Role of cerebrospinal fluid biomarkers in clinical trials for Alzheimer's disease modifying therapies

Korean Journal of Physiology and Pharmacology

Volumn 18, Issue 6, 2014, Pages 447-456

  Kang, Ju Hee ^a,c   Ryoo, Na Young ^a   Shin, Dong Wun ^b   Trojanowski, John Q ^c   Shaw, Leslie M ^c  

^a Inha University School of Medicine   (South Korea)

^b Inje University   (South Korea)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

A 1 42; Alzheimer's disease; Cerebrospinal fluid biomarker; Clinical trial; Tau

Indexed keywords

AD 02; ADVANCED GLYCATION END PRODUCT RECEPTOR; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; AMYLOID BETA PROTEIN[25-35]; AMYLOID PRECURSOR PROTEIN; AVAGACESTAT; BAPINEUZUMAB; BEGACESTAT; BETA SECRETASE; BETA SECRETASE INHIBITOR; BIOLOGICAL MARKER; ELND 005; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IMMUNOGLOBULIN; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; MONOCLONAL ANTIBODY; NIC 515; NOOTROPIC AGENT; PF 3804014; PIOGLITAZONE; ROSIGLITAZONE; SEMAGACESTAT; SOLANEZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; V 950; VANUTIDE CRIDIFICAR;

ACTIVE IMMUNIZATION; ALZHEIMER DISEASE; AMYLOID PLAQUE; ARTICLE; BLOOD BRAIN BARRIER; CEREBROSPINAL FLUID LEVEL; CLINICAL TRIAL (TOPIC); DISABILITY; DISEASE ASSESSMENT; DRUG TARGETING; EARLY DIAGNOSIS; HUMAN; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROPATHOLOGY; NONHUMAN; OLIGOMERIZATION; PASSIVE IMMUNIZATION; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN CEREBROSPINAL FLUID LEVEL; PROTEIN PHOSPHORYLATION; SENSITIVITY AND SPECIFICITY; TANDEM MASS SPECTROMETRY;

EID: 84921499885     PISSN: 12264512     EISSN: 20933827     Source Type: Journal    
DOI: 10.4196/kjpp.2014.18.6.447     Document Type: Article

References (90)

1. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734-746.
2. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010;9:1118-1127.
3. Albert MS, De Kosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. 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;7:270-279.
4. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. 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;7:263-269.
5. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228-234.
6. Herukka SK, Helisalmi S, Hallikainen M, Tervo S, Soininen H, Pirttilä T. CSF Abeta42, Tau and phosphorylated Tau, APOE epsilon4 allele and MCI type in progressive MCI. Neurobiol Aging. 2007;28:507-514.
7. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ. Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009;65:403-413.
8. De Meyer G, Shapiro F, Vanderstichele H, Vanmechelen E, Engelborghs S, De Deyn PP, Coart E, Hansson O, Minthon L, Zetterberg H, Blennow K, Shaw L, Trojanowski JQ; Alzheimer's Disease Neuroimaging Initiative. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010;67:949-956.
9. Buchhave P, Minthon L, Zetter Berg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β-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.
10. Palmqvist S, Hertze J, Minthon L, Wattmo C, Zetterberg H, Blennow K, Londos E, Hansson O. Comparison of brief cognitive tests and CSF biomarkers in predicting Alzheimer's disease in mild cognitive impairment: six-year follow-up study. PLoS One. 2012;7:e38639.
11. Yoshiyama Y, Lee VM, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry. 2013;84:784-795.
12. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007;3:186-191.
13. Scott TJ, O'Connor AC, Link AN, Beaulieu TJ. Economic analysis of opportunities to accelerate Alzheimer's disease research and development. Annals of the New York Academy of Sciences. 2014;1313:Annals Reports pages 17-34.
14. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study Steering Committee, Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369:341-350.
15. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69:1430-1440.
16. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012;51:681-693.
17. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC. Multicenter, randomized, doubleblind, placebo-controlled, single-ascending dose study of the oral Y-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012;34:654-667.
18. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci. 2003;23:7504-7509.
19. Escribano L, Simón AM, Gimeno E, Cuadrado-Tejedor M, López de Maturana R, García-Osta A, Ricobaraza A, Pérez-Mediavilla A, Del Río J, Frechilla D. Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology. 2010;35:1593-1604.
20. Landreth G, Jiang Q, Mandrekar S, Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics. 2008;5:481-489.
21. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-tomoderate Alzheimer's disease. Pharmacogenomics J. 2006;6:246-254.
22. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebocontrolled phase III study. Dement Geriatr Cogn Disord. 2010;30:131-146.
23. l8F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis. 2010;22:1241-1256.
24. Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011;8:592-606.
25. Geldmacher DS1, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol. 2011;68:45-50.
26. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32:1626-1633.
27. Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 2001;24:219-224.
28. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353-356.
29. Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, Duong A, Suhy J, Oh J, Lau WC, Sampalis J. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, doubleblind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci. 2011;7:102-111.
30. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham KJ, Bush AI. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008;59:43-55.
31. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008;7:779-786.
32. McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, St George-Hyslop P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006;12:801-808.
33. Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J. Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease. Eur J Neurosci. 2010;31:203-213.
34. Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S, Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak A, Cedarbaum JM; ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77:1253-1262.
35. Fukumoto H, Tokuda T, Kasai T, Ishigami N, Hidaka H, Kondo M, Allsop D, Nakagawa M. High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J. 2010;24:2716-2726.
36. Yang T, Hong S, O'Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF. Alzheimers Dement. 2013;9:99-112.
37. Savage MJ, Kalinina J, Wolfe A, Tugusheva K, Korn R, Cash-Mason T, Maxwell JW, Hatcher NG, Haugabook SJ, Wu G, Howell BJ, Renger JJ, Shughrue PJ, McCampbell A. A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid. J Neurosci. 2014;34:2884-2897.
38. Lame ME, Chambers EE, Blatnik M. Quantitation of amyloid beta peptides Aβ (1-38), Aβ (1-40), and Aβ (1-42) in human cerebrospinal fluid by ultra-performance liquid chromatographytandem mass spectrometry. Anal Biochem. 2011;419:133-139.
39. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss (1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106:1489-1499.
40. Deane R, Du Yan S, Submamaryan RK, La Rue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907-913.
41. Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Münch G. Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiol Aging. 2011;32:763-777.
42. Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014;82:1536-1542.
43. Miners JS, Barua N, Kehoe PG, Gill S, Love S. Aβ-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol. 2011;70:944-959.
44. Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ. Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer's disease? J Neurochem. 2012;120 Suppl 1:167-185.
45. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46-54.
46. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012;11:597-604.
47. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M; Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061-2070.
48. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E; AAB-001 201/202 Investigators. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol. 2012;69:1002-1010.
49. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebocontrolled, ascending-dose study. Lancet Neurol. 2010;9:363-372.
50. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR; Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-tomoderate Alzheimer's disease. N Engl J Med. 2014;370:322-333.
51. Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, De Mattos RB, Mohs R, Paul SM, Siemers ER. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement. 2012;8:261-271.
52. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370:311-321.
53. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795-804.
54. Worley S. After disappointments, Alzheimer's researchers seek out new paths: biomarkers and combination therapies may lead to disease-modifying treatments, experts say. P T. 2014;39:365-374.
55. National Institute on Aging. Preventing Alzheimer's disease; What do we know? http://www.nia.nih.gov/alzheimers/publication/preventing-alzheimers-disease/introduction
56. Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004;75:1472-1474.
57. Fillit H, Hess G, Hill J, Bonnet P, Toso C. IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders. Neurology. 2009;73:180-185.
58. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009;30:1728-1736.
59. Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Haag S, Wietek S, Farlow M, Jessen F. Intravenous immunoglobulin for treatment of mild-tomoderate Alzheimer's disease: a phase 2, randomised, doubleblind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013;12:233-243.
60. Weill Cornell Medical College. Updated results from phase 3 trial of IVIG for Alzheimer's disease. http://www.sciencedaily.com/releases/2013l07/130716092743.htm.
61. Knight EM, Gandy S. Immunomodulation and AD-down but not out. J Clin Immunol. 2014;34 Suppl 1: S70-73.
62. Lee VM, Brunden KR, Hutton M, Trojanowski JQ. Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med. 2011;1:a006437.
63. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. 2009;15:112-119.
64. Jin N, Kovacs AD, Sui Z, Dewhurst S, Maggirwar SB. Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun. expression and neuronal cell death. Neuropharmacology. 2005;48:576-583.
65. Profenno LA, Jakimovich L, Holt CJ, Porsteinsson A, Tariot PN. A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Curr Alzheimer Res. 2005;2:553-558.
66. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebocontrolled, multicenter 10-week study. J Clin Psychiatry. 2009;70:922-931.
67. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-356.
68. Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, Clarimón J, Lleó A, Gómez-Isla T. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35:359-367.
69. del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, León T. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33:205-215.
70. Wischik CM, Bentham P, Wischik DJ, Seng KM. Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks. Alzheimers Dement. 2008;4 Suppl 2: T167.
71. Schmechelemail DE, Gerard G, Vatakis NG, Harper L, Ross JS, Bari M, Walling D, Stedman M, Winston JL, Morimoto B, Keith JR. A phase 2, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Alzheimers Dement. 2008;4(4 Suppl 2):T483.
72. Kang JH, Korecka M, Toledo JB, Trojanowski JQ, Shaw LM. Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β (1-42) and t proteins as Alzheimer disease biomarkers. Clin Chem. 2013;59:903-916.
73. Shaw LM, Vanderstichele H, Knapik-Czajka M, Figurski M, Coart E, Blennow K, Soares H, Simon AJ, Lewczuk P, Dean RA, Siemers E, Potter W, Lee VM, Trojanowski JQ; Alzheimer's Disease Neuroimaging Initiative. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 2011;121:597-609.
74. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Shen L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ; Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement. 2013;9:e111-194.
75. Cui Y, Liu B, Luo S, Zhen X, Fan M, Liu T, Zhu W, Park M, Jiang T, Jin JS; Alzheimer's Disease Neuroimaging Initiative. Identification of conversion from mild cognitive impairment to Alzheimer's disease using multivariate predictors. PLoS One. 2011;6:e21896.
76. Hinrichs C, Singh V, Xu G, Johnson SC; Alzheimers Disease Neuroimaging Initiative. Predictive markers for AD in a multi-modality framework: an analysis of MCI progression in the ADNI population. Neuroimage. 2011;55:574-589.
77. Zhang D, Shen D; Alzheimer's Disease Neuroimaging Initiative. Predicting future clinical changes of MCI patients using longitudinal and multimodal biomarkers. PLoS One. 2012;7:e33182.
78. Lista S, Garaci FG, Ewers M, Teipel S, Zetterberg H, Blennow K, Hampel H. CSF Aβ1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease. Alzheimers Dement. 2014;10:381-392.
79. Mattsson N, Zetterberg H. What is a certified reference material? Biomark Med. 2012;6:369-370.
80. Mattsson N, Andreasson U, Persson S, Carrillo MC, Collins S, Chalbot S, Cutler N, Dufour-Rainfray D, Fagan AM, Heegaard NH, Robin Hsiung GY, Hyman B, Iqbal K, Lachno DR, Lleó A, Lewczuk P, Molinuevo JL, Parchi P, Regeniter A, Rissman R, Rosenmann H, Sancesario G, Schröder J, Shaw LM, Teunissen CE, Trojanowski JQ, Vanderstichele H, Vandijck M, Verbeek MM, Zetterberg H, Blennow K, Käser SA; Alzheimer's Association QC Program Work Group. CSF biomarker variability in the Alzheimer's Association quality control program. Alzheimers Dement. 2013;9:251-261.
81. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119-128.
82. Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M; AN1792 (QS-21) -201 Study. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005;64:1563-1572.
83. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebocontrolled phase I trial. Lancet. 2008;372:216-223.
84. Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M; AN1792 (QS-21) -251 Study Team. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res. 2009;6:144-151.
85. Ereshefsky L, Jhee SS, Yen M, Moran SV. The role for CSF dynabridging studies in developing new therapies for Alzheimer's disease. Alzheimers Dement. 2009;5 Suppl 4: P414-415.
86. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, Ivnik RJ, Tangalos EG, Boeve BF, Knopman DS, Braak H, Petersen RC. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol. 2006;63:674-681.
87. Okonkwo OC, Mielke MM, Griffith HR, Moghekar AR, O'Brien RJ, Shaw LM, Trojanowski JQ, Albert MS; Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid profiles and prospective course and outcome in patients with amnestic mild cognitive impairment. Arch Neurol. 2011;68:113-119.
88. van Rossum IA, Vos S, Handels R, Visser PJ. Biomarkers as predictors for conversion from mild cognitive impairment to Alzheimer-type dementia: implications for trial design. J Alzheimers Dis. 2010;20:881-891.
89. Holland D, McEvoy LK, Desikan RS, Dale AM; Alzheimer's Disease Neuroimaging Initiative. Enrichment and stratification for predementia Alzheimer disease clinical trials. PLoS One. 2012;7:e47739.
90. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385-393.