Skip to main content

Advertisement

SpringerLink
Log in

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

  • Report
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

To date, we still lack disease-modifying therapies for Alzheimer’s disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with β-amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of disease-modifying therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008, 372: 216–223.

    Article  CAS  PubMed  Google Scholar 

  2. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370: 322–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014, 370: 311–321.

    Article  CAS  PubMed  Google Scholar 

  4. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 2013, 369: 341–350.

    Article  CAS  PubMed  Google Scholar 

  5. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology 2007, 68: 501–508.

    Article  CAS  PubMed  Google Scholar 

  6. Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996, 334: 752–758.

    Article  CAS  PubMed  Google Scholar 

  7. Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B, et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 1988, 45: 836–840.

    Article  CAS  PubMed  Google Scholar 

  8. Mastrogiacoma F, Bettendorff L, Grisar T, Kish SJ. Brain thiamine, its phosphate esters, and its metabolizing enzymes in Alzheimer’s disease. Ann Neurol 1996, 39: 585–591.

    Article  CAS  PubMed  Google Scholar 

  9. Heroux M, Raghavendra Rao VL, Lavoie J, Richardson JS, Butterworth RF. Alterations of thiamine phosphorylation and of thiamine-dependent enzymes in Alzheimer’s disease. Metab Brain Dis 1996, 11: 81–88.

    Article  CAS  PubMed  Google Scholar 

  10. Pan X, Fei G, Lu J, Jin L, Pan S, Chen Z, et al. Measurement of blood thiamine metabolites for Alzheimer’s disease diagnosis. EBioMedicine 2016, 3: 155–162.

    Article  PubMed  Google Scholar 

  11. Karuppagounder SS, Xu H, Shi Q, Chen LH, Pedrini S, Pechman D, et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiol Aging 2009, 30: 1587–1600.

    Article  CAS  PubMed  Google Scholar 

  12. Wang D, Hazell AS. Microglial activation is a major contributor to neurologic dysfunction in thiamine deficiency. Biochem Biophys Res Commun 2010, 402: 123–128.

    Article  CAS  PubMed  Google Scholar 

  13. Zhao J, Sun X, Yu Z, Pan X, Gu F, Chen J, et al. Exposure to pyrithiamine increases beta-amyloid accumulation, Tau hyperphosphorylation, and glycogen synthase kinase-3 activity in the brain. Neurotox Res 2011, 19: 575–583.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Q, Yang G, Li W, Fan Z, Sun A, Luo J, et al. Thiamine deficiency increases beta-secretase activity and accumulation of beta-amyloid peptides. Neurobiol Aging 2011, 32: 42–53.

    Article  PubMed  Google Scholar 

  15. Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 2013, 108: 21–43.

    Article  CAS  PubMed  Google Scholar 

  16. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003, 9: 294–299.

    Article  CAS  PubMed  Google Scholar 

  17. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res 2010, 61: 482–488.

    Article  CAS  PubMed  Google Scholar 

  18. Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain 2010, 133: 1342–1351.

    Article  PubMed  Google Scholar 

  19. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 2003, 46: 2740–2754.

    Article  CAS  PubMed  Google Scholar 

  21. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004, 55: 306–319.

    Article  CAS  PubMed  Google Scholar 

  22. Ng S, Villemagne VL, Berlangieri S, Lee ST, Cherk M, Gong SJ, et al. Visual assessment versus quantitative assessment of 11C-PIB PET and 18F-FDG PET for detection of Alzheimer’s disease. J Nucl Med 2007, 48: 547–552.

    Article  CAS  PubMed  Google Scholar 

  23. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis 2005, 7: 63–80.

    CAS  PubMed  Google Scholar 

  24. Blass JP, Gleason P, Brush D, DiPonte P, Thaler H. Thiamine and Alzheimer’s disease. A pilot study. Arch Neurol 1988, 45: 833–835.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Key Fund for Developing New Drugs from the Ministry of Science and Technology of China (2014ZX09101005-005), the National Natural Science Foundation of China (81071019), the National Key Basic Research Program of China (2011CBA00400), the Natural Science Foundation of Shanghai Municipality, China (13JC1401500), and the Fund for Medical Emerging Cutting-Edge Technology in Shanghai of China (SHDC12012114). We thank Dr. Mu-ming Poo (Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) for his valuable insight and critique of the article. We also thank Dr. Alexandra H. Marshal (Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital, University of Toronto) for her careful editing of the article. We gratefully acknowledge all of the participants for their contributions to this study.

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurology, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China

      Xiaoli Pan, Zhichun Chen, Guoqiang Fei, Shumei Pan & Chunjiu Zhong

    2. PET Center, Huashan Hospital, Fudan University, Shanghai, 200443, China

      Weiqi Bao, Shuhua Ren & Yihui Guan

    Authors
    1. Xiaoli Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhichun Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Guoqiang Fei
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Shumei Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Weiqi Bao
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shuhua Ren
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yihui Guan
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Chunjiu Zhong
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Chunjiu Zhong.

    Additional information

    Xiaoli Pan and Zhichun Chen have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 125 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Pan, X., Chen, Z., Fei, G. et al. Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease. Neurosci. Bull. 32, 591–596 (2016). https://doi.org/10.1007/s12264-016-0067-0

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12264-016-0067-0

    Keywords

    Search

    Navigation