Publikationsserver der Universitätsbibliothek Marburg

Titel:Evaluierung des natürlich vorkommenden Autoantikörpers gegen α-Synuclein als potentieller Biomarker für das idiopathische Parkinsonsyndrom
Autor:Wolf, Elias
Weitere Beteiligte: Dodel, Richard (Prof. Dr. med.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/1026
URN: urn:nbn:de:hebis:04-z2012-10265
DOI: https://doi.org/10.17192/z2012.1026
DDC:610 Medizin
Titel (trans.):Evaluation of the natural occurring autoantibody against α-Synuclein as a potential biomarker in Parkinson's disease
Publikationsdatum:2012-12-06
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Autoantikörper, Parkinson-Krankheit, Parkinsons disease, Biomarker, biomarker, autoantibodies

Zusammenfassung:
Das idiopathische Parkinsonsyndrom (IPS) gehört mit einer Prävalenz von 100-200/100.000 zu den häufigsten neurodegenerativen Erkrankungen. Das klinische Erscheinungsbild setzt sich aus Tremor, Rigor, Bradykinese und einer posturalen Haltungsinstabilität zusammen. Das histopathologische Korrelat der Symptome zeigt sich in der neuronalen Degeneration vor allem dopaminerger Neurone der Substantia nigra pars compacta. Zudem finden sich zytoplasmatische Amyloideinschlüsse, sogenannte Lewy-Körperchen, in den überlebenden Zellen. Die Lewy-Körperchen bestehen hauptsächlich aus fibrilliertem α-Synuclein, einem neuronalen Protein der Präsynapse. Der Amyloid-bildenden Eigenschaft des α-Synucleins wird eine zentrale Rolle in der Pathogenese des IPS zugesprochen. Es gibt zunehmend Hinweise, dass α-Synuclein Oligomere, Vorstufen der reifen α-Synuclein Fibrillen, das eigentliche zelltoxische Potential tragen. Kürzlich wurden im Serum von IPS-Patienten und gesunden Kontrollprobanden polyklonale Autoantikörper gegen α-Synuclein nachgewiesen. Sie könnten eine Rolle in der physiologischen Metabolisierung des Proteins spielen und besitzen in-vitro einen neuroprotektiven Effekt. Die Diagnostik des IPS wird durch das heterogene Erscheinungsbild und durch die überlappende Symptomatik mit anderen neurologischen Erkrankungen erschwert. Verlässliche diagnostische Biomarker stehen trotz umfangreicher Forschung für den praktisch-klinischen Einsatz bislang nicht zur Verfügung. Insbesondere vor dem Hintergrund aufkommender neuroprotektiver Medikamente sind Biomarker dringend nötig. Die vorliegende Arbeit befasste sich mit dem Potential der natürlichen Autoantikörper gegen α-Synuclein als diagnostischer Biomarker für das IPS. Hierzu wurde ein indirekter ELISA etabliert und nach gängigen laborchemischen Kriterien validiert, um die Verteilung des Autoantikörpers im humanen Serum quantitativ zu erfassen. Mittels Affinitätschromatographie wurde aus einem kommerziell erhältlichem Antikörperkonzentrat der natürliche Autoantikörper gegen α-Synuclein extrahiert. Im Western-Blot erfolgte die Prüfung der Bindungsspezifität, bevor er als Standard- und Referenzprobe im ELISA verwendet wurde. Diverse Blockierungsreagenzien wurden bezüglich ihrer Reduktion unspezifischer Hintergrundaktivität von humanem Serum im indirekten ELISA getestet. Der etablierte ELISA zeigte eine spezifische Abnahme in der Verdünnungslinearität mit einer Fehlerrate von unter 20%, eine 91%ige mittlere Spike-Recovery und eine Intra- und Inter-Assay Variation von 3,7 bzw. 8,8%. Patienten mit IPS (n=63), Alzheimer Demenz (AD) (n=43) und gesunden Kontrollprobanden (n=46) wurden für die Studie rekrutiert. Neben dem Alter der Probanden, wurde bei IPS Patienten zusätzlich die Krankheitsdauer und –schwere, nach Hoehn und Yahr und dem motorischen Anteil der UPDRS, erhoben. In allen Fällen wurde die Konzentration des natürlichen Autoantikörpers im Serum bestimmt. In einigen Fällen folgte zusätzlich die Bestimmung des freien α-Synucleins im Serum nach einem publizierten ELISA Protokoll. Es zeigte sich ein signifikanter Unterschied in der Konzentration des Autoantikörpers zwischen den gesunden Kontrollen, Patienten mit IPS und AD (p=0,005; Kruskal-Wallis-Test). In der post-hoc paarweisen Analyse der Gruppen mittels der Dunn’s-Test ergab sich ein Unterschied zwischen gesunden Kontrollen vs. IPS-Patienten (p<0,05), AD- vs. IPS-Patienten (p<0,05) und kein Unterschied zwischen gesunden Kontrollen vs. AD-Patienten. Eine Korrelation zwischen Alter, der Dauer oder Schwere des IPS, der α-Synucleinmenge und der Konzentration des natürlichen Autoantikörpers konnte nicht nachgewiesen werden. Mittels Receiver Operating Characteristic (ROC) Analyse wurde die diagnostische Sensitivität und Spezifität des Assays evaluiert. Die Fläche unterhalb der ROC Kurve ergab einen Wert von 0,662 (95% Konfidenzintervall: 0,561-0,763; p<0.05) für IPS-Patienten vs. gesunde Kontrollen und einen Wert von 0,650 (95% Konfidenzintervall: 0,545-0,754; p<0.05) für IPS vs. AD-Patienten. Nach Bestimmung des Youden-Index zeigte sich für IPS-Patienten vs. gesunden Kontrollen bzw. IPS- vs. AD-Patienten eine Sensitivität und Spezifität von 32% und 98% bzw. von 30% und 95%. Unter Festlegung einer klinisch relevanten Sensitivität von mindestens 85% wurde eine Spezifität für beide Vergleichsgruppen von 25% erreicht. Hinsichtlich des α-Synucleingehalts im Serum unterschieden sich die Gruppen nicht. In der Arbeit konnte zum ersten Mal nachgewiesen werden, dass der natürliche Autoantikörper gegen α-Synuclein im Serum bei IPS-Patienten in geringerer Konzentration vorliegt als bei gesunden Kontrollen und AD-Patienten. Der etablierte Assay erreicht als diagnostischer Test eine mäßig ausgeprägte Genauigkeit in der Differenzierung der diagnostischen Gruppen. Weitere differenzierte Untersuchungen sind daher nötig, um die Wertigkeit der natürlichen Autoantikörper gegen α-Synuclein als potentieller Biomarker für das IPS abschließend zu prüfen.

Bibliographie / References

  1. Laemmli UK. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680-685.
  2. Crowther JR. 2001. The ELISA Guidebook. Totowa, New Jersey: Humana Press Inc.
  3. Fearnley JM, Lees AJ. 1991. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114 ( Pt 5):2283-2301.
  4. Schapira AH. 2008. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol 7(1):97-109.
  5. Elbaz A, Bower JH, Peterson BJ, Maraganore DM, McDonnell SK, Ahlskog JE, Schaid DJ, Rocca WA. 2003. Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 60(1):91-96.
  6. Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, Factor SA, Galasko DR, Ginghina C, Griffith A, Higgins DS, Kay DM, Kim H, Leverenz JB, Quinn JF, Roberts JW, Samii A, Snapinn KW, Tsuang DW, Yearout D, Zhang J, Payami H, Zabetian CP. 2010. SNCA variant associated with Parkinson disease and plasma alpha- synuclein level. Arch Neurol 67(11):1350-1356.
  7. Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow CW, Penney JB, Tanner C, Kieburtz K, Rudolph A, Parkinson Study G. 2002. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 51(5):604-612.
  8. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG. 2004. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55(2):164-173.
  9. Marek K, Jennings D, Tamagnan G, Seibyl J. 2008. Biomarkers for Parkinson's [corrected] disease: tools to assess Parkinson's disease onset and progression.
  10. Simon-Sanchez J, Scholz S, Matarin Mdel M, Fung HC, Hernandez D, Gibbs JR, Britton A, Hardy J, Singleton A. 2008. Genomewide SNP assay reveals mutations underlying Parkinson disease. Hum Mutat 29(2):315-322.
  11. Tinsley RB, Kotschet K, Modesto D, Ng H, Wang Y, Nagley P, Shaw G, Horne MK. 2010. Sensitive and specific detection of alpha-synuclein in human plasma. J Neurosci Res 88(12):2693-2700.
  12. ANHANG Literaturverzeichnis VII Bostantjopoulou S, Katsarou Z, Papadimitriou A, Veletza V, Hatzigeorgiou G, Lees A. 2001. Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation. Mov Disord 16(6):1007-1013.
  13. ANHANG Literaturverzeichnis XIII Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H. 2007. Olfactory loss may be a first sign of idiopathic Parkinson's disease. Mov Disord 22(6):839-842.
  14. Mollenhauer B, Trenkwalder C. 2009. Neurochemical biomarkers in the differential diagnosis of movement disorders. Mov Disord 24(10):1411-1426.
  15. Rodrigues e Silva AM, Geldsetzer F, Holdorff B, Kielhorn FW, Balzer-Geldsetzer M, Oertel WH, Hurtig H, Dodel R. 2010. Who was the man who discovered the "Lewy bodies"? Mov Disord 25(12):1765-1773.
  16. Richards M, Marder K, Cote L, Mayeux R. 1994. Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination. Mov Disord 9(1):89-91.
  17. Goetz CG, Stebbins GT, Chmura TA, Fahn S, Klawans HL, Marsden CD. 1995. Teaching tape for the motor section of the unified Parkinson's disease rating scale. Mov Disord 10(3):263-266.
  18. Wucherpfennig KW. 1994. Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition. Clin Immunol Immunopathol 72(3):293- 306.
  19. Bouvet JP, Stahl D, Rose S, Quan CP, Kazatchkine MD, Kaveri SV. 2001. Induction of natural autoantibody activity following treatment of human immunoglobulin with dissociating agents. J Autoimmun 16(2):163-172.
  20. Lee PH, Lee G, Park HJ, Bang OY, Joo IS, Huh K. 2006. The plasma alpha-synuclein levels in patients with Parkinson's disease and multiple system atrophy. J Neural Transm 113(10):1435-1439.
  21. Lohle M, Storch A, Reichmann H. 2009. Beyond tremor and rigidity: non-motor features of Parkinson's disease. J Neural Transm 116(11):1483-1492.
  22. Rupin A, Gruel Y, Watier H, Girard AC, Leroy J, Bardos P. 1991. ELISA for the detection of anticardiolipin antibodies. High specificity based on the use of adult bovine serum as buffer and systematic subtraction of non-specific binding. J Immunol Methods 138(2):225-231.
  23. Cheng HM. 1996. Tween 20 selectively enhances naturally occurring anticardiolipin antibody binding in ELISA procedures. J Immunol Methods 191(1):87-91.
  24. Piechaczyk M, Bouanani M, Salhi SL, Baldet L, Bastide M, Pau B, Bastide JM. 1987. Antigenic domains on the human thyroglobulin molecule recognized by autoantibodies in patients' sera and by natural autoantibodies isolated from the sera of healthy subjects. Clin Immunol Immunopathol 45(1):114-121.
  25. Jellinger KA. 2009. A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792(7):730-740.
  26. Waragai M, Wei J, Fujita M, Nakai M, Ho GJ, Masliah E, Akatsu H, Yamada T, Hashimoto M. 2006. Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson's disease. Biochem Biophys Res Commun 345(3):967-972.
  27. Marchalonis JJ, Adelman MK, Schluter SF, Ramsland PA. 2006. The antibody repertoire in evolution: chance, selection, and continuity. Dev Comp Immunol 30(1-2):223-247.
  28. von Campenhausen S, Bornschein B, Wick R, Botzel K, Sampaio C, Poewe W, Oertel W, Siebert U, Berger K, Dodel R. 2005. Prevalence and incidence of Parkinson's disease in Europe. Eur Neuropsychopharmacol 15(4):473-490.
  29. Lutz HU. 2007. Homeostatic roles of naturally occurring antibodies: an overview. J Autoimmun 29(4):287-294.
  30. Rowley B, Tang L, Shinton S, Hayakawa K, Hardy RR. 2007. Autoreactive B-1 B cells: constraints on natural autoantibody B cell antigen receptors. J Autoimmun 29(4):236-245.
  31. Klaver AC, Patrias LM, Coffey MP, Finke JM, Loeffler DA. 2010. Measurement of anti- Abeta1-42 antibodies in intravenous immunoglobulin with indirect ELISA: the problem of nonspecific binding. J Neurosci Methods 187(2):263-269.
  32. ANHANG Literaturverzeichnis XXIII Szabo P, Mujalli DM, Rotondi ML, Sharma R, Weber A, Schwarz HP, Weksler ME, Relkin N. 2010. Measurement of anti-beta amyloid antibodies in human blood. J Neuroimmunol 227(1-2):167-174.
  33. Maita C, Tsuji S, Yabe I, Hamada S, Ogata A, Maita H, Iguchi-Ariga SM, Sasaki H, Ariga H. 2008. Secretion of DJ-1 into the serum of patients with Parkinson's disease. Neurosci Lett 431(1):86-89.
  34. Shi M, Zabetian CP, Hancock AM, Ginghina C, Hong Z, Yearout D, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Leverenz JB, Zhang J. 2010. Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease. Neurosci Lett 480(1):78-82.
  35. Hunot S, Hirsch EC. 2003. Neuroinflammatory processes in Parkinson's disease. Ann Neurol 53 Suppl 3:S49-58; discussion S58-60.
  36. Ma SY, Roytta M, Rinne JO, Collan Y, Rinne UK. 1997. Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts. J Neurol Sci 151(1):83-87.
  37. Racke MK, Ratts RB, Arredondo L, Perrin PJ, Lovett-Racke A. 2000. The role of costimulation in autoimmune demyelination. J Neuroimmunol 107(2):205-215.
  38. Braak H, Sandmann-Keil D, Gai W, Braak E. 1999. Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Neurosci Lett 265(1):67-69.
  39. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I. 2009. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol 8(12):1150-1157.
  40. Gasser T. 2009. Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 11:e22.
  41. ANHANG Literaturverzeichnis XIX O'Nuallain B, Acero L, Williams AD, Koeppen HP, Weber A, Schwarz HP, Wall JS, Weiss DT, Solomon A. 2008. Human plasma contains cross-reactive Abeta conformer-specific IgG antibodies. Biochemistry 47(47):12254-12256.
  42. Fuchtenbusch M, Karges W, Standl E, Dosch HM, Ziegler AG. 1997. Antibodies to bovine serum albumin (BSA) in type 1 diabetes and other autoimmune disorders. Exp Clin Endocrinol Diabetes 105(2):86-91.
  43. Sveinbjornsdottir S, Hicks AA, Jonsson T, Petursson H, Gugmundsson G, Frigge ML, Kong A, Gulcher JR, Stefansson K. 2000. Familial aggregation of Parkinson's disease in Iceland. N Engl J Med 343(24):1765-1770.
  44. Hastings TG, Lewis DA, Zigmond MJ. 1996. Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections. Proc Natl Acad Sci U S A 93(5):1956-1961.
  45. Kamp F, Beyer K. 2006. Binding of alpha-synuclein affects the lipid packing in bilayers of small vesicles. J Biol Chem 281(14):9251-9259.
  46. Gao YC, Yuan ZB, Yang YD, Lu HK. 2007. Effect of freeze-thaw cycles on serum measurements of AFP, CEA, CA125 and CA19-9. Scand J Clin Lab Invest 67(7):741-747.
  47. Gislefoss RE, Grimsrud TK, Morkrid L. 2008. Long-term stability of serum components in the Janus Serum Bank. Scand J Clin Lab Invest 68(5):402-409.
  48. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM. 2003. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157(11):1015-1022.
  49. Morrish PK, Sawle GV, Brooks DJ. 1996. An [18F]dopa-PET and clinical study of the rate of progression in Parkinson's disease. Brain 119(Pt 2):585-591.
  50. Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, Parisi JE, Benarroch EE, Ahlskog JE, Smith GE, Caselli RC, Tippman-Peikert M, Olson EJ, Lin SC, Young T, Wszolek Z, Schenck CH, Mahowald MW, Castillo PR, Del Tredici K, Braak H. 2007. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130(Pt 11):2770-2788.
  51. Bogdanov M, Matson WR, Wang L, Matson T, Saunders-Pullman R, Bressman SS, Flint Beal M. 2008. Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain 131(Pt 2):389-396.
  52. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J. 2010. DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain 133(Pt 3):713- 726.
  53. Lotharius J, Brundin P. 2002. Impaired dopamine storage resulting from alpha- synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum Mol Genet 11(20):2395-2407.
  54. Irizarry MC, Kim TW, McNamara M, Tanzi RE, George JM, Clayton DF, Hyman BT. 1996. Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol 55(8):889-895.
  55. Schisterman EF, Perkins NJ, Liu A, Bondell H. 2005. Optimal cut-point and its corresponding Youden Index to discriminate individuals using pooled blood samples. Epidemiology 16(1):73-81.
  56. Patrias LM, Klaver AC, Coffey MP, Loeffler DA. 2010. Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations. Clin Exp Immunol 161(3):527-535.
  57. Hawkes CH, Del Tredici K, Braak H. 2007. Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33(6):599-614.
  58. Djoumerska I, Tchorbanov A, Pashov A, Vassilev T. 2005. The autoreactivity of therapeutic intravenous immunoglobulin (IVIG) preparations depends on the fractionation methods used. Scand J Immunol 61(4):357-363.
  59. Wilhelm KR, Yanamandra K, Gruden MA, Zamotin V, Malisauskas M, Casaite V, Darinskas A, Forsgren L, Morozova-Roche LA. 2007. Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients. Eur J Neurol 14(3):327-334.
  60. Kearney JF, Vakil M. 1986. Idiotype-directed interactions during ontogeny play a major role in the establishment of the adult B cell repertoire. Immunol Rev 94:39-50.
  61. Marchalonis JJ, Schluter SF, Bernstein RM, Hohman VS. 1998. Antibodies of sharks: revolution and evolution. Immunol Rev 166:103-122.
  62. Uversky VN. 2010. Mysterious oligomerization of the amyloidogenic proteins. FEBS J 277(14):2940-2953.
  63. Pinsky NA, Huddleston JM, Jacobson RM, Wollan PC, Poland GA. 2003. Effect of multiple freeze-thaw cycles on detection of measles, mumps, and rubella virus antibodies. Clin Diagn Lab Immunol 10(1):19-21.
  64. Gibb WR, Lees AJ. 1988. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51(6):745-752.
  65. Lees AJ, Hardy J, Revesz T. 2009. Parkinson's disease. Lancet 373(9680):2055-2066.
  66. Gibb WR. 1988. Accuracy in the clinical diagnosis of parkinsonian syndromes. Postgrad Med J 64(751):345-351.
  67. Hornykiewicz O. 2008. Basic research on dopamine in Parkinson's disease and the discovery of the nigrostriatal dopamine pathway: the view of an eyewitness. Neurodegener Dis 5(3-4):114-117.
  68. Reichmann H. 2010. Clinical criteria for the diagnosis of Parkinson's disease. Neurodegener Dis 7(5):284-290.
  69. Bassetti CL. 2010. Nonmotor disturbances in Parkinson's disease. Neurodegener Dis 8(3):95-108.
  70. Siminovitch KA, Misener V, Kwong PC, Song QL, Chen PP. 1989. A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation. J Clin Invest 84(5):1675-1678.
  71. Middleton BA, Morgan LM, Aherne GW, Marks V. 1988. The effect of storage temperature and physical state on the performance of antisera in radioimmunoassay after long-term storage. Ann Clin Biochem 25 ( Pt 1):89-95.
  72. Pellegrino NM, Caccavo D. 2007. Variability in anticardiolipin antibody detection: role of nonspecific IgG binding and different microtiter plates. Clin Appl Thromb Hemost 13(4):404-409.
  73. Buter TC, van den Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D. 2008. Dementia and survival in Parkinson disease: a 12-year population study. Neurology 70(13):1017-1022.
  74. Braak H, Del Tredici K. 2008. Invited Article: Nervous system pathology in sporadic Parkinson disease. Neurology 70(20):1916-1925.
  75. Gagne JJ, Power MC. 2010. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74(12):995-1002.
  76. Carraro P, Plebani M. 2007. Errors in a stat laboratory: types and frequencies 10 years later. Clin Chem 53(7):1338-1342.
  77. Lippi G, Salvagno GL, Montagnana M, Brocco G, Guidi GC. 2006b. Influence of hemolysis on routine clinical chemistry testing. Clin Chem Lab Med 44(3):311- 316.
  78. Lippi G, Guidi GC, Mattiuzzi C, Plebani M. 2006a. Preanalytical variability: the dark side of the moon in laboratory testing. Clin Chem Lab Med 44(4):358-365.
  79. Chaigneau C, Cabioch T, Beaumont K, Betsou F. 2007. Serum biobank certification and the establishment of quality controls for biological fluids: examples of serum biomarker stability after temperature variation. Clin Chem Lab Med 45(10):1390-1395.
  80. Breen DP, Michell AW, Barker RA. 2011. Parkinson's disease--the continuing search for biomarkers. Clin Chem Lab Med 49(3):393-401.
  81. O'Nuallain B, Hrncic R, Wall JS, Weiss DT, Solomon A. 2006. Diagnostic and therapeutic potential of amyloid-reactive IgG antibodies contained in human sera. J Immunol 176(11):7071-7078.
  82. Swann PG, Shapiro MA. 2011. Regulatory considerations for development of bioanalytical assays for biotechnology products. Bioanalysis 3(6):597-603.
  83. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 1984. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34(7):939-944.
  84. Petrakis NL. 1985. Biologic banking in cohort studies, with special reference to blood. Natl Cancer Inst Monogr 67:193-198.
  85. Parkinson J. 2002. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 14(2):223-236; discussion 222.
  86. Hughes AJ, Daniel SE, Kilford L, Lees AJ. 1992. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181-184.
  87. Noelker C, Hampel H, Dodel R. 2011. Blood-based protein biomarkers for diagnosis and classification of neurodegenerative diseases: current progress and clinical potential. Mol Diagn Ther 15(2):83-102.
  88. Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. 2010. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol 119(6):703-713.
  89. Abb. 13: Vergleich unterschiedlicher Konzentrationen der α-Synucleinbeschichtung . 74
  90. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 2009. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 30(11):1728-1736.
  91. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. 2000. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408(6815):982-985.
  92. Steiner JA, Angot E, Brundin P. 2011. A deadly spread: cellular mechanisms of alpha- synuclein transfer. Cell Death Differ 18(9):1425-1433.
  93. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E, Investigators AS. 2009. A double- blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 361(13):1268-1278.
  94. ANHANG KLINISCHE Beurteilungsskalen XXXI Aktions-oder Haltungstremor der Hände – je rechts und links. 0. Fehlt. 1. Leicht; bei Bewegung vorhanden. 2. Mäßige Amplitude, bei Bewegung vorhanden.
  95. Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG. 2005. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 118(Pt 15):3523-3530.
  96. Nuscher B, Kamp F, Mehnert T, Odoy S, Haass C, Kahle PJ, Beyer K. 2004. Alpha- synuclein has a high affinity for packing defects in a bilayer membrane: a thermodynamics study. J Biol Chem 279(21):21966-21975.
  97. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destee A. 2004. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364(9440):1167-1169.
  98. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K. 2003. alpha-Synuclein locus triplication causes Parkinson's disease. Science 302(5646):841.
  99. Norris EH, Giasson BI, Lee VM. 2004. Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17-54.
  100. Bartels T, Choi JG, Selkoe DJ. 2011. alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107-110.
  101. ANHANG XXV Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, Morozova-Roche LA. 2011. alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients. PLoS One 6(4):e18513.
  102. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B. 1999. alpha- Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19(14):5782-5791.
  103. Caudle WM, Colebrooke RE, Emson PC, Miller GW. 2008. Altered vesicular dopamine storage in Parkinson's disease: a premature demise. Trends Neurosci 31(6):303-308.
  104. Burnet FM. 1976. A modification of Jerne's theory of antibody production using the concept of clonal selection. CA Cancer J Clin 26(2):119-121.
  105. Greiner M, Sohr D, Gobel P. 1995. A modified ROC analysis for the selection of cut-off values and the definition of intermediate results of serodiagnostic tests. J Immunol Methods 185(1):123-132.
  106. Patton A, Mullenix MC, Swanson SJ, Koren E. 2005. An acid dissociation bridging ELISA for detection of antibodies directed against therapeutic proteins in the presence of antigen. J Immunol Methods 304(1-2):189-195.
  107. ANHANG Literaturverzeichnis XV Lacroix-Desmazes S, Mouthon L, Coutinho A, Kazatchkine MD. 1995. Analysis of the natural human IgG antibody repertoire: life-long stability of reactivities towards self antigens contrasts with age-dependent diversification of reactivities against bacterial antigens. Eur J Immunol 25(9):2598-2604.
  108. Mouthon L, Haury M, Lacroix-Desmazes S, Barreau C, Coutinho A, Kazatchkine MD. 1995. Analysis of the normal human IgG antibody repertoire. Evidence that IgG autoantibodies of healthy adults recognize a limited and conserved set of protein antigens in homologous tissues. J Immunol 154(11):5769-5778.
  109. ANHANG Literaturverzeichnis XII
  110. ANHANG Literaturverzeichnis XXII
  111. Fujii K, Tsuji M, Murota K, Terato K, Shimozuru Y, Nagai Y. 1989. An improved enzyme-linked immunosorbent assay of anti-collagen antibodies in human serum. J Immunol Methods 124(1):63-70.
  112. Kemeny DM, Challacombe Sj. 1988. An Introduction to ELISA. In: Kemeny DM, Challacombe Sj, editors. ELISA and other solid phase immunoassays; theoretical and practical aspects. Chichester: John Wiley & Sons Ltd. p 1-23.
  113. Double KL, Rowe DB, Carew-Jones FM, Hayes M, Chan DK, Blackie J, Corbett A, Joffe R, Fung VS, Morris J, Riederer P, Gerlach M, Halliday GM. 2009. Anti- melanin antibodies are increased in sera in Parkinson's disease. Exp Neurol 217(2):297-301.
  114. Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM. 2005. A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128(Pt 11):2665- 2674.
  115. Trieb K, Ransmayr G, Sgonc R, Lassmann H, Grubeck-Loebenstein B. 1996. APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer's disease. Neurobiol Aging 17(4):541-547.
  116. ANHANG Literaturverzeichnis XX Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ. 2002. A role for alpha- synuclein in the regulation of dopamine biosynthesis. J Neurosci 22(8):3090- 3099.
  117. Spillantini MG, Divane A, Goedert M. 1995. Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27(2):379-381.
  118. Braggio S, Barnaby RJ, Grossi P, Cugola M. 1996. A strategy for validation of bioanalytical methods. J Pharm Biomed Anal 14(4):375-388.
  119. Shoenfeld Y, Gershwin ME, Meroni PL. 2007. Autoantibodies. Amsterdam: Elsevier.
  120. Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. 2005. Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem 280(17):17458-17463.
  121. Gruden MA, Davudova TB, Malisauskas M, Zamotin VV, Sewell RD, Voskresenskaya NI, Kostanyan IA, Sherstnev VV, Morozova-Roche LA. 2004. Autoimmune responses to amyloid structures of Abeta(25-35) peptide and human lysozyme in the serum of patients with progressive Alzheimer's disease. Dement Geriatr Cogn Disord 18(2):165-171.
  122. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 5(1):49-55.
  123. Kuen LS, Ming CH, Fan YS. 1993. Background noise in ELISA procedures. Influence of the pH of the coating buffer and correlations with serum IgM concentration. J Immunol Methods 163(2):277-278.
  124. Schrohl AS, Wurtz S, Kohn E, Banks RE, Nielsen HJ, Sweep FC, Brunner N. 2008. Banking of biological fluids for studies of disease-associated protein biomarkers. Mol Cell Proteomics 7(10):2061-2066.
  125. Minimale Verlangsamung, Bewegung wirkt beabsichtigt; könnte bei manchen Menschen normal sein. Möglicherweise herabgesetzte Amplitude.
  126. Eller M, Williams DR. 2009. Biological fluid biomarkers in neurodegenerative parkinsonism. Nat Rev Neurol 5(10):561-570.
  127. Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89- 95.
  128. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M. 1999. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274(14):9843-9846.
  129. Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A. 2004. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364(9440):1169-1171.
  130. Compta Y, Marti MJ, Ibarretxe-Bilbao N, Junque C, Valldeoriola F, Munoz E, Ezquerra M, Rios J, Tolosa E. 2009. Cerebrospinal tau, phospho-tau, and beta-amyloid and neuropsychological functions in Parkinson's disease. Mov Disord 24(15):2203-2210.
  131. George JM, Jin H, Woods WS, Clayton DF. 1995. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15(2):361-372.
  132. Goetz CG. 1986. Charcot on Parkinson's disease. Mov Disord 1(1):27-32.
  133. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. 2004. Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24(8):1888-1896.
  134. De Gruttola VG, Clax P, DeMets DL, Downing GJ, Ellenberg SS, Friedman L, Gail MH, Prentice R, Wittes J, Zeger SL. 2001. Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. Control Clin Trials 22(5):485-502.
  135. Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, Chung KA, Millard SP, Nutt JG, Montine TJ. 2008. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol 129(4):526-529.
  136. Morley JF, Hurtig HI. 2010. Current understanding and management of Parkinson disease: five new things. Neurology 75(18 Suppl 1):S9-15.
  137. Perlmutter JD, Braun AR, Sachs JN. 2009. Curvature dynamics of alpha-synuclein familial Parkinson disease mutants: molecular simulations of the micelle-and bilayer-bound forms. J Biol Chem 284(11):7177-7189.
  138. Tokuda T, Salem SA, Allsop D, Mizuno T, Nakagawa M, Qureshi MM, Locascio JJ, Schlossmacher MG, El-Agnaf OM. 2006. Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem Biophys Res Commun 349(1):162-166.
  139. Brettschneider S, Morgenthaler NG, Teipel SJ, Fischer-Schulz C, Burger K, Dodel R, Du Y, Moller HJ, Bergmann A, Hampel H. 2005. Decreased serum amyloid beta(1-42) autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid beta(1-42) peptide. Biol Psychiatry 57(7):813-816.
  140. Fahn S. 2003. Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1-14.
  141. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, Ishigami N, Tamaoka A, Nakagawa M, El-Agnaf OM. 2010. Detection of elevated levels of alpha-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75(20):1766-1772.
  142. El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D. 2006. Detection of oligomeric forms of alpha- synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 20(3):419-425.
  143. Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, Pepivani I, Ng J, Schulz- Schaeffer W, Kretzschmar HA, McLean PJ, Trenkwalder C, Sarracino DA, Vonsattel JP, Locascio JJ, El-Agnaf OM, Schlossmacher MG. 2008. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol 213(2):315-325.
  144. Rascol O, Ferreira JJ, Thalamas C, Galitsky M, Montastruc JL. 2001. Dopamine agonists. Their role in the management of Parkinson's disease. Adv Neurol 86:301-309.
  145. Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. 2002. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8(6):600-606.
  146. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D. 2005. Effects of alpha- synuclein immunization in a mouse model of Parkinson's disease. Neuron 46(6):857-868.
  147. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M, Parkinson Study G. 2002. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59(10):1541-1550.
  148. Flower L, Ahuja RH, Humphries SE, Mohamed-Ali V. 2000. Effects of sample handling on the stability of interleukin 6, tumour necrosis factor-alpha and leptin. Cytokine 12(11):1712-1716.
  149. Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.
  150. Crowther JR. 1995. ELISA: theory and practice. Totowa, New Jersey: Humana Press Inc.
  151. Engvall E, Perlmann P. 1971. Enzyme-linked immunosorbent assay (ELISA).
  152. Tanner CM, Aston DA. 2000. Epidemiology of Parkinson's disease and akinetic syndromes. Curr Opin Neurol 13(4):427-430.
  153. Bonini P, Plebani M, Ceriotti F, Rubboli F. 2002. Errors in laboratory medicine. Clin Chem 48(5):691-698.
  154. Chen S, Le WD, Xie WJ, Alexianu ME, Engelhardt JI, Siklos L, Appel SH. 1998. Experimental destruction of substantia nigra initiated by Parkinson disease immunoglobulins. Arch Neurol 55(8):1075-1080.
  155. Shin EC, Cho SE, Lee DK, Hur MW, Paik SR, Park JH, Kim J. 2000. Expression patterns of alpha-synuclein in human hematopoietic cells and in Drosophila at different developmental stages. Mol Cells 10(1):65-70.
  156. Ravindranath MH, Ravindranath RM, Morton DL, Graves MC. 1994. Factors affecting the fine specificity and sensitivity of serum antiganglioside antibodies in ELISA. J Immunol Methods 169(2):257-272.
  157. Fehlen einer Haltungsreaktion; würde fallen, wenn er nicht vom Untersucher aufgefangen würde.
  158. Gehen schwierig, benötigt aber wenig oder keine Hilfe; eventuell leichtes Trippeln, kurze Schritte oder Propulsion.
  159. Geht langsam, kann einige kurze Schritte schlurfen, jedoch keine Festination oder Propulsion.
  160. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. 2009. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 41(12):1303-1307.
  161. Rigidität (Geprüft bei passiver Bewegung der großen Gelenke am sitzenden Patienten. Zahnradphänomen kann ignoriert werden) – Nacken und je rechte und linke obere Extremität, je rechte und linke untere Extremität. 0. Fehlt.
  162. Geringe Amplitude persistierend; oder mäßige Amplitude, aber nur intermittierend auftretend.
  163. Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ. 2002. Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem 277(50):48984-48992.
  164. Große Amplitude; beim Essen störend.
  165. Große Amplitude, die meiste Zeit vorhanden.
  166. Hardy J. 2006. Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res 3(1):71-73.
  167. Manoussakis MN, Tzioufas AG, Silis MP, Pange PJ, Goudevenos J, Moutsopoulos HM. 1987. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol 69(3):557-565.
  168. Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L, Oertel WH, Farlow M. 2003. Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity. Brain 126(Pt 9):1935-1939.
  169. Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jackel S, Wei X, Buerger K, Hoft C, Hemmer B, Moller HJ, Farlow M, Oertel WH, Sommer N, Du Y. 2002. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. Ann Neurol 52(2):253-256.
  170. Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R. 2008. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. Acta Neuropathol 116(1):47-55.
  171. Underwood JR, Pedersen JS, Chalmers PJ, Toh BH. 1985. Hybrids from normal, germ free, nude and neonatal mice produce monoclonal autoantibodies to eight different intracellular structures. Clin Exp Immunol 60(2):417-426.
  172. Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE. 1997. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 57(4):759-764.
  173. Jakes R, Spillantini MG, Goedert M. 1994. Identification of two distinct synucleins from human brain. FEBS Lett 345(1):27-32.
  174. Ceballos-Baumann AO. 2006. Idiopathisches Parkinson-Syndrom (IPS). In: Berlit P (Hrsg.). Klinische Neurologie. 2. akutalisierte Auflage. Heidelberg: Springer Medizin Verlag. S. 852-871.
  175. ANHANG Literaturverzeichnis XVIII Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL. 2001. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease. Proc Natl Acad Sci U S A 98(18):10273-10278.
  176. Terness PI, Navolan D, Dufter C, Welschof M, Opelz G. 2002. Immunosuppressive anti-immunoglobulin autoantibodies: specificity, gene structure and function in health and disease. Cell Mol Biol (Noisy-le-grand) 48(3):271-278.
  177. Neff F, Wei X, Nolker C, Bacher M, Du Y, Dodel R. 2008. Immunotherapy and naturally occurring autoantibodies in neurodegenerative disorders. Autoimmun Rev 7(6):501-507.
  178. Li Q, Gordon M, Cao C, Ugen KE, Morgan D. 2007a. Improvement of a low pH antigen- antibody dissociation procedure for ELISA measurement of circulating anti- Abeta antibodies. BMC Neurosci 8:22.
  179. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ. 2009. Inclusion formation and neuronal cell death through neuron-to- neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31):13010- 13015.
  180. Youden WJ. 1950. Index for rating diagnostic tests. Cancer 3(1):32-35.
  181. Baumgarth N, Tung JW, Herzenberg LA. 2005. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 26(4):347-362.
  182. Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, Oertel W. 2010. Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence. Drugs 70(5):513-528.
  183. Sommer N, Oertel WH. 2004. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry 75(10):1472-1474.
  184. Olanow CW, Prusiner SB. 2009. Is Parkinson's disease a prion disorder? Proc Natl Acad Sci U S A 106(31):12571-12572.
  185. Thomas L. 2007. Analytik, analytische Beurteilung und klinische Bewertung von Laborbefunden. In: Thomas L (Hrsg.). Labor und Diagnose: Indikation und Bewertung von Laborbefunden für die medizinische Diagnostik. 7. Auflage. Frankfurt am Main: Th-Books GmbH. S. 1974-1985.
  186. Langsam; kann mehr als einen Versuch benötigen.
  187. Leichte Verlangsamung und/oder Verringerung der Amplitude.
  188. Leicht oder nur erkennbar bei Aktivierung durch spiegelbildliche oder andere Bewegungen.
  189. Eggert KM, Oertel WH. 2008. Leitlinie Parkinson-Syndrome Diagnostik und Therapie / hrsg. von der Expertengruppe des Kompetenznetz Parkinson. Teilausg. von: Diener, H. C.: Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Georg Thieme Verlag.
  190. Olanow CW, Perl DP, DeMartino GN, McNaught KS. 2004. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3(8):496-503.
  191. Mäßig verminderte Mimik; Lippen zeitweise geöffnet. 4. Maskenhaftes oder erstarrtes Gesicht mit stark oder völlig fehlendem Ausdruck; der Mund steht mindestens 0,5cm offen.
  192. Swets JA. 1988. Measuring the accuracy of diagnostic systems. Science 240(4857):1285-1293.
  193. Bronstein J, Carvey P, Chen H, Cory-Slechta D, DiMonte D, Duda J, English P, Goldman S, Grate S, Hansen J, Hoppin J, Jewell S, Kamel F, Koroshetz W, Langston JW, Logroscino G, Nelson L, Ravina B, Rocca W, Ross GW, Schettler T, Schwarzschild M, Scott B, Seegal R, Singleton A, Steenland K, Tanner CM, Van Den Eeden S, Weisskopf M. 2009. Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007. Environ Health Perspect 117(1):117-121.
  194. Kenna JG, Major GN, Williams RS. 1985. Methods for reducing non-specific antibody binding in enzyme-linked immunosorbent assays. J Immunol Methods 85(2):409-419.
  195. Bergmeyer HU. 1983. Methods of Enzymatic Analysis: Fundamentals. Bergmeyer HU, editor. Weinheim: Verlag Chemie GmbH.
  196. Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T. 2005. Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 57(2):168-175.
  197. Mäßige Amplitude, bei Beibehalten der Haltung und bei Bewegung vorhanden.
  198. Mäßige Amplitude, die meiste Zeit vorhanden.
  199. Mäßig vorgebeugte Haltung; eindeutig abnorm, kann leicht zu einer Seite geneigt sein.
  200. Minimal veränderte Mimik, könnte ein normales "Pokergesicht" sein.
  201. Folstein MF, Folstein SE, McHugh PR. 1975. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189-198.
  202. Lin MT, Beal MF. 2006. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787-795.
  203. Purves D. 2004. Modulation of Movement by Basal Ganglia. In: Neuroscience: Third Edition. 3. Auflage. Sunderland: Sinauer Associates, Inc. S. 417-434.
  204. Yang YX, Wood NW, Latchman DS. 2009. Molecular basis of Parkinson's disease. Neuroreport 20(2):150-156.
  205. Thomas B, Beal MF. 2011. Molecular insights into Parkinson's disease. F1000 Med Rep 3:1-7.
  206. Waxman EA, Giasson BI. 2009. Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta 1792(7):616-624.
  207. Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L, Movement Disorder Society Task Force on Rating Scales for Parkinson's D. 2004. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19(9):1020-1028.
  208. Ternynck T, Avrameas S. 1986. Murine natural monoclonal autoantibodies: a study of their polyspecificities and their affinities. Immunol Rev 94:99-112.
  209. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT, Jr. 1996. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35(43):13709-13715.
  210. Chen C, Stenzel-Poore MP, Rittenberg MB. 1991. Natural auto-and polyreactive antibodies differing from antigen-induced antibodies in the H chain CDR3. J Immunol 147(7):2359-2367.
  211. Marchalonis JJ, Kaveri S, Lacroix-Desmazes S, Kazatchkine MD. 2002. Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system. FASEB J 16(8):842-848.
  212. Elkon K, Casali P. 2008. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 4(9):491-498.
  213. Brundin P, Barker RA, Parmar M. 2010. Neural grafting in Parkinson's disease Problems and possibilities. Prog Brain Res 184:265-294.
  214. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT, Jr. 2002. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418(6895):291.
  215. Uversky VN. 2007. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17-37.
  216. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. 2007. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 117(3):712-718.
  217. Nicht ganz aufrecht, leicht vorgebeugte Haltung; könnte bei einem älteren Menschen normal sein.
  218. Poewe W. 2008. Non-motor symptoms in Parkinson's disease. Eur J Neurol 15 Suppl 1:14-20.
  219. Hoehn MM, Yahr MD. 1967. Parkinsonism: onset, progression and mortality. Neurology 17(5):427-442.
  220. ANHANG Literaturverzeichnis XXI Richard IH, Papka M, Rubio A, Kurlan R. 2002. Parkinson's disease and dementia with Lewy bodies: one disease or two? Mov Disord 17(6):1161-1165.
  221. Granieri E, Carreras M, Casetta I, Govoni V, Tola MR, Paolino E, Monetti VC, De Bastiani P. 1991. Parkinson's disease in Ferrara, Italy, 1967 through 1987. Arch Neurol 48(8):854-857.
  222. Chaudhuri KR, Odin P, Antonini A, Martinez-Martin P. 2011. Parkinson's disease: The non-motor issues. Parkinsonism Relat Disord.
  223. Fingerklopfen (Patient berührt in rascher Reihenfolge und bei größtmöglicher Amplitude und mit jeder Hand gesondert den Daumen mit dem Zeigefinger) – je rechts und links. 0. Normal.
  224. Handbewegungen (Patient öffnet und schließt die Hände in rascher Reihenfolge bei größtmöglicher Amplitude und mit jeder Hand gesondert) – je rechts und links. 0. Normal.
  225. Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. 2002. Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol 37(7):943-948.
  226. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. 2000. Peripherally administered antibodies against amyloid beta- peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8):916-919.
  227. Kayed R, Sokolov Y, Edmonds B, McIntire TM, Milton SC, Hall JE, Glabe CG. 2004. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279(45):46363-46366.
  228. Duran R, Barrero FJ, Morales B, Luna JD, Ramirez M, Vives F. 2010. Plasma alpha- synuclein in patients with Parkinson's disease with and without treatment. Mov Disord 25(4):489-493.
  229. Li QX, Mok SS, Laughton KM, McLean CA, Cappai R, Masters CL, Culvenor JG, Horne MK. 2007b. Plasma alpha-synuclein is decreased in subjects with Parkinson's disease. Exp Neurol 204(2):583-588.
  230. Candore G, Di Lorenzo G, Mansueto P, Melluso M, Frada G, Li Vecchi M, Esposito Pellitteri M, Drago A, Di Salvo A, Caruso C. 1997. Prevalence of organ-specific ANHANG Literaturverzeichnis VIII and non organ-specific autoantibodies in healthy centenarians. Mech Ageing Dev 94(1-3):183-190.
  231. Greiner M, Pfeiffer D, Smith RD. 2000. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev Vet Med 45(1-2):23-41.
  232. Jimenez R, Salazar G, Yin J, Joo T, Romesberg FE. 2004. Protein dynamics and the immunological evolution of molecular recognition. Proc Natl Acad Sci U S A 101(11):3803-3808.
  233. Quantitative assay of immunoglobulin G. Immunochemistry 8(9):871-874.
  234. Vogt RF, Jr., Phillips DL, Henderson LO, Whitfield W, Spierto FW. 1987. Quantitative differences among various proteins as blocking agents for ELISA microtiter plates. J Immunol Methods 101(1):43-50.
  235. Porat YB, Zan-Bar I, Ravid A. 1995. Quantitative dot-blot assay for low titer anti- lipopolysaccharide antibodies in human plasma. J Immunol Methods 180(2):213-218.
  236. Haltungsstabilität (Reaktion auf plötzliches Verlagern nach hinten durch Ziehen an den Schultern des Patienten; der mit geöffneten Augen und leicht auseinander stehenden Füßen geradesteht. Der Patient ist darauf vorbereitet). 0. Normal.
  237. Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, Parish T, Scott G, Shankar G, Shores E, Swanson SJ, Taniguchi G, Wierda D, Zuckerman LA. 2004. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods 289(1-2):1-16.
  238. Literaturverzeichnis VI Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Goldstein JM, Soriano F, Seubert P, Chilcote TJ. 2008. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5(2):55-59.
  239. Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B, Bales K, Gao F, Moeller HJ, Oertel W, Farlow M, Paul S. 2001. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 57(5):801-805.
  240. Murray IV, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, Trojanowski JQ, Lee VM. 2003. Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42(28):8530-8540.
  241. Devic I, Hwang H, Edgar JS, Izutsu K, Presland R, Pan C, Goodlett DR, Wang Y, Armaly J, Tumas V, Zabetian CP, Leverenz JB, Shi M, Zhang J. 2011. Salivary alpha-synuclein and DJ-1: potential biomarkers for Parkinson's disease. Brain 134(Pt 7):e178.
  242. Mein besonderer Dank gilt Frau Dr. sc. hum. Daniela Besong-Agbo, die diese Arbeit mit ihrem unermüdlichen Engagement und ihrer konstruktiven wissenschaftlichen Betreuung überhaupt erst möglich gemacht hat. Zu dem sind Frau Christine Forbach und Herr Andreas Kautz zu nennen, auf deren hilfreiche Unterstützung ich mich bei der praktischen Laborarbeit immer verlassen konnte.
  243. Sehr instabil; neigt dazu, spontan das Gleichgewicht zu verlieren.
  244. Lacroix-Desmazes S, Kaveri SV, Mouthon L, Ayouba A, Malanchere E, Coutinho A, Kazatchkine MD. 1998. Self-reactive antibodies (natural autoantibodies) in healthy individuals. J Immunol Methods 216(1-2):117-137.
  245. Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A. 2008. Single particle characterization of iron-induced pore-forming alpha- synuclein oligomers. J Biol Chem 283(16):10992-11003.
  246. ANHANG Literaturverzeichnis IX Davidson WS, Jonas A, Clayton DF, George JM. 1998. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273(16):9443-9449.
  247. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24(2):197-211.
  248. Kim TD, Paik SR, Yang CH. 2002. Structural and functional implications of C-terminal regions of alpha-synuclein. Biochemistry 41(46):13782-13790.
  249. Mandelkow E, von Bergen M, Biernat J, Mandelkow EM. 2007. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 17(1):83-90.
  250. Stößt sich an den Armlehnen hoch.
  251. Studie bereit erklärt haben. Ohne sie wäre diese Arbeit nicht möglich gewesen.
  252. Weiß C. 2010. Studien zu Diagnostik und Prävention. In: Weiß C, editor. Basiswissen Medizinische Statistik. Heidelberg: Springer Medizin Verlag. p 287-302.
  253. Wilson SS, Guillan RA, Hocker EV. 1972. Studies of the stability of 18 chemical constituents of human serum. Clin Chem 18(12):1498-1503.
  254. ANHANG Literaturverzeichnis XVII Maroteaux L, Campanelli JT, Scheller RH. 1988. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804- 2815.
  255. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. 2000. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20(9):3214-3220.
  256. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. 2002. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125(Pt 4):861-870.
  257. Mannisto T, Surcel HM, Bloigu A, Ruokonen A, Hartikainen AL, Jarvelin MR, Pouta A, Vaarasmaki M, Suvanto-Luukkonen E. 2007. The effect of freezing, thawing, and short-and long-term storage on serum thyrotropin, thyroid hormones, and thyroid autoantibodies: implications for analyzing samples stored in serum banks. Clin Chem 53(11):1986-1987.
  258. Lewczuk P, Kornhuber J, Wiltfang J. 2006. The German Competence Net Dementias: standard operating procedures for the neurochemical dementia diagnostics. J Neural Transm 113(8):1075-1080.
  259. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. 2002. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277(3):1641-1644.
  260. Hanley JA, McNeil BJ. 1982. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143(1):29-36.
  261. Langston JW. 2006. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59(4):591-596.
  262. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T. 1995. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14(2):467-475.
  263. Greffard S, Verny M, Bonnet A, Seilhean D, Hauw J, Duyckaerts C. 2008. The proportion of neurons containing Lewy bodies remains stable with time in the substantia nigra. A proposed model of neuronal death in relation to Lewy bodies. Clin Neuropathol 27:179.
  264. Mouthon L, Lacroix-Desmazes S, Nobrega A, Barreau C, Coutinho A, Kazatchkine MD. 1996. The self-reactive antibody repertoire of normal human serum IgM is acquired in early childhood and remains conserved throughout life. Scand J Immunol 44(3):243-251.
  265. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. 2008. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord 23(6):837-844.
  266. Lavedan C. 1998. The synuclein family. Genome Res 8(9):871-880.
  267. Dimitrov JD, Lacroix-Desmazes S, Kaveri SV, Vassilev TL. 2007. Transition towards antigen-binding promiscuity of a monospecific antibody. Mol Immunol 44(8):1854-1863.
  268. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. 2002. Treatment interventions for Parkinson's disease: an evidence based assessment. Lancet 359(9317):1589- 1598.
  269. Abb. 29: Two-Graph-ROC Analyse. A: IPS-Patienten vs. gesunde Kontrollen.
  270. Fahn S, Elton R, UPDRS pm. 1987. Unified Parkinsons Disease Rating Scale. In: Fahn S, Marsden C, Goldstein M, Calne D, editors. Recent developments in Parkinson's disease. Florham Park, NJ: Macmillan Healthcare Information. p 153-163.
  271. Schulz JB. 2008. Update on the pathogenesis of Parkinson's disease. J Neurol 255 Suppl 5:3-7.
  272. Findlay JW, Smith WC, Lee JW, Nordblom GD, Das I, DeSilva BS, Khan MN, Bowsher RR. 2000. Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective. J Pharm Biomed Anal 21(6):1249-1273.
  273. Bolelli G, Muti P, Micheli A, Sciajno R, Franceschetti F, Krogh V, Pisani P, Berrino F. 1995. Validity for epidemiological studies of long-term cryoconservation of steroid and protein hormones in serum and plasma. Cancer Epidemiol Biomarkers Prev 4(5):509-513.
  274. Sanz I, Dang H, Takei M, Talal N, Capra JD. 1989. VH sequence of a human anti-Sm autoantibody. Evidence that autoantibodies can be unmutated copies of germline genes. J Immunol 142(3):883-887.
  275. Duda JE, Giasson BI, Chen Q, Gur TL, Hurtig HI, Stern MB, Gollomp SM, Ischiropoulos H, Lee VM, Trojanowski JQ. 2000. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol 157(5):1439-1445.
  276. Volles MJ, Lansbury PT, Jr. 2003. Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42(26):7871-7878.
  277. Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, Brundin P. 2010. Characterization of Lewy body pathology in 12-and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov Disord 25(8):1091-1096.
  278. Marder K, Levy G, Louis ED, Mejia-Santana H, Cote L, Andrews H, Harris J, Waters C, Ford B, Frucht S, Fahn S, Ottman R. 2003. Familial aggregation of early-and late-onset Parkinson's disease. Ann Neurol 54(4):507-513.
  279. Brucale M, Sandal M, Di Maio S, Rampioni A, Tessari I, Tosatto L, Bisaglia M, Bubacco L, Samori B. 2009. Pathogenic mutations shift the equilibria of alpha-synuclein single molecules towards structured conformers. Chembiochem 10(1):176-183.
  280. Hawkes CH. 2008. The prodromal phase of sporadic Parkinson's disease: does it exist and if so how long is it? Mov Disord 23(13):1799-1807.
  281. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. 1989. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1(8649):1269.
  282. Zucca FA, Giaveri G, Gallorini M, Albertini A, Toscani M, Pezzoli G, Lucius R, Wilms H, Sulzer D, Ito S, Wakamatsu K, Zecca L. 2004. The neuromelanin of human substantia nigra: physiological and pathogenic aspects. Pigment Cell Res 17(6):610-617.
  283. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O. 1998. Ala30Pro mutation in the gene encoding alpha- synuclein in Parkinson's disease. Nat Genet 18(2):106-108.
  284. Shulman JM, De Jager PL, Feany MB. 2011. Parkinson's disease: genetics and pathogenesis. Annu Rev Pathol 6:193-222.
  285. Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J 17(13):1945-1947.
  286. FDA. 2009. Guidance for Industry: Guidances for the Validation of Analytical Methods Used in Residue Depletion Studies. U.S. Department of Health and Human Services (Hrsg). Rockville: Food and Drug Administration (FDA). http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcem ent/GuidanceforIndustry/UCM207942.pdf (Zugriff am 08.09.2011)
  287. FDA. 2005. Guidance for Industry: Pharmacogenomic Data Submissions. U.S. Department of Health and Human Services (Hrsg.). Rockville: Food and Drug Administration (FDA). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio n/Guidances/ucm079849.pdf (Zugriff am 08.09.2011)
  288. Schlossmacher MG, Mollenhauer B. 2010. Biomarker research in Parkinson's disease: objective measures needed for patient stratification in future cause-directed trials. Biomark Med 4(5):647-650.
  289. ANHANG Literaturverzeichnis XXIV Uversky VN, Li J, Fink AL. 2001. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. J Biol Chem 276(47):44284-44296.
  290. Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F, Andrei-Selmer LC, Roskam S, Stuer C, Al-Abed Y, Noelker C, Balzer-Geldsetzer M, Oertel W, Du Y, Bacher M. 2011. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease. J Neurosci 31(15):5847-5854.
  291. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. 1997. Alpha-synuclein in Lewy bodies. Nature 388(6645):839-840.
  292. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. 1999. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173-177.
  293. Goldberg MS, Lansbury PT, Jr. 2000. Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nat Cell Biol 2(7):E115- 119.
  294. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T. 2002. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4(2):160-164.
  295. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. 2008. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 14(5):504-506.
  296. Cowchock S, Fort J, Munoz S, Norberg R, Maddrey W. 1988. False positive ELISA tests for anticardiolipin antibodies in sera from patients with repeated abortion, rheumatologic disorders and primary biliary cirrhosis: correlation with elevated polyclonal IgM and implications for patients with repeated abortion. Clin Exp Immunol 73(2):289-294.
  297. Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A, Kalofoutis A, Buchman VL. 2007. Autoantibodies to alpha- synuclein in inherited Parkinson's disease. J Neurochem 101(3):749-756.
  298. Towbin H, Staehelin T, Gordon J. 1979. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76(9):4350-4354.
  299. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. 1993. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 90(23):11282-11286.
  300. Marek K, Innis R, van Dyck C, Fussell B, Early M, Eberly S, Oakes D, Seibyl J. 2001. [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson's disease progression. Neurology 57(11):2089-2094.
  301. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT, Jr. 2000. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci U S A 97(2):571- 576.
  302. Mohammad K, Esen A. 1989. A blocking agent and a blocking step are not needed in ELISA, immunostaining dot-blots and western blots. J Immunol Methods 117(1):141-145.
  303. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. 1973. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20(4):415-455.
  304. Borghi R, Marchese R, Negro A, Marinelli L, Forloni G, Zaccheo D, Abbruzzese G, Tabaton M. 2000. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci Lett 287(1):65-67.
  305. Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, Blennow K, Zetterberg H. 2009. Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss? Neurosci Lett 450(3):332-335.
  306. Betz JM, Brown PN, Roman MC. 2011. Accuracy, precision, and reliability of chemical measurements in natural products research. Fitoterapia 82(1):44-52.
  307. Notkins AL. 2004. Polyreactivity of antibody molecules. Trends Immunol 25(4):174-179.
  308. ANHANG Literaturverzeichnis XI Eriksen JL, Przedborski S, Petrucelli L. 2005. Gene dosage and pathogenesis of Parkinson's disease. Trends Mol Med 11(3):91-96.
  309. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. 1997. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276(5321):2045-2047.
  310. Boyd JC. 1997. Mathematical tools for demonstrating the clinical usefulness of biochemical markers. Scand J Clin Lab Invest Suppl 227:46-63.
  311. Giasson BI, Murray IV, Trojanowski JQ, Lee VM. 2001. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J Biol Chem 276(4):2380-2386.
  312. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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(15):8850-8855.


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