Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?

Journal of Alzheimer's Disease

Volumn 15, Issue 2, 2008, Pages 303-325

  Becker, Robert E ^a,c   Greig, Nigel H ^a   Giacobini, Ezio ^b  

^a NATIONAL INSTITUTE ON AGING   (United States)

^b UNIVERSITY OF GENEVA MEDICAL SCHOOL   (Switzerland)

^c NONE   (United States)

Author keywords

Alzheimer's disease; Bias; Biomarkers; Clinical trials; Errors

Indexed keywords

3 METHYL 5 (1 METHYL 2 PYRROLIDINYL)ISOXAZOLE; 6 QUINOXALINECARBOXYLIC ACID PIPERIDIDE; ACETYLSALICYLIC ACID; ALPHA TOCOPHEROL; ALVAMELINE; AMIRIDINE; ASCORBIC ACID; CELECOXIB; CEREBROLYSIN; DOCOSAHEXAENOIC ACID; DONEPEZIL; ESTROGEN; GALANTAMINE; HOMOTAURINE; HUPERZINE A; MEMANTINE; MILAMELINE; OXIRACETAM; PF 4494700; PIRACETAM; PROGESTERONE; PROPENTOFYLLINE; RIVASTIGMINE; ROFECOXIB; SABELUZOLE; TACRINE; THIOCTIC ACID; UBIQUINONE; UNINDEXED DRUG; ZIFROSILONE;

ALZHEIMER DISEASE; ANALYTICAL ERROR; CLINICAL PRACTICE; CLINICAL RESEARCH; CLINICAL TRIAL; COGNITIVE DEFECT; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG DOSE TITRATION; HUMAN; INFORMATION PROCESSING; NUCLEAR MAGNETIC RESONANCE IMAGING; OUTCOME ASSESSMENT; PHARMACOKINETICS; PLACEBO EFFECT; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; RATING SCALE; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY;

EID: 54249124057     PISSN: 13872877     EISSN: None     Source Type: Journal    
DOI: 10.3233/JAD-2008-15213     Document Type: Review

References (159)

1. ADAPT Research Group, C.G. Lyketsos, J.C. Breitner, R.C. Green, B.K. Martin, C. Meinert, S. Piantadosi and M. Sabbagh, Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial, Neurology 68 (2007), 1800-1808.
2. P.S. Aisen, K.A. Schafer, M. Grundman, E. Pfeiffer, M. Sano, K.L. Davis, M.R. Farlow, S. Jin, R.G. Thomas, L.J. Thal and the Alzheimer's Disease Cooperative Study, Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial, JAMA 289 (2003), 2819-2826.
3. P.S. Aisen, S. Gauthier, B. Vellas, R. Briand, D. Saumier, J. Laurin and D. Garceau, Alzhemed: a potential treatment for Alzheimer's disease, Curr Alzheimer Res 4 (2007), 473-478.
4. G.E. Alexander, K. Chen, P. Pietrini, S.I. Rapoport and E.M. Reiman, Longitudinal PET evaluation of cerebral metabolic decline in dementia: A potential outcome measure in Alzheimer's disease treatment studies, Am J Psychiatry 159 (2002), 738-745.
5. X.A. Alvarez, R. Cacabelos, M. Laredo, V. Couceiro, C. Sampedro, M. Varela, L. Corzo, L. Fernandez-Novoa, M. Vargas, M. Aleixandre, C. Linares, E. Granizo, D. Muresanu and H. Moessler, A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer's disease, Eur J Neurol 13 (2006), 43-45.
6. Alzheimer Research Forum, Drugs in Clinical Trials: Milameline, http://www.alzforum.org/drg/drc/detail.asp?id=75, Accessed April 4, 2008.
7. American Psychiatric Association (APA), Practice guidelines. Acute stress disorder and posttraumatic stress disorder, Amer J Psychiatry 161 (2004), Supplement.
8. C. Ballard, M. Margallo-Lana, E. Juszczak, S. Douglas, A. Swann, A. Thomas, J. O'Brien, A. Everratt, S. Sadler, C. Maddison, L. Lee, C. Bannister, R. Elvish and R. Jacoby, Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomized double blind placebo controlled trial, BMJ 330 (2005), 874-878.
9. R.E. Becker and E. Giacobini, Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological, and therapeutic aspects, Drug Dev Res 12 (1988), 163-195.
10. R. Becker, J. Colliver, R. Elble, E. Feldman, E. Giacobini, V. Kumar, S. Markwell, P. Moriearty, R. Parks, S. Shillcutt, L. Unni, S.Vicari, C.Womack and R. Zec, Effects of metifonate, a long acting cholinesterase inhibitor in Alzheimer disease: Report of an open trial, Drug Dev Res 9 (1990), 425-434.
11. R.E. Becker, Therapy of the cognitive deficit in Alzheimer's disease: the cholinergic system, in: Cholinergic Basis for Alzheimer Therapy, R. Becker and E. Giacobini, eds, Birkhauser, Boston, 1991, pp. 1-22.
12. R.E. Becker, J.A. Colliver, S.J. Markwell, P.L. Moriearty, L.K. Unni and S. Vicari, A double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer's disease, Alzheimer Dis Assoc Disord 10 (1996), 124-131.
13. R.E. Becker, J.A. Colliver, S.J. Markwell, P.L. Moriearty, L.K. Unni, A. Varney and S. Vicari, A six month study of the effects of metrifonate on cognitive decline in Alzheimer's disease, Alzheimer Dis Assoc Disord 12 (1998), 54-57.
14. R.E. Becker and S. Markwell, Problems arising from generalizing of treatment efficacy from clinical trials in Alzheimer's disease, Clin Drug Invest 19 (2000), 33-41.
15. R.E. Becker, Focusing pharmaceutical research on patient care: using clinical trials to develop clinical decision rules, Clin Drug Invest 22 (2002), 269-278.
16. R.E. Becker, Lessons from Darwin: Evolutionary biology implications for Alzheimer's disease research and patient care, Curr Alzheimer Res 2 (2005), 319-326.
17. R. E. Becker, Lessons from Darwin: 21st Century designs for clinical trials, Curr Alzheimer Res 4 (2007), 458-467.
18. R. Becker and N.H. Greig, Alzheimer's disease drug development in 2008 and beyond: problems and opportunities, Curr Alzheimer Res 5 (2008), 346-357.
19. Y. Beers, Introduction to the Theory of Error, Palo Alto: Addison-Wesley Publishing Co. Inc., 1959.
20. G. Bellilli, E. Lucchi, N. Minicuci, L. Rozzini, A. Bianchetti, A. Padovani and M. Trabucchi, Results of a multi-level therapeutic approach for Alzheimer's disease subjects in the "real world" (CRONOS project): a 36-week follow-up study, Aging Clin Exp Res 17 (2005), 54-61.
21. K. Blennow and H. Hampel, CSF markers for incipient Alzheimer's disease, Lancet Neurol 2 (2003), 605-613.
22. T.J. Bramley, P.P. Gerbino, B.S. Nightengale and F. Frech-Tamas, Relationship of blood pressure control to adherence with antihypertensive monotherapy in 13 managed care organizations, J Manag Care Pharm 12 (2006), 239-245.
23. M. Brys, E. Pirraglia, K. Rich, L. Mosconi, R. Switalski, L. Glodzik-Sobanska, S. De Santi, R. Zinkowski, P. Mehta, D. Pratico, L.A. Saint Louis, A. Wallin, K. Blennow and M. J. Leon, Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment, Neurobiol Aging (2007) e-pub ahead of print.
24. K. Buerger, M. Ewers, T. Pirttila, R. Zinkowski, I. Alafuzoff, S.J. Teipel, J. DeBernardis, D. Kerkman, C. McCulloch, H. Soininen and H. Hampel, CSF phosphorylated tau protein correlates with neurofibrillary pathology in Alzheimer's disease, Brain 129 (2006), 3035-3041.
25. J. Butcher, The hunt for drugs to modify Alzheimer's disease, Lancet Neurol 6 (2007), 1038-1039.
26. R.M. Califf, Simple principles of clinical trials remain powerful, JAMA 293 (2005), 489-491.
27. B.J. Carroll, Letter to Editor, Lancet 367 (2006), 1235-1236.
28. I. Chalmers, Underreporting research is scientific misconduct, JAMA 263 (1990), 1405-1408.
29. D. Chan, J.C. Janssen, J.L. Whitwell, H.C.Watt, R. Jenkins, C. Frost, M.N. Rossor and N.C. Fox, Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study, Lancet 362 (2003), 1121-1122.
30. Clinicalstudyresults.org, Protocol No.: GAL-INT-11, http://www. clinicalstudyresults.org/documents/company-study_961.pdf, Accessed April 4, 2008.
31. Clinicalstudyresults.org, Protocol No.: GAL-INT-18, http://www. clinicalstudyresults.org/documents/company-study_962.pdf, Accessed April 4, 2008.
32. ClinicalTrials.gov, Anti-oxidant treatment of Alzheimer's disease, http://clinicaltrials.gov/ct2/show/NCT00117403?term=vitamin+e++CoQ&rank=1, Last updated on November 20, 2007, Accessed on April 4, 2008.
33. ClinicalTrials.gov, DHA(docosahexaenoic acid), an omega 3 fatty acid, in slowing the progression of Alzheimer's disease, http://clinicaltrials.gov/ct2/ show/NCT00440050?term=Docosahexaenoic+Acid&rank=2, Last updated on February 28, 2008, Accessed on April 4, 2008.
34. ClinicalTrials.gov, Efficacy and safety of piracetam taken for 12 months in subjects suffering from mild cognitive impairment (MCI), http:// clinicaltrials.gov/ct2/show/NCT00567060?term=piracetam&rank=1, Last updated March 7, 2008, Accessed April 4, 2008.
35. ClinicalTrials.gov, Evaluation of 3APS in patients with mild to moderate Alzheimer's disease, http://clinicaltrials.gov/ct2/show/NCT00088673?term= tramiprosate&rank=2, Last updated on February 27, 2008, Accessed on April 4, 2008.
36. ClinicalTrials.gov, Huperzine A in Alzheimer's disease, http://clinicaltrials.gov/ct2/show/NCT00083590?term=HUPERZINE&rank=1, Last updated February 19, 2008, Accessed April 4, 2008.
37. ClinicalTrials.gov, Safety of TTP488 in patients with mild to moderate Alzheimer's disease, http://clinicaltrials.gov/ct2/show/NCT00141661?term= TTP+488&rank=2, Last updated June 25, 2007, Accessed on April 4, 2008.
38. Study evaluating safety, tolerability, and immunogenicity of ACC-001 in subjects with Alzheimer's disease, http:// clinicaltrials.gov/ct2/show/ NCT00479557?term=acc-001&rank=1, Last updated December 21, 2007, Accessed April 4, 2008.
39. ClinicalTrials.gov, Study evaluating the safety, tolerability and efficacy of PBT2 in patients with early Alzheimer's disease, http://clinicaltrials.gov/ct2/show/NCT00471211?term=PBT2&rank=1, Last updated January 13, 2008, Accessed on April 4, 2008.
40. K.O. Cogger, Rating rater improvement: a method for estimating increased effect size and reduction of clinical trial costs, J Clin Psychopharmacol 27 (2007), 418-420.
41. J.L. Cummings, Clinical evaluation as a biomarker for Alzheimer's disease, J Alzheimers Dis 8 (2005), 327-337.
42. N.R. Cutler, R.C. Shrotriya, J.J. Sramek, A.E. Veroff, R.D. Seifert, L.A. Reich and D.Y. Hironaka, The use of the Computerized Neuropsychological Test Battery (CNTB) in an efficacy and safety trial of BMY 21,502 in Alzheimer's disease, Ann N Y Acad Sci695 (1993), 332-336.
43. N.R. Cutler, R.D. Seifert, M.M. Schleman, J.J. Sramek, O.J. Szylleyko, D.R. Howard, A. Barchowsky, T.S. Wardle and E.P. Brass. Acetylcholinesterase inhibition by zilfrosilone: pharmacokinetics and pharmacodynamics, Clin Pharmacol Ther 58 (1995), 54-61.
44. K.L. Davis, L.J. Thal, E.R. Gamzu, C.S. Davis, R.F. Woolson, S.I. Gracon, D.A. Drachman, L.S. Schneider, P.J. Whitehouse, T.M. Hoover and The Tacrine Collaborative Study Group, Tacrine in patients with Alzheimer's disease: a double-blind placebo-controlled multicenter study, N Engl J Med 327 (1992), 1253-1259.
45. M.A. Demitrack, D. Faries, J.M. Herrera, D. DeBrota and W.Z. Potter, The problem of measurement error in multisite clinical trials, Psychopharmacol Bull 34 (1998), 19-24.
46. T. den Heijer, M.I. Geerlings, F.E. Hoebeek, A. Hofman, P.J. Koudstaal and M.M. Breteler, Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people, Arch Gen Psychiatry 63 2006), 57-62.
47. B. Dubois, H.H. Feldman, C. Jacova, S.T. DeKosky, P. Barberger-Gateau, J. Cummings, A. Delacourte, D. Galasko, S. Gauthier, G. Jicha, K. Meguro, J. O'Brien, F. Pasquier, P. Pobert, M. Rossor, S. Salloway, Y. Stern, P.J. Visser and P. Scheltens, Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6 (2007), 734-746.
48. R.H. Dworkin, J. Katz and M. J. Gitlin, Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain, Neurology 65 (2005), S17-S19.
49. S.B. Dybicz, D.J. Keohane, W.G. Erwin, T. McRae and S.N. Shah, Patterns of cholinesterase-inhibitor use in the nursing home setting: a retrospective analysis, Am J Geriatr Psychother 4 (2006), 154-160.
50. P.J. Easterbrook, J.A. Berlin, R. Gopalan and D.R. Mattews, Publication bias in clinical research, Lancet 337 (1991), 867-872.
51. P. Edison, H.A. Archer, R. Hinz, A. Hammers, N. Pavese, Y.F. Tai, G. Hotton, D. Cutler, N. Fox, A. Kennedy, M. Rossor and D.J. Brooks, Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study, Neurology 68 (2007), 501-508.
52. N. Engelhardt, A.D. Feiger, K.O. Cogger, D. Sikich, D.J. Derota, J.D. Lipsitz, K.A. Kobak, K.R. Evans and W.Z. Potter, Rating the Raters: Assessing the Quality of Hamilton Rating Scale for Depression Clinical Interviews in Two Industry-sponsored Clinical Drug Trials, J Clin Psychopharmacol 26 (2006), 71-74.
53. H. Engler, A. Forsberg, O. Almkvist, G. Blomquist, E. Larsson, I. Savitcheva, A. Wall, A. Ringheim, B. Langstrom and A. Nordberg, Two-year followup of amyloid deposition in patients with Alzheimer's disease, Brain 129 (2006), 2856-2866.
54. European Medicines Agency, EMEA/CHMP/EWP Workshop. Slowing the progression of neurodegenerative diseases: medicinal products clinical development, London: European Medicines Agency, Doc Ref. EMEA/512562/2006, 2006.
55. M. Farlow, S.I. Gracon, L.A. Hershey, K.W. Lewis, C.H. Sadowsky and J. Dolan-Ureno, A 12-week, double-blind, placebo-controlled, parallel-group study of tacrine in patients with probable Alzheimer's disease, JAMA 268 (1992), 2523-2529.
56. H. Feldman, S. Gauthier, J. Hecker, B. Vellas, P. Subbiah, E. Whalen and Donepezil MSAD Study Investigators Group, A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease, Neurology 57 (2001), 613-620.
57. H.H. Feldman, S. Ferris, B. Winblad, N. Sfikas, L. Mancione, Y. He, S. Tekin, A. Burns, J. Cummings, T. del Ser, J.-M. Ogogozo-M, H. Sauer, P. Scheltens, E. Scarpini, N. Herrmann, M. Farlow, S. Potkin, H.C. Charles, N.C. Fox and R. Lane, Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study, Lancet Neurol 6 (2007), 501-512.
58. S.H. Ferris, Are placebo controls still placebo controls? Neurobiol Aging 27(S1 Suppl) (2006), S29.
59. Food and Drug Administration, Guideline for the format and content of the clinical and statistical sections of new drug applications, FDA, US Department of Health and Human Services, Rockville, MD, USA (1989).
60. Forest Laboratories Clinical Trial Registry, Study No. MEMMD-01, http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf? file id=scsr/SCSRMEM-MD-01_final.pdf, Accessed April 4, 2008.
61. N. Foster, Imaging Advances for Early Detection and New Drug Assessment in Alzheimer's Disease, Nov 28, 2007, Clinical Neurosciences Center University of Utah.
62. N.L. Foster, J.L. Heidebrink, C.M. Clark, W.J. Jagust, S.E. Arnold, N.R. Barbas, C.S. DeCarli, R.S. Turner, R.A. Koeppe, R. Higdon and S. Minoshima, FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease, Brain 130 (2007), 2616-2635.
63. N.C. Fox, W.R. Crum, R.I. Scahill, J.M. Stevens, J.C. Janssen and M.N. Rosso, Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images, Lancet 358 (2001), 201-205.
64. N.C. Fox and J.M. Schott, Imaging cerebral atrophy: normal ageing to Alzheimer's disease, Lancet 363 (2004), 392-394.
65. M. Frampton, R.J. Harvey and V. Kirchner, Propentofyllin for dementia. Cochrane Database Syst Rev 2 (2003), CD002853.
66. G.B. Frisoni, P. Scheltens, S. Galluzzi, F.M. Nobili, N.C. Fox, P.H. Robert, H. Soininen, L.O. Wahlund, G. Waldemar and E. Salmon, Neuroimaging tools to rate regional atrophy, subcortical cerebrovascular disease, and regional cerebral blood flow and metabolism: consensus paper of the EADC, J Neurol Neurosurg Psychiatry 74 (2003), 1371-1381.
67. G.B. Frisoni, C. Testa, F. Sabattoli, A. Beltramello, H. Soininen and M.P. Laakso, Structural correlates of early and late onset Alzheimer's disease: voxel based morphometric study, J Neurol Neurosurg Psychiatry 76 (2005), 112-114.
68. D.R. Galasko, N. Graff-Radford, S. May, S. Hendrix, B.A. Cottrell, S.A. Sagi, G. Mather, M. Laughlin, K.H. Zavitz, E. Swabb, T.E. Golde, M.P. Murphy and E.H. Koo, Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals, Alzheimer Dis Assoc Disord 21 (2007), 292-299.
69. F. Gaultieri, D. Manetti, M.N. Romanelli and C. Ghelardini, Design and study of piracetam-like nootropics: controversial members of the problematic class of cognition-enhancing drugs, Curr Pharm Des 8 (2002), 125-138.
70. S. Gauthier and J. Touchon, Mild cognitive impairment is not a clinical entity and should not be treated, Arch Neurol 62 (2005), 1164-1166.
71. E. Giacobini and R.E. Becker, One hundred years after the discovery of Alzheimer's disease. A turning point for therapy? J Alzheimers Dis 12 (2007), 37-52.
72. C.B. Granger and J.J.V. McMurray, Using measures of disease progression to determine therapeutic effect: a Siren's song, J Am Coll Cardiol 48 (2006), 434-437.
73. M. Grundman, C.R. Jack, R.C. Petersen, H.T. Kim, C. Taylor, M. Datvian, M.F. Weiner, C. DeCarli, S.T. DeKosky, C. van Dyck, S. Darvesh, K. Yaffe, J. Kaye, S.H. Ferris, R.G. Thomas, L.J. Thal and The Alzheimer's Disease Cooperative Study, Hippocampal volume is associated with memory but not nonmemory cognitive performance in patients with mild cognitive impairment, J Mol Neurosci 20 (2003), 241-248.
74. M. Hallak and E. Giacobini, A comparison of the effects of two inhibitors on brain cholinesterase, Neuropharmacology 26 (1987), 521-530.
75. M. Hallak and E. Giacobini, Physostigmine, tacrine, and metrifonate: the effect of multiple doses on acetylcholine metabolism in rat brain, Neuropharmacology 28 (1989), 190-206.
76. M. Hamilton, A rating scale for depression. J Neurol Neurosurg Psychiatr 23 (1960), 56-62.
77. O. Hansson, H. Zeterberg, P. Buchhave, U. Andreasson, E. Londos, L. Minthon and K. Blennow, Prediction of Alzheimer's disease using the CSF Abeta42/Abeta40 ration in patients with mild cognitive impairments, Dement Geriatr Cogn Disord 23 (2007), 316-320.
78. J. Harrison, S.L. Minassian, L. Jenkins, R.S. Black, M.Koller and M. Grundman, A neuropsychological test battery for use in Alzheimer disease clinical trials, Arch Neurol 64 (2007), 1323-1329.
79. E.D. Huey, N. Mirza, K.T. Putnam, H. Soares, G. Csako, J.A. Levy, B. Copenhaver, R.M. Cohen and T. Sunderland, Stability of CSF beta-amyloid(1-42) and tau levels by APOE genotype in Alzheimer patients, Dement Geriatr Cogn Disord 22 (2006), 48-53.
80. Institute of Medicine, Committee on Treatment of Post Traumatic Stress Disorder, Treatment of Post Traumatic Stress Disorder, An Assessment of the Evidence, Washington (DC): The National Academies Press, 2007.
81. C.R. Jack Jr., R.C. Petersen, Y. Xu, P.C. O'Brien, G.E. Smith, R.J. Ivnik, B.F. Boeve, E.G. Tangalos and E. Kokmen, Rates of hippocampal atrophy correlate with change in clinical status in aging and AD, Neurology 55 (2000), 484-489.
82. C.R. Jack Jr., D.W. Dickson, J.E. Parisi, Y.C. Xu, R.H. Cha, P.C. O'Brien, S.D. Edland, G.E. Smith, B.F. Boeve, E.G. Tangalos, E. Kokmen and R.C. Petersen, Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia, Neurology 58 (2002), 750-757.
83. C.R. Jack Jr., M.M. Shiung, S.D. Weigand, P.C. O'Brien, J.L. Gunter, B.F. Boeve, D.S. Knopman, G.E. Smith, R.J. Ivnik, E.G. Tangalos and R.C. Petersen, Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI, Neurology 65 (2005), 1227-1231.
84. C.R. Jack Jr., S.D. Weigand, M.M. Shiung, S.A. Przybelski, P.C. O'Brien, J.L. Gunter, D.S. Knopman, B.F. Boeve, G.E. Smith and R.C. Petersen, Atrophy rates accelerate in amnestic mild cognitive impairment, Neurology (2007), in press.
85. W. Jagust, R. Thisted, M.D. Devous Sr., R. Van Heertum, H. Mayberg, K. Jobst, A.D. Smith and N. Borys, SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study, Neurology 56 (2001), 950-956.
86. V. Jelic, Clinical trials in MCI and what we have learned, Neurobiol Aging 27(S1: Suppl) (2006), S47.
87. J.H. Kang, N. Cook, J. Manson, J.E. Buring and F. Grodstein, Lowdose aspirin and cognitive function in the women's health study cognitive cohort, BMJ 334 (2007), 987-994.
88. K. Kantarci and C.R. Jack, Neuroimaging in Alzheimer disease: an evidence-based review, Neuroimaging Clin N Am 13 (2003), 197-209.
89. R. Katz, FDA evidentiary standards for drug development and approval, NeuroRx 1 (2004), 307-316.
90. G.J. Kelloff, R.C. Bast, D.S. Cofffey, A.V. D'Amico, R.S. Kerbel, J.W. Park, R.W. Ruddon, G.J.S. Rustin, R.L. Schilsky, C.C. Sigman and G.F.V. Woude, Biomarkers, surrogate end points, and the acceleration of drug development for cancer prevention and treatment: an update, Clin Cancer Res 10 (2004), 3881-3884.
91. D.M. Kent and R.A. Hayward, Limitations of applying summary results of clinical trials to individual patients, JAMA 298 (2006), 1209-1212.
92. A. Khan, R.M. Leventhal, S.R. Khan and W.A. Brown. Severity of depression and response to antidepressants and placebo: analysis of the Food and Drug Administration database, J Clin Psychopharmacol 22 (2002), 40-45.
93. J. Kim, L. Onstead, S. Randle, R. Price, L. Smithson, C. Zwizinski, D.W. Dickson, T. Golde and E. McGowan, Abeta40 inhibits amyloid deposition in vivo, J Neurosci 17 (2007), 627-633.
94. W.E. Klunk, H. Engler, A. Nordberg, Y.Wang, G. Blomqvist, D.P. Holt, M. Bergström, I. Savitcheva, G.F. Huang, S. Estrada, B. Ausén, M.L. Debnath, J. Barletta, J.C. Price, J. Sandell, B.J. Lopresti, A. Wall, P. Koivisto, G. Antoni, C.A. Mathis and B. Långström, Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B, Ann Neurol 55 (2004), 306-319.
95. K.A. Kobak, J.D. Lipsitz and A. Feiger, Development of a standardized training program for the Hamilton Depression Scale using internet-based technologies: results from a pilot study, J Psychiatr Res 37 (2003), 509-515.
96. K.A. Kobak, J.D. Lipsitz, J.B. Williams, N. Engelhardt and K.N. Bellew, A new approach to rater training and certification in a multicenter clinical trial, J Clin Psychopharmacol 25 (2005), 407-412.
97. K.A. Kobak, D.J. DeBrota, N. Engelhardt and J.B.W. Williams, Site vs. centralized raters in a clinical depression trial, National Institute of Mental Health, New Clinical Drug Evaluation Unit, 46th Annual Meeting, Boca Raton, Fl. (2006, June).
98. K.A. Kobak, N. Engelhardt and J.D. Lipsitz, Enriched rater training using Internet-based technologies: a comparison to traditional rater training, J Psychiatr Res 3 (2006), 192-199.
99. K.A. Kobak, J.M. Kane, T.E. Thase and A.A. Nierenberg, Reply to comments by Drs Rickels and Robinson, J Clin Psychopharmacol 27 (2007), 421.
100. J. Kralawish, Alzheimer's disease - clinical trials and logic of clinical purpose, N Engl J Med 355 (2006), 1604-1605.
101. M.O. Kwon and P. Herrling, List of drugs in development for neurodegenerative diseases, Neurodegener Dis 2 (2005), 61-108.
102. J.M. Lachin, The role of measurement reliability in clinical trials, Clin Trials 1 (2004), 553-566.
103. A.C. Leon, P.M. Marzuk and L. Portera, More reliable outcome measures can reduce sample size requirements, Arch Gen Psychiatry 52 (1995), 867-871.
104. L.J. Lesko and A.J. Atkinson, Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies, Ann Rev Pharmacol Toxicol 41 (2001), 347-366.
105. O.L. Lopez, A.A. Swihart, J.T. Becker, O.M. Reinmuth, C.F. Reynolds, D.L. Rezek and F.L. Daly, Reliability of NINCDS-ADRDA clinical criteria for the diagnosis of Alzheimer's disease, Neurology 40 (1990), 1517-1522.
106. R.B. Mani, The evaluation of disease modifying therapies in Alzheimer's disease: a regulatory viewpoint, Stat Med 23 (2004), 305-314.
107. J. Marcusson, M. Rother, B. Kittner, M. Rössner, B.J. Smith, T. Babic, V. Folnegovic-Smalc, H.J. Möller and K.H. Labs, A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-R. The European Propentofylline Study Group, Dement Geriatr Cogn Disord 8 (1997), 320-328.
108. M. Mazza, A. Capuano, P. Bria and S. Mazza, Ginkgo bilboa and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study, Eur J Neurol 13 (2006), 981-985.
109. S. Minoshima, B. Giordani, S. Berent, K.A. Frey, N.L. Foster and D.E. Kuhl, Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease, Ann Neurol 42 (1997), 85-94.
110. E. Mohr, N.P. Nair, M. Sampson, S. Murtha, G. Belanger, B. Pappas and T. Mendis, Treatment of Alzheimer's disease with sabeluzole: functional and structural correlates, Clin Neuropharmacol 20 (1997), 338-345.
111. G. Molenberghs, T. Burzykowski, A. Alonso and M. Buyse. Stat Methods Med Res 13 (2004), 177-206.
112. M.D.J.M. Moreno, Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, doubleblind, randomized, placebo-controlled trial, Clin Ther 25 (2003), 178-193.
113. F. Mori, G. Cuadra and E. Giacobini, Metrifonate effects on acetylcholine and biogenic amines in rat cortex, Neurochem Res 20 (1995), 1081-1088.
114. M.J. Muller and A. Szegedi, Effects of interrater reliability of psychopathologic assessments on power and sample size calculations in clinical trials, J Clin Psychopharmacol 22 (2002), 318-325.
115. A. Nordberg, PET imaging of amyloid in Alzheimer's disease, Lancet Neurol 3 (2004), 519-527.
116. Nordic Council on Medicines, Good clinical trial practice: Nordic Guidelines, NLN Publication No. 28, Uppsala, Sweden, 1989.
117. M.N. Pangalos, L.E. Schechter and O. Hurko, Drug development for CNS disorders: strategies for balancing risk and reducing attrition, Nat Rev Drug Discov 6 (2007), 521-532.
118. B.M. Patsy, N.S. Weiss, C.D. Furberg, T.D. Koepsell, D.S. Siscovick, F.R. Rosendaal, N.L. Smith, S.R. Heckbert, R.C. Kaplan, D. Lin, T.R. Fleming and E.H. Wagner, Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors in cardiovascular disease, JAMA 282 (1999), 786-790.
119. D.O. Perkins, R.J. Wyatt and J.J. Bartko, Penny-wise and pound-foolish: the impact of measurement error on sample size requirements in clinical trials, Biol Psychiatry 47 (2000), 762-766.
120. R.C. Petersen and J.C. Morris, Mild cognitive impairment as a clinical entity and treatment target, Arch Neurol 62 (2005), 1160-1163.
121. R.C. Petersen, R.G. Thomas, M. Grundman, D. Bennett, R. Doody, S. Ferris, D. Galasko, S. Jin, J. Kaye, A. Levey, E. Pfeiffer, M. Sano, C.H. van Dyck, L.J. Thal and Alzheimer's Disease Cooperative Study Group, ViPamin E and donepezil for thE treatment of mild cognitive impairment, N Engl J Med 352 (2005), 2379-2388.
122. R.C. Petersen, MCI treatment trials: failure or not? Lancet Neurol 6 (2007), 473-475.
123. T. Pincus and C.M. Stein, Why randomized controlled clinical trials do not depict accurately long-term outcomes in rheumatoid arthritis: some explanations and suggestions for future studies, Clin Exp Rheumatol 15 (1997), S27-S38.
124. A. Potter, J. Corwin, J. Lang, M. Piasecki, R. Lenox and P.A. Newhouse, Acute effects of the selective cholinergic channel activator (nicotinic agonist)ABT-418 in Alzheimer's disease, Psychopharmacol 142 (1999), 334-342.
125. N.N. Qureshi, J. Hatcher, N. Chaturvedi and T.H. Jafar, Hypertension Research Group. Effect of general practitioner education on adherence to antihypertensive drugs: cluster randomized controlled trail, BMJ 335 (2007), 1030-1037.
126. R. Raschetti, E. Albanese, N. Vanacore and M. Maggini, Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomized trials, Plos Medicine 4 (2007), 1818-1828.
127. B. Reisberg, R. Doody, A. Stoffler, F. Schmitt, S. Ferris and H.J. Mobius, for the Memantine Study Group, Mematine in moderate-to-severe Alzheimer's disease, N Engl J Med 348 (2003), 1333-1341.
128. S.M. Resnick, L.H. Coker, P.M. Maki, S.R. Rapp, M.A. Espeland and S.A. Shumaker, The Women's Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline, Clin Trials 1 (2004), 440-450.
129. M.W. Rich, From clinical trials to clinical practice, JAMA 287 (2002), 1321-1323.
130. K. Rickels and D.S. Robinson, Why do clinical trials fail? J Clin Psychopharmacol 27 (2007), 420-421.
131. Royal Society of Chemistry, Drugs for dementia, http://www.rsc.org/ Education/EiC/issues/2007Jan/DrugsDementia.asp, Accessed April 4, 2008.
132. S. Salloway, S. Ferris, A. Kluger, R. Goldman, T. Griesing, D. Kumar and S. Richardson, for the Donepezil "401" Study Group, Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial, Neurology 63 (2004), 651-657.
133. M. Sano, C. Ernesto, R.G. Thomas, M.R. Klauber, K. Schafer, M. Grundman, P. Woodbury, J. Growdon, C.W. Cotman, E. Pfeiffer and L.S. Schneider, A controlled trial of selegilene, alpha-tocopherol, or both as treatment for Alzheimer's disease, N Engl J Med 336 (1997), 1216-1222.
134. P. Scheltens, N. Fox, F. Barkhof and C. De Carli, Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion, Lancet Neurol 1 (2002), 13-21.
135. R. Schmidt, A. Lechner and K. Petrovic, Rivastigmine in outpatient services: experience of 114 neurologists in Austria, Int Clin Psychopharmacol 17 (2002), 81-85.
136. L.S. Schneider, Relevance of clinical trials: can new strategies offer more? Neurobiol Aging 27(S1 Suppl) (2006), S76.
137. A.H. Simonsen, J. McGuire, V.N. Podust, N.O. Hagnelius, T.K. Nilsson, E. Kapaki, D. Vassilopoulos and G. Waldemar, A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer's disease versus normal aging and frontotemporal dementia, Dement Geriatr Cogn Disord 24 (2007), 434-440.
138. A.H. Simonsen, J. McGuire, V.N. Podust, H. Davies, L. Minthon, I. Skoog, N. Andreasen, A. Wallin, G. Waldemar and K. Blennow, Identification of a novel panel of cerebrospinal fluid biomarkers for Alzheimer's Disease, Neurobiol Aging (2007), in press.
139. A. Stefani, A. Martorana, S. Bernardini, M. Panella, F. Mercati, A. Orlacchio and M. Pierantozzi, CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment, J Neurol Sci 251 (2006), 124-128.
140. T. Tapiola, T. Pirttila, M. Mikkonen, P.D. Mehta, I. Alafuzoff, K. Koivisto and H. Soininen, Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer's disease, Neurosci Lett 18 (2000), 119-122.
141. S.D. Targum, Evaluating rater competency for CNS clinical trials, J Clin Psychopharmacol 26 (2006), 308-310.
142. P.N. Tariot, M.R. Farlow, G.T. Grossberg, S.M. Graham, S. McDonald and I. Gergel, for the Memantine Study Group, Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial, JAMA 291 (2004), 317-324.
143. R. Temple, Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282 (1999), 790-795.
144. L.J. Thal, K. Kantarci, E.M. Reiman, W.E. Klunk, M.W. Weiner, H. Zetterberg, D. Galasko, D. Praticò, S. Griffin, D. Schenk and E. Siemers, The role of biomarkers in clinical trials for Alzheimer disease, Alzheimer Dis Assoc Disord 20 (2006), 6-15.
145. M.E. Thase, Studying new antidepressants: if there were a light at the end of the tunnel couldwe see it? J Clin Psychiatry 63(Suppl 2) (2002), 24-28.
146. S.R. Tunis, D.B. Stryer and C.M. Clancy, Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy, JAMA 290 (2003), 1624-1632.
147. A.R. Varma, J.S. Snowden, J.J. Lloyd, P.R. Talbot, D.M. Mann and D. Neary, Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer's disease and frontotemporal dementia, J Neurol Neurosurg Psychiatry 66 (1999), 184-188.
148. P.J. Visser, P. Scheltens and F.R. Verhey, Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer's disease? J Neurol Neurosurg Psychiatry 76 (2005), 1348-1354.
149. M. Weiner, Appendix. Introductory section background and significance of the overall proposal, http://www.loni.ucla.edu/ADNI/PDF/ADNI_Introduction.pdf, Accessed on April 4, 2008.
150. J.B.W.Williams, A structured interview guide for the Hamilton Depression Rating Scale, Arch Gen Psychiatry 45 (1988), 742-747.
151. B. Winbald, K. Engedal, H. Soinenen, F. Verhey, G. Waldemar, A. Wimo, A.-L. Wetterholm, R. Zhang, A. Haglund, P. Subbiah and the Donepezil Nordic Study Group, A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD, Neurology 57 (2001), 489-495.
152. B.Winblad, E. Giacobini, L. Froelich, G. Bruinsma, E.Walters and L. Friedhoff, Double-blind placebo-controlled evaluation of the safety and efficacy of phenserine tartrate for the treatment of mild to moderate Alzheimer disease, 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy, Abstract 11A, April (2006), 19-22.
153. B. Winblad, L. Kilander, S. Eriksson, L. Minthon, S. Batsman, A.-L. Wetterholm, C. Jansson-Blixt, A. Haglund, for the Severe Alzheimer's Disease Study Group, Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study, Lancet 367 (2006), 1057-1065.
154. H.Wolf, V. Jelic, H.-J. Gertz, A. Nordberg, P. Julin and L.-O. Wahlund, A critical discussion of the role of neuroimaging in mild cognitive impairment, Acta Neurol Scand 107 (2003), 52-76.
155. P.C. Wood and C.M. Castleden, A double-blind, placebo-controlled, multicenter study of tacrine for Alzheimer's disease, Int J Geriatric Psychiatry 9 (1994), 649-654.
156. S.W. Woods, R.V. Gueorguieva, C.B. Baker and R.W. Makuch, Control group bias in randomized atypical antipsychotic medication trials for schizophrenia, Arch Gen Psychiatry 62 (2005), 961-970.
157. Y. Yan and C. Wang, Abeta40 protects non-toxic Abeta42 monomer from aggregation, J Mol Biol 369 (2007), 909-916.
158. J.R. Young, 'Superarchives' could hold all scholarly output, Chron High Educ 48 (2002), 43.
159. Z. Zhong, M. Ewers, S. Teipel, K. Burger, A. Wallin, K. Blennow, P. He, C. McAllister, H. Hampel and Y. Shen, Levels of gamma secretase I cerebrospinal fluid as a predictor of risk in mild cognitive impairment, Arch Gen Psychiatry 64 (2007), 718-726.