Display options
Cite
Insel PS, Mattsson N, Mackin RS, et al. Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease. Ann Clin Transl Neurol. 2015;2(5):534-47doi: 10.1002/acn3.192.
Insel, P. S., Mattsson, N., Mackin, R. S., Kornak, J., Nosheny, R., Tosun-Turgut, D., Donohue, M. C., Aisen, P. S., Weiner, M. W. (2015). Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease. Annals of clinical and translational neurology, 2(5), 534-47. https://doi.org/10.1002/acn3.192
Insel, Philip S, et al. "Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease." Annals of clinical and translational neurology vol. 2,5 (2015): 534-47. doi: https://doi.org/10.1002/acn3.192
Insel PS, Mattsson N, Mackin RS, Kornak J, Nosheny R, Tosun-Turgut D, Donohue MC, Aisen PS, Weiner MW. Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease. Ann Clin Transl Neurol. 2015 May;2(5):534-47. doi: 10.1002/acn3.192. Epub 2015 Mar 21. PMID: 26000325; PMCID: PMC4435707.
Copy Download .nbib Format: NLM
Share it on

Ann Clin Transl Neurol. 2015 May;2(5):534-47. doi: 10.1002/acn3.192. Epub 2015 Mar 21.

Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease.

Annals of clinical and translational neurology

Philip S Insel, Niklas Mattsson, R Scott Mackin, John Kornak, Rachel Nosheny, Duygu Tosun-Turgut, Michael C Donohue, Paul S Aisen, Michael W Weiner,

Affiliations

  1. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California.
  2. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California ; Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg Mölndal, Sweden.
  3. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Psychiatry, University of California San Francisco, California.
  4. Department of Epidemiology and Biostatistics, University of California San Francisco, California.
  5. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California.
  6. Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California San Diego, California ; Department of Neurosciences, University of California San Diego, California.
  7. Department of Neurosciences, University of California San Diego, California.

PMID: 26000325 PMCID: PMC4435707 DOI: 10.1002/acn3.192

Abstract

OBJECTIVE: To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease.

METHODS: Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-ε4 allele carriers, cerebrospinal fluid biomarkers (Aβ 42, total tau, and phosphorylated tau), and those with small hippocampi.

RESULTS: Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials.

INTERPRETATION: Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.

References

  1. J Biopharm Stat. 2009;19(2):227-46 - PubMed
  2. Lancet Neurol. 2013 Apr;12(4):357-67 - PubMed
  3. Radiology. 1989 Aug;172(2):549-54 - PubMed
  4. J Alzheimers Dis. 2011;26 Suppl 3:321-9 - PubMed
  5. Clin Chem. 2005 Feb;51(2):336-45 - PubMed
  6. Neurology. 2012 May 15;78(20):1568-75 - PubMed
  7. N Engl J Med. 2009 Jul 16;361(3):255-63 - PubMed
  8. Lancet Neurol. 2013 Oct;12(10):957-65 - PubMed
  9. Ann Neurol. 2009 Apr;65(4):403-13 - PubMed
  10. Arch Gen Psychiatry. 2012 Jan;69(1):98-106 - PubMed
  11. Neurology. 2010 Mar 9;74(10 ):807-15 - PubMed
  12. Neurology. 2012 Jan 24;78(4):232-40 - PubMed
  13. N Engl J Med. 2014 Jan 23;370(4):311-21 - PubMed
  14. PLoS One. 2013 Sep 09;8(9):e74062 - PubMed
  15. Neurobiol Aging. 2003 Nov;24(7):947-52 - PubMed
  16. Brain. 2014 Jan;137(Pt 1):221-31 - PubMed
  17. Neurology. 1992 Mar;42(3 Pt 1):631-9 - PubMed
  18. J Int Neuropsychol Soc. 2008 Mar;14(2):266-78 - PubMed
  19. J Neuropathol Exp Neurol. 1993 Nov;52(6):594-600 - PubMed
  20. Ann Neurol. 2012 Jun;71(6):765-75 - PubMed
  21. Neurology. 2012 Oct 16;79(16):1636-44 - PubMed
  22. Ann Clin Transl Neurol. 2014 Aug;1(8):534-43 - PubMed
  23. Neurology. 2009 Dec 15;73(24):2061-70 - PubMed
  24. Arch Neurol. 2007 Sep;64(9):1306-11 - PubMed
  25. Ann Neurol. 2012 Oct;72 (4):578-86 - PubMed
  26. Neurology. 2003 Feb 25;60(4):652-6 - PubMed
  27. Neurology. 2011 Jan 18;76(3):280-6 - PubMed
  28. Lancet. 2008 Jul 19;372(9634):216-23 - PubMed
  29. Neurology. 2013 Apr 9;80(15):1378-84 - PubMed
  30. Neurology. 2013 May 7;80(19):1784-91 - PubMed
  31. Brain. 2015 Mar;138(Pt 3):772-83 - PubMed
  32. J Magn Reson Imaging. 2008 Apr;27(4):685-91 - PubMed
  33. Neurology. 2014 May 20;82(20):1760-7 - PubMed
  34. Sci Transl Med. 2014 Mar 19;6(228):228fs13 - PubMed
  35. Alzheimers Dement. 2011 May;7(3):280-92 - PubMed
  36. Neurology. 2004 Mar 23;62(6):925-31 - PubMed
  37. Am J Psychiatry. 1984 Nov;141(11):1356-64 - PubMed
  38. JAMA Neurol. 2014 Aug;71(8):961-70 - PubMed

Publication Types

Grant support