011;7:386–95. e386.PubMedCrossRef
57.
go back to reference Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement. 2012;8:65–73.PubMedCrossRef Vanderstichele H, Bibl M, Engelborghs S, et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement. 2012;8:65–73.PubMedCrossRef
58.
go back to reference Johansson P, Mattsson N, Hansson O, et al. Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population. J Alzheimers Dis. 2011;24:537–46.PubMed Johansson P, Mattsson N, Hansson O, et al. Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population. J Alzheimers Dis. 2011;24:537–46.PubMed
59.
go back to reference Albert MS, DeKosky ST, Dickson D, et al. 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. 2011;7:270–9.PubMedCrossRef Albert MS, DeKosky ST, Dickson D, et al. 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. 2011;7:270–9.PubMedCrossRef
60.
go back to reference McKhann GM, Knopman DS, Chertkow H, et al. 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. 2011;7:263–9.PubMedCrossRef McKhann GM, Knopman DS, Chertkow H, et al. 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. 2011;7:263–9.PubMedCrossRef
61.
go back to reference Isaac M, Vamvakas S, Abadie E, et al. Qualification opinion of novel methodologies in the predementia stage of Alzheimer’s disease: cerebro-spinal-fluid related biomarkers for drugs affecting amyloid burden–regulatory considerations by European Medicines Agency focusing in improving benefit/risk in regulatory trials. Eur Neuropsychopharmacol. 2011;21:781–8.PubMedCrossRef Isaac M, Vamvakas S, Abadie E, et al. Qualification opinion of novel methodologies in the predementia stage of Alzheimer’s disease: cerebro-spinal-fluid related biomarkers for drugs affecting amyloid burden–regulatory considerations by European Medicines Agency focusing in improving benefit/risk in regulatory trials. Eur Neuropsychopharmacol. 2011;21:781–8.PubMedCrossRef
62.
go back to reference •• Holtzman DM, Goate A, Kelly J, Sperling R. Mapping the road forward in Alzheimer’s disease. Sci Transl Med 2011;3:114ps148. This is an important critical review of current biomarker approaches in neurodegeneration, and a studied proposal for future efforts. •• Holtzman DM, Goate A, Kelly J, Sperling R. Mapping the road forward in Alzheimer’s disease. Sci Transl Med 2011;3:114ps148. This is an important critical review of current biomarker approaches in neurodegeneration, and a studied proposal for future efforts.
63.
go back to reference Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6:131–44.PubMedCrossRef Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6:131–44.PubMedCrossRef
64.
go back to reference Bjorkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS One. 2012;7:e29868.PubMedCrossRef Bjorkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS One. 2012;7:e29868.PubMedCrossRef
65.
go back to reference Iwatsubo T. Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol. 2003;250(3):III11–4.PubMed Iwatsubo T. Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol. 2003;250(3):III11–4.PubMed
66.
go back to reference Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci. 2005;25:6016–24.PubMedCrossRef Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci. 2005;25:6016–24.PubMedCrossRef
67.
go back to reference Liu J, Zhang JP, Shi M, et al. Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein. J Neurosci. 2009;29:1480–5.PubMedCrossRef Liu J, Zhang JP, Shi M, et al. Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein. J Neurosci. 2009;29:1480–5.PubMedCrossRef
68.
go back to reference El-Agnaf OM, Salem SA, Paleologou KE, et al. Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003;17:1945–7.PubMed El-Agnaf OM, Salem SA, Paleologou KE, et al. Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003;17:1945–7.PubMed
69.
go back to reference Mollenhauer B, El-Agnaf OM, Marcus K, et al. Quantification of alpha-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. Biomark Med. 2010;4:683–99.PubMedCrossRef Mollenhauer B, El-Agnaf OM, Marcus K, et al. Quantification of alpha-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. Biomark Med. 2010;4:683–99.PubMedCrossRef
70.
go back to reference Edwards TL, Scott WK, Almonte C, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet. 2010;74:97–109.PubMedCrossRef Edwards TL, Scott WK, Almonte C, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet. 2010;74:97–109.PubMedCrossRef
71.
go back to reference Beyer K. Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol. 2006;112:237–51.PubMedCrossRef Beyer K. Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol. 2006;112:237–51.PubMedCrossRef
72.
go back to reference Beyer K, Domingo-Sabat M, Lao JI, et al. Identification and characterization of a new alpha-synuclein isoform and its role in Lewy body diseases. Neurogenetics. 2008;9:15–23.PubMedCrossRef Beyer K, Domingo-Sabat M, Lao JI, et al. Identification and characterization of a new alpha-synuclein isoform and its role in Lewy body diseases. Neurogenetics. 2008;9:15–23.PubMedCrossRef
73.
go back to reference Beyer K, Lao JI, Carrato C, et al. Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol. 2004;30:601–7.PubMedCrossRef Beyer K, Lao JI, Carrato C, et al. Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol. 2004;30:601–7.PubMedCrossRef
74.
go back to reference Chen L, Periquet M, Wang X, et al. Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest. 2009;119:3257–65.PubMedCrossRef Chen L, Periquet M, Wang X, et al. Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest. 2009;119:3257–65.PubMedCrossRef
75.
go back to reference Hasegawa M, Fujiwara H, Nonaka T, et al. Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem. 2002;277:49071–6.PubMedCrossRef Hasegawa M, Fujiwara H, Nonaka T, et al. Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem. 2002;277:49071–6.PubMedCrossRef
76.
go back to reference Inglis KJ, Chereau D, Brigham EF, et al. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem. 2009;284:2598–602.PubMedCrossRef Inglis KJ, Chereau D, Brigham EF, et al. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem. 2009;284:2598–602.PubMedCrossRef
77.
go back to reference Mbefo MK, Paleologou KE, Boucharaba A, et al. Phosphorylation of synucleins by members of the Polo-like kinase family. J Biol Chem. 2010;285:2807–22.PubMedCrossRef Mbefo MK, Paleologou KE, Boucharaba A, et al. Phosphorylation of synucleins by members of the Polo-like kinase family. J Biol Chem. 2010;285:2807–22.PubMedCrossRef
78.
go back to reference Paleologou KE, Oueslati A, Shakked G, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci. 2010;30:3184–98.PubMedCrossRef Paleologou KE, Oueslati A, Shakked G, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci. 2010;30:3184–98.PubMedCrossRef
79.
go back to reference Duda JE, Giasson BI, Chen Q, et al. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol. 2000;157:1439–45.PubMedCrossRef Duda JE, Giasson BI, Chen Q, et al. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol. 2000;157:1439–45.PubMedCrossRef
80.
go back to reference Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–9.PubMedCrossRef Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–9.PubMedCrossRef
81.
go back to reference Souza JM, Giasson BI, Chen Q, et al. Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem. 2000;275:18344–9.PubMedCrossRef Souza JM, Giasson BI, Chen Q, et al. Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem. 2000;275:18344–9.PubMedCrossRef
82.
go back to reference Hoyer W, Cherny D, Subramaniam V, Jovin TM. Impact of the acidic C-terminal region comprising amino acids 109–140 on alpha-synuclein aggregation in vitro. Biochemistry. 2004;43:16233–42.PubMedCrossRef Hoyer W, Cherny D, Subramaniam V, Jovin TM. Impact of the acidic C-terminal region comprising amino acids 109–140 on alpha-synuclein aggregation in vitro. Biochemistry. 2004;43:16233–42.PubMedCrossRef
83.
go back to reference Li W, West N, Colla E, et al. Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci U S A. 2005;102:2162–7.PubMedCrossRef Li W, West N, Colla E, et al. Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci U S A. 2005;102:2162–7.PubMedCrossRef
84.
go back to reference Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson’s disease pathogenesis and therapies. Prog Brain Res. 2010;183:115–45.PubMedCrossRef Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson’s disease pathogenesis and therapies. Prog Brain Res. 2010;183:115–45.PubMedCrossRef
85.
go back to reference Anderson NL. The clinical plasma proteome: a survey of clinical assays for proteins in plasma and serum. Clin Chem. 2010;56:177–85.PubMedCrossRef Anderson NL. The clinical plasma proteome: a survey of clinical assays for proteins in plasma and serum. Clin Chem. 2010;56:177–85.PubMedCrossRef
86.
go back to reference Nyhlen J, Constantinescu R, Zetterberg H. Problems associated with fluid biomarkers for Parkinson’s disease. Biomark Med. 2010;4:671–81.PubMedCrossRef Nyhlen J, Constantinescu R, Zetterberg H. Problems associated with fluid biomarkers for Parkinson’s disease. Biomark Med. 2010;4:671–81.PubMedCrossRef
87.
go back to reference Goodsaid F, Frueh F. Biomarker qualification pilot process at the US Food and Drug Administration. AAPS J. 2007;9:E105–8.PubMedCrossRef Goodsaid F, Frueh F. Biomarker qualification pilot process at the US Food and Drug Administration. AAPS J. 2007;9:E105–8.PubMedCrossRef
88.
go back to reference Goodsaid FM, Mendrick DL. Translational medicine and the value of biomarker qualification. Sci Transl Med. 2010;2:47ps44.PubMedCrossRef Goodsaid FM, Mendrick DL. Translational medicine and the value of biomarker qualification. Sci Transl Med. 2010;2:47ps44.PubMedCrossRef
89.
go back to reference Dieterle F, Sistare F, Goodsaid F, et al. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat Biotechnol. 2010;28:455–62.PubMedCrossRef Dieterle F, Sistare F, Goodsaid F, et al. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat Biotechnol. 2010;28:455–62.PubMedCrossRef
90.
go back to reference Woodcock J, Woosley R. The FDA critical path initiative and its influence on new drug development. Annu Rev Med. 2008;59:1–12.PubMedCrossRef Woodcock J, Woosley R. The FDA critical path initiative and its influence on new drug development. Annu Rev Med. 2008;59:1–12.PubMedCrossRef
91.
go back to reference Romero K, de Mars M, Frank D, et al. The coalition against major diseases: Developing tools for an integrated drug development process for Alzheimer’s and Parkinson’s diseases. Clin Pharmacol Ther. 2009;86:365–7.PubMedCrossRef Romero K, de Mars M, Frank D, et al. The coalition against major diseases: Developing tools for an integrated drug development process for Alzheimer’s and Parkinson’s diseases. Clin Pharmacol Ther. 2009;86:365–7.PubMedCrossRef
92.
go back to reference Goodsaid F, Papaluca M. Evolution of biomarker qualification at the health authorities. Nat Biotechnol. 2010;28:441–3.PubMedCrossRef Goodsaid F, Papaluca M. Evolution of biomarker qualification at the health authorities. Nat Biotechnol. 2010;28:441–3.PubMedCrossRef
93.
go back to reference Broich K, Weiergraber M, Hampel H. Biomarkers in clinical trials for neurodegenerative diseases: regulatory perspectives and requirements. Prog Neurobiol. 2011;95:498–500.PubMedCrossRef Broich K, Weiergraber M, Hampel H. Biomarkers in clinical trials for neurodegenerative diseases: regulatory perspectives and requirements. Prog Neurobiol. 2011;95:498–500.PubMedCrossRef
94.
go back to reference Regnier FE, Skates SJ, Mesri M, et al. Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration. Clin Chem. 2010;56:165–71.PubMedCrossRef Regnier FE, Skates SJ, Mesri M, et al. Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration. Clin Chem. 2010;56:165–71.PubMedCrossRef
95.
go back to reference Anderson L. Within sight of a rational pipeline for development of protein diagnostics. Clin Chem. 2012;58:28–30.PubMedCrossRef Anderson L. Within sight of a rational pipeline for development of protein diagnostics. Clin Chem. 2012;58:28–30.PubMedCrossRef
96.
go back to reference Scherf U, Becker R, Chan M, Hojvat S. Approval of novel biomarkers: FDA’s perspective and major requests. Scand J Clin Lab Invest Suppl. 2010;242:96–102.PubMedCrossRef Scherf U, Becker R, Chan M, Hojvat S. Approval of novel biomarkers: FDA’s perspective and major requests. Scand J Clin Lab Invest Suppl. 2010;242:96–102.PubMedCrossRef
99.
go back to reference Frasier M, Chowdhury S, Eberling J, Sherer T. Biomarkers in Parkinson’s disease: a funder’s perspective. Biomarkers Med. 2010;4:723–9.CrossRef Frasier M, Chowdhury S, Eberling J, Sherer T. Biomarkers in Parkinson’s disease: a funder’s perspective. Biomarkers Med. 2010;4:723–9.CrossRef
Metadata
Title
The Analytical Aspects and Regulatory Challenges of Biomarker Discovery: Examples from the Field of Neurodegeneration
Authors
Robert L. Martone
Richard Snyder
Arron S. L. Xu
Rachel Y. Reams
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Current Geriatrics Reports / Issue 2/2012
Electronic ISSN: 2196-7865
DOI
https://doi.org/10.1007/s13670-012-0015-4

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