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Neurodegenerative Diseases Alzheimer’s Disease
and representation of clinical benefit.
57
The effect of therapy on a Neuroimaging Initiative
62
and the German Dementia Network, are
surrogate end-point must reliably predict the effect on a clinical involved with phase III development of the key CSF biomarker and
outcome. It is highly unlikely that a single surrogate end-point will imaging candidates in AD. Furthermore, biomarkers are in the
capture all of the pharmacological benefits and adverse effects of a process of being implemented as primary outcome variables into
drug in a diverse population, and combinations of biomarkers will regulatory guideline documents regarding study design and
probably be required. approval for compounds claiming to modify the disease.
10
In addition to their use as surrogate end-points, biomarkers may be Summary and Conclusions
employed in clinical trials as markers of disease progression, in which Currently, clinical assessment is the standard means of diagnosing
case treatment would be expected to slow the rate of change of the and assessing AD progression. However, mounting evidence
biomarker, e.g. hippocampal atrophy. Since individual biomarkers supports the fact that the analysis of CSF biomarkers such as
correlate to specific brain pathology, they may be used to classify Aβ
1–42
, T-tau and P-tau, together with neuroimaging techniques
subjects into groups based on the underlying AD pathology.
58
such as MRI and PET, performs well in the diagnosis of AD, even in
Furthermore, they could potentially shorten the time-frame of clinical its early clinical stages. Analysis of a combination of biomarkers has
trials from years to months, an attractive prospect given the slow improved sensitivity and specificity and allowed differential
rate of clinical progression of AD. Another useful function is as diagnosis between AD and related complaints.
predictors of future AD or identification of Alzheimer’s pathology in
non-demented patients, allowing high-risk individuals to be selected Each step in the series of physiological events leading to dementia in
for trials and therefore enriching the sample cohort. In previous trials AD may be linked to a unique biomarker. It is likely that advances
based on MCI selection, half of the patients did not develop AD, in research will result in new, more specific biomarkers.
impairing identification of drug efficacy.
59
Diagnosis of AD based on
biomarkers is superior to using the intrinsically heterogeneous MCI Research is currently most advanced at the diagnostic stage, but it is
state, and could eventually make it superfluous as a diagnostic state.
60
anticipated that these methods will become routine procedures in
Most importantly, biomarkers are the only means of demonstrating evaluating patients with cognitive symptoms. Their use in clinical
that a therapeutic intervention reaches the pathological mechanism practice is likely to become widespread, especially if the disease-
of the disease. modifying therapies currently under investigation prove successful.
Clinical research should diminish the technical difficulties
An example of the successful use of biomarkers in clinical trials was encountered in accurate measurement of neurochemical biomarkers
a recent randomised, double-blind, placebo-controlled pilot study in in biological fluids and may discover improved assays for Aβ in
which 36 patients with moderate AD symptoms were given plasma that more accurately reflect the neurochemical metabolism
memantine 20mg/day or placebo. Patients were evaluated at in the brain.
baseline and 26 and 52 weeks using a number of outcome measures,
including global and regional glucose metabolism measured by PET The ultimate validation of the use of biomarkers in AD will be
and total brain and hippocampal volumes measured using MRI. achieved by clinical trials using imaging/biomarkers to select high-
These imaging techniques proved useful in demonstrating the risk subjects and as surrogate end-points to assess therapeutic
efficacy of the drug and were considerably more reliable than benefits. Multiple therapeutic interventions must result in changes
chemical shift-imaging-derived global and regional N-acetylaspartate in biomarkers that can be correlated to clinical outcomes.
and myoinositol concentrations.
61
Biomarkers will then be able to stand alone as surrogate end-points
in clinical trials. Long-term monitoring of AD patients using
Large-scale international controlled multicentre trials, such as the biomarkers will be valuable in developing new treatments and,
US, European, Australian and Japanese Alzheimer’s Disease ultimately, preventing AD. n
1. Blennow K, et al., Lancet, 2006;368:387–403. 22. van der Flier WM, Scheltens P, J Nutr Health Aging, 42. Teipel SJ, et al., Psychopharmacology (Berl), 2006;187:86–94.
2. Gauthier S, et al., Lancet, 2006;367:1262–70. 2009;13:353–5. 43. Klunk WE, et al., Neuroimaging Clin N Am, 2003;13:781–9.
3. Zhang J, et al., J Alzheimers Dis, 2005;8:377–86. 23. Sluimer JD, et al., Neurobiol Aging, 2008 (Epub ahead of print). 44. Kemppainen NM, et al., Neurology, 2007;68:1603–6.
4. Herrmann N, et al., J Am Geriatr Soc, 2007;55:1517–23. 24. Peskind ER, et al., Alzheimer Dis Assoc Disord, 45. Klunk WE, et al., Ann Neurol, 2004;55:306–19.
5. Herrmann N, Lanctôt KL, Can J Psychiatry, 2007;52:630–46. 2005;19:220–25. 46. Leinonen V, et al., Arch Neurol, 2008;65:1304–9.
6. Tang BL, Kumar R, Ann Acad Med Singapore, 2008;37:406–10. 25. Galasko D, J Alzheimers Dis, 2005;8:339–46. 47. Herholz K, et al., Neuroimage, 2004;21:136–43.
7. Andreasen N, Minthon L, Arch Neurol, 2001;58:373–9. 26. Verwey NA, et al., Ann Clin Biochem, 2009;46:235–40. 48. Hansson O, et al., Neurobiol Aging, 2009;30:165–73.
8. Blennow K, Expert Rev Mol Diagn, 2005;5:661–72. 27. Mrak RE, Griffin WS, J Alzheimers Dis, 2005;8:369–75. 49. Visser PJ, et al., Lancet Neurol, 2009;8:619–27.
9. Blennow K, Hampel H, Lancet Neurol, 2003;2:605–13. 28. de Leon MJ, et al., J Neurol, 2007;254:1666–75. 50. Raber J, et al., Neurobiol Aging, 2004;25:641–50.
10. Hampel H, et al., Alzheimers Dement, 2008;4:38–48. 29. Zhong Z, et al., Arch Gen Psychiatry, 2007;64:718–26. 51. van der Flier WM, et al., Neurology, 2006;67:526–7.
11. Bürger nee Buch K, et al., Neurosci Lett, 1999;277:21–4. 30. Verwey NA, et al., Dement Geriatr Cogn Disord, 52. Kester MI, et al., J Alzheimers Dis, 2009;16:601–7.
12. Höglund K, et al., Neurodegener Dis, 2008;5:268–76. 2008;26:522–7. 53. Wilcock GK, et al., Lancet Neurol, 2008;7:483–93.
13. Snider BJ, et al., Arch Neurol, 2009;66:638–45. 31. Jack CR, Jr., et al., Neurology, 1999;52:1397–1403. 54. Risner ME, et al., Pharmacogenomics J, 2006;6:246–54.
14. Stomrud E, et al., Dement Geriatr Cogn Disord, 32. Wang PN, et al., Neurobiol Aging, 2006;27:1797–1806. 55. Dubois B, J Nutr Health Aging, 2009;13:356–7.
2007;24:118–24. 33. Pennanen C, et al., Neurobiol Aging, 2004;25:303–10. 56. Kaduszkiewicz H, et al., BMJ, 2005;331:321–7.
15. Hansson O, et al., Dement Geriatr Cogn Disord, 34. McEvoy LK, et al., Radiology, 2009;251:195–205. 57. Cummings JL, J Alzheimers Dis, 2005;8:327–37.
2007;23:316–20. 35. Hsu YY, et al., J Magn Reson Imaging, 2002;16:305–10. 58. Blennow K, Zetterberg H, J Nutr Health Aging,
16. Lewczuk P, et al., Neurobiol Aging, 2004;25:273–81. 36. Baron JC, et al., Neuroimage, 2001;14:298–309. 2009;13:358–61.
17. Wiltfang J, et al., Ann Neurol, 2003;54:263–7. 37. Teipel SJ, et al., Neuroimage, 2007;38:13–24. 59. Bateman RJ, et al., Nat Med, 2006;12:856–61.
18. Sunderland T, et al., JAMA, 2003;289:2094–2103. 38. Lerch JP, et al., Neurobiol Aging, 2008;29:23–30. 60. Dubois B, et al., Lancet Neurol, 2007;6:734–46.
19. van der Vlies AE, et al., Neurology, 2009;72:1056–61. 39. Misturi R, et al., Future Neurology, 2009;4:23–38. 61. Schmidt R, et al., J Neurol Neurosurg Psychiatry,
20. Zetterberg H, et al., J Alzheimers Dis, 2007;12:255–60. 40. Alexander GE, et al., Am J Psychiatry, 2002;159:738–45. 2008;79:1312–17.
21. Bouwman FH, et al., Neurobiol Aging, 2007;28:1070–74. 41. Potkin SG, et al., Int J Neuropsychopharmacol, 2001;4:223–30. 62. Frisoni GB, et al., Alzheimers Dement, 2008;4:255–64.
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