Anti-TNF treatment for Alzheimer's Disease at the INR Los Angeles

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Independent scientific contributions

Foreword: Science is a collaborative effort; each scientific advance builds upon, and is dependent upon, the work of the many scientists who have broken the original ground, and built the foundation. The INR wishes to acknowledge the many scientists worldwide who have helped make the anti-TNF treatment program at the INR possible, through their independent research which helped provide the scientific basis for INR's work, and to apologize in advance for not individually enumerating their contributions. Without their tireless efforts, none of this could have been possible.

The Tobinick Method™ is a unique, pioneering, patented** off-label treatment method for selected patients with Alzheimer's Disease who have failed to adequately respond to conventional medical treatment. It is now made possible by three inter-related elements:
1. The recognition of the central importance of neuroinflammation in general, and excess TNF-alpha in specific, in the development of Alzheimer's Disease;
2. The clinical availability of a potent anti-TNF therapeutic molecule; and
3. The recognition of the specific ways in which excess TNF-alpha may interfere with memory and other brain mechanisms in patients with Alzheimer's and other forms of dementia.

The following are just a small number of the many scientists whose work, independent of the INR, has helped decipher the exact ways in which excess TNF-alpha may be deleterious to the brain: Elizabeth Tarkowski, Kaj Blennow and their colleagues from Goteborg University, first documented excess TNF in the spinal fluid of patients with AD, and subsequently correlated these high levels with clinical deterioration[1, 2]; Simon Laws and his colleagues in Australia, correlated mutations in TNF genes with AD risk[3]; scientists from UC Davis and the University of Washington provided further genetic evidence connecting TNF genes and AD risk, and suggested the possible utility of anti-TNF agents for treatment of AD[4]; David Stellwagen and Robert Malenka from Stanford University demonstrated that glial TNF-alpha regulates the function of neuronal networks[5]; Marty Watterson and Linda Van Eldik and their colleagues from Northwestern investigated the mechanisms of glial activation, release of proinflammatory cytokines, and synaptic damage in AD models[6, 7]; Nigel Grieg and his colleagues from the National Institute on Aging published a review of the potential of TNF-alpha inhibition for the treatment of neurodegenerative diseases[8]; Phillip Haydon and his colleagues at the Silvio Conte Center for Integration at the Tripartite Synapse, and Jaideep Bains and Stephane Oliet from the Hotchkiss Brain Institute in Calgary, have helped establish the exciting concept of TNF-alpha as a gliotransmitter[9, 10]; and Michael Rowan and his colleagues from the Trinity College Institute of Neuroscience in Dublin showed that the memory dysfunction caused by beta-amyloid and beta-amyloid oligomers is mediated by TNF-alpha, thereby connecting amyloid mechanisms with TNF-alpha and neuroinflammation[11, 12].

For additional discussion and citations, please see the For Physicians and Scientists webpage.

1. Tarkowski, E., et al., Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull, 2003. 61(3): p. 255-60.
2. Tarkowski, E., N. Andreasen, A. Tarkowski, and K. Blennow, Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry, 2003. 74(9): p. 1200-5.
3. Laws, S.M., et al., TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat, 2005. 26(1): p. 29-35.
4. Ramos, E.M., et al., Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol, 2006. 63(8): p. 1165-9.
5. Stellwagen, D. and R.C. Malenka, Synaptic scaling mediated by glial TNF-alpha. Nature, 2006. 440(7087): p. 1054-9.
6. Van Eldik, L.J., et al., Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases: Function-Based and Target-Based Discovery Approaches. International Review of Neurobiology, 2007. 82: p. 278-297.
7. Ralay Ranaivo, H., et al., Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci, 2006. 26(2): p. 662-70.
8. Tweedie, D., K. Sambamurti, and N.H. Greig, TNF-alpha Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets. Curr Alzheimer Res, 2007. 4(4): p. 375-8.
9. Halassa, M.M., T. Fellin, and P.G. Haydon, The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med, 2007. 13(2): p. 54-63.
10. Bains, J.S. and S.H. Oliet, Glia: they make your memories stick! Trends Neurosci, 2007. 30(8): p. 417-24.
11. Wang, Q., J. Wu, M.J. Rowan, and R. Anwyl, Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor. Eur J Neurosci, 2005. 22(11): p. 2827-32.
12. Rowan, M.J., et al., Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans, 2007. 35(Pt 5): p. 1219-23.

Institute for Neurological Research, a private medical group, inc.
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Copyright ©2007, the Institute for Neurological Research® (INR®), a private medical group, inc., all rights reserved. **U.S. patents 6015557, 6177077, 6419934, 6419944, 6471961, 6537549, 6982089, 7214658 and additional issued and pending U.S. and foreign patents. These patents are assigned to TACT IP LLC.