Skip to main content

Challenges in the conduct of disease-modifying trials in ad: Practical experience from a phase 2 trial of TAU-aggregation inhibitor therapy

This is a preview of subscription content, access via your institution.

References

  1. 1.

    US Food and Drug Administration. Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. Code of Federal Regulations.21CFR314 §510.

  2. 2.

    Cummings JL. Challenges to demonstrating disease-modifying effects in Alzheimer’s disease clinical trials. Alzheimer’s and Dementia. 2006;2:263–271.

    Article  Google Scholar 

  3. 3.

    Bradley KM, Bydder GM, Budge MM, Hajnal JV, White SJ, Ripley BD, et al. Serial brain MRI at 3–6 month intervals as a surrogate marker for Alzheimer’s disease. Br J Radiol. 2002;75:506–513.

    PubMed  CAS  Google Scholar 

  4. 4.

    Jobst KA, Smith AD, Barker CS, Wear A, King EM, Smith A, et al. Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1992;55:190–194.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Brown DRP, Hunter R, Wyper DJ, Patterson J, Kelly RC, Montaldi D, et al. Longitudinal changes in cognitive function and regional cerebral function in Alzheimer’s disease: A SPECT blood flow study. J Psychiatr Res. 1996;30:109–126.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Venneri A, Shanks MF. Charting patterns of progression in treated and untreated patients with Alzheimer’s disease using SPECT. Neurobiol Aging. 2002;23:S125–S126.

    Article  Google Scholar 

  7. 7.

    Cabranes JA, de Juan R, Encinas M, Marcos A, Gil P, Fern C, et al. Relevance of functional neuroimaging in the progression of mild cognitive impairment. Neurol Res. 2004;26:496–501.

    PubMed  Article  Google Scholar 

  8. 8.

    Caroli A, Testa C, Geroldi C, Nobili F, Barnden LR, Guerra UP, et al. Cerebral perfusion correlates of conversion to Alzheimer’s disease in amnestic mild cognitive impairment. J Neurol 2007;254:1698–1707.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC. Mild cognitive impairment — Can FDG-PET predict who is to rapidly convert to Alzheimer’s disease? Neurology. 2003;60:1374–1377.

    PubMed  CAS  Google Scholar 

  10. 10.

    Encinas M, Juan R, Marcos A, Gil P, Barabash A, Fernández C, et al. Regional cerebral blood flow assessed with 99mTc-ECD SPET as a marker of progression of mild cognitive impairment to Alzheimer’s disease. Eur J Nuc Med Mol Imaging. 2003;30:1473–1480.

    Article  Google Scholar 

  11. 11.

    Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–1500.

    PubMed  CAS  Google Scholar 

  12. 12.

    Katsuno T, Morishima-Kawashima M, Saito Y, Yamanouchi H, Ishiura S, Murayama S, et al. Independent accumulations of tau and amyloid -protein in the human entorhinal cortex. Neurology. 2005;64:687–692.

    PubMed  CAS  Google Scholar 

  13. 13.

    Mani RB. The evaluation of disease modifying therapies in Alzheimer’s disease: a regulatory viewpoint. Stat Med. 2004;23:305–314.

    PubMed  Article  Google Scholar 

  14. 14.

    Aisen PS. Commentary on “Challenges to demonstrating disease-modifying effects in Alzheimer’s disease clinical trials.”. Alzheimer’s and Dementia. 2006;2:272–274.

    Article  Google Scholar 

  15. 15.

    Matsuda H, Kitayama N, Ohnishi T, Asada T, Nakano S, Sakamoto S, et al. Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer’s disease. J Nuc Med. 2002;43:304–311.

    Google Scholar 

  16. 16.

    Mukaetova-Ladinska EB, Garcia-Sierra F, Hurt J, Gertz HJ, Xuereb JH, Hills R, et al. Staging of cytoskeletal and -amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol. 2000;157:623–636.

    PubMed  CAS  Google Scholar 

  17. 17.

    Garcia-Sierra F, Hauw JJ, Duyckaerts C, Wischik CM, Luna-Muñoz J, Mena R. The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol. 2000;100:29–35.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–746.

    PubMed  Article  Google Scholar 

  19. 19.

    Jagust W, Thisted R, Devous MD, Sr., Van Heertum R, Mayberg H, Jobst K, et al. SPECT perfusion imaging in the diagnosis of Alzheimer’s disease. A clinicopathologic study. Neurology. 2001;56:950–956.

    PubMed  CAS  Google Scholar 

  20. 20.

    Matsuda H, Mizumura S, Nagao T, Ota T, Iizuka T, Nemoto K, et al. Automated discrimination between very early Alzheimer disease and controls using an easy Zscore imaging system for multicenter brain perfusion single-photon emission tomography. Am J Neuroradiol. 2007;28:731–736.

    PubMed  CAS  Google Scholar 

  21. 21.

    El Fakhri G, Kijewski MF, Albert MS, Johnson KA, Moore SC. Quantitative SPECT leads to improved performance in discrimination tasks related to prodromal Alzheimer’s disease. J Nuc Med. 2004;45:2026–2031.

    Google Scholar 

  22. 22.

    Imabayashi E, Matsuda H, Asada T, Ohnishi T, Sakamoto S, Nakano S, et al. Superiority of 3-dimensional stereotactic surface projection analysis over visual inspection in discrimination of patients with very early Alzheimer’s disease from controls using brain perfusion SPECT. J Nuc Med. 2004;45:1450–1457.

    Google Scholar 

  23. 23.

    Shimizu S, Hanyu H, Kanetaka H, Iwamoto T, Koizumi K, Abe.K. Differentiation of dementia with Lewy bodies from Alzheimer’s disease using brain SPECT. Dementia Geriat Cognit Disord. 2005;20:25–30.

    Article  Google Scholar 

  24. 24.

    Hanyu H, Shimizu S, Hirao K, Kanetaka H, Sakurai H, Iwamoto T, et al. Differentiation of dementia with Lewy bodies from Alzheimer’s disease using minimental state examination and brain perfusion SPECT. J Neurol Sci. 2006;250:97–102.

    PubMed  Article  Google Scholar 

  25. 25.

    Nagao M, Sugawara Y, Ikeda M, Fukuhara R, Hokoishi K, Murase K, et al. Heterogeneity of cerebral blood flow in frontotemporal lobar degeneration and Alzheimer’s disease. Eur J Nuc Med Mol Imaging. 2004;31:162–168.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to C. Wischik.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wischik, C., Staff, R. Challenges in the conduct of disease-modifying trials in ad: Practical experience from a phase 2 trial of TAU-aggregation inhibitor therapy. J Nutr Health Aging 13, 367–369 (2009). https://doi.org/10.1007/s12603-009-0046-5

Download citation

Keywords

  • Single Photon Emission Compute Tomography
  • Mild Cognitive Impairment
  • Braak Stage
  • Single Photon Emission Compute Tomography Data
  • Brain Single Photon Emission Compute Tomography