The Institute of Neurological Recovery (INR) is pleased to provide this detailed introduction to its pioneering medical concepts, research, and treatment programs. Cascading basic science, genetic, and clinical evidence now supports a key role of the inflammatory cytokine, TNF, in the pathogenesis of Alzheimer’s Disease. This is perhaps not surprising, in view of the fact that inflammation of the brain has long been established to be present in Alzheimer’s Disease. Alzheimer’s Disease therefore joins a long list of conditions, including rheumatoid arthritis, Crohn’s Disease, psoriasis, and ankylosing spondylitis, which affect tens of millions of people across the globe, in which there is evidence that inflammation is initiated, maintained, or amplified by TNF.
The INR is unique in that it has pioneered, refined, and developed new methods of anti-TNF treatment for patients with a variety of conditions involving neurologic inflammation. The INR has active and on-going anti-TNF treatment programs for selected patients with Alzheimer’s Disease and related disorders in which excess TNF has been implicated as a causative factor. The INR is available to evaluate patients with memory impairment who have failed to adequately respond to medical treatment.
The INR welcomes telephone inquiries from physicians, patients, or family members with questions regarding its treatment programs or research. In addition, the INR welcomes inquiries from academic medical centers, and biotechnology or pharmaceutical companies that have interest in anti-TNF research related to the causation and treatment of Alzheimer’s Disease, frontotemporal dementia, traumatic brain injury, stroke, and primary progressive aphasia. The INR has conducted collaborative research with academic medical centers both in the U.S. and abroad.
Consultation and treatment with an INR physician is by appointment only. Appointments can be scheduled by calling the INR at (310) 824-6199, Monday through Friday, 8 AM to 5 PM.
The INR welcomes referrals from neurologists, geriatricians, internists, family physicians, other health care providers, or family members of patients with conditions associated with neurologic inflammation, such as Alzheimer’s Disease, frontotemporal dementia, primary progressive aphasia and other forms of dementia, traumatic brain injury, and stroke. Individual treatment recommendations are only made following physician evaluation, including history, physical examination, and review of imaging studies.
The INR welcomes telephone inquiries from physicians and family members. In particular, the INR encourages telephone inquiry and discussion with an INR physician for those patients referred from locations at a geographic distance from Los Angeles prior to appointment scheduling. This is recommended especially for those patients who will
be flying across country or from overseas for treatment at the INR, due to the special nature of the services provided at the INR, and the unique experience which the INR has performing anti-TNF treatment for Alzheimer’s Disease.
The INR encourages referrals of patients with the following diagnoses who have failed to respond adequately to medical treatment.
The INR has invented and pioneered unique, anti-TNF therapeutic approaches for a variety of medical disorders with enormous unmet need, including Alzheimer’s disease and other neurological disorders[1-9].
The INR’s scientific findings have been published in multiple, peer-reviewed medical journals, including Expert Review of Neurotherapeutics, CNS Drugs, BMC Neurology, Current Alzheimer Research, Clinical Therapeutics, Drug Discovery Today, and Current Medical Research and Opinion. INR publications, findings, and research have advanced the science of neurology, dementia, and spine medicine, and have been cited and discussed by physicians and scientists from academic centers around the world. In 2008 alone there were more than 45 scientific citations to INR publications, including in Nature Clinical Practice Neurology and F1000 Biology.
The INR has presented its scientific findings at multiple U.S. and international medical and scientific conferences, including the Karolinska Institute in Sweden; the 2008 Drug Repositioning Summit in Boston; the International Conference on Alzheimer’s Disease in Chicago; the 7th Annual Alzheimer’s Drug Discovery Conference in New York; the 2008 Best Practices in the Continuum of Care: Advances in Alzheimer’s Disease Management conference at the University of Arkansas Medical Sciences in Little Rock, Arkansas; and, in 2009, the 3rd International Restauracion Neurologica Conference in Havana, Cuba, the World Pharmaceutical Congress in Philadelphia and the 5th Modern Drug Discovery Conference in San Diego.
The INR has performed collaborative research with scientists from Stanford University School of Medicine and additional academic centers.
The central role of excess TNF in the pathogenesis of Alzheimer’s disease and sciatica is now supported by multiple scientific studies from academic centers around the world, including genetic, basic science, epidemiologic, and clinical studies[11, 13-33] (reviewed in [2, 5, 6]). The perispinal etanercept treatment method for sciatica invented by Edward Tobinick MD in 2001 (U.S. patent 6,419,944) has recently (May 2009) received further robust scientific support due to publication of a favorable randomized, double-blind, placebo-controlled clinical trial conducted at the Walter Reed Army Medical Center [34], and a new basic science study conducted by scientists from UC San Diego[35].
Edward Tobinick MD, Director of the INR, has been an invited expert reviewer for the medical journals Neuroscience, Experimental Neurology, Current Alzheimer Research, Journal of Neurochemistry, Pharmaceutical Medicine, Journal of Neuroimmunology, CNS Drugs and Brain Research. Dr. Tobinick is a frequent invited speaker at international medical and scientific conferences, and the author of multiple, peer-reviewed articles in the scientific and medical literature. Dr. Tobinick is the inventor of perispinal and epidural etanercept for neurological disorders, including Alzheimer’s disease, other forms of dementia, sciatica, and disc-related back and neck pain. Download a copy of Dr Tobinick’s Curriculum Vitae PDF Here
Please download the full-text of the following independent, published scientific opinion: Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. [download free full-text PDF].
References
1. Tobinick, E.L. and H. Gross, Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol, 2008. 8: p. 27.
2. Tobinick, E.L. and H. Gross, Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation, 2008. 5: p. 2.
3. Tobinick, E., Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med, 2008. 10(6): p. 135.
4. Griffin, W.S., Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation, 2008. 5: p. 3.
5. Tobinick, E., Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res, 2007. 4(5): p. 550-2.
6. Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF-alpha modulation for treatment of Alzheimer’s Disease: A six month pilot study. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2006. 2(3): p. S364-S365.
7. Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF Modulation for Treatment of Alzheimer’s Disease: A 6-month Pilot Study. Medscape General Medicine: Neurology, 2006. 8(2): p. 25f.
8. Tobinick, E. and S. Davoodifar, Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin, 2004. 20(7): p. 1075-85.
9. Tobinick, E.L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12): p. 170-7.
10. Youn, D.H., H. Wang, and S.J. Jeong, Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res, 2008.
11. Rowan, M.J., I. Klyubin, Q. Wang, N.W. Hu, and R. Anwyl, Synaptic memory mechanisms: Alzheimer’s disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans, 2007. 35(Pt 5): p. 1219-23.
12. Wang, Y., Modification of synaptic plasticity by TNF and sphingomyelinase: Implications for cognitive impairment in AD, in ICAD 2008: Molecular mechanisms of neurodegeneration; synaptic disruption. 2008: Chicago.
13. Perry, R.T., J.S. Collins, H. Wiener, R. Acton, and R.C. Go, The role of TNF and its receptors in Alzheimer’s disease. Neurobiol Aging, 2001. 22(6): p. 873-83.
14. 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.
15. Laws, S.M., R. Perneczky, S. Wagenpfeil, U. Muller, H. Forstl, R.N. Martins, A. Kurz, and M. Riemenschneider, TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat, 2005. 26(1): p. 29-35.
16. Pickering, M., D. Cumiskey, and J.J. O’Connor, Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol, 2005. 90(5): p. 663-70.
17. 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.
18. Chiarini, A., I. Dal Pra, J.F. Whitfield, and U. Armato, The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol, 2006. 111(4): p. 221-46.
19. Ramos, E.M., M.T. Lin, E.B. Larson, I. Maezawa, L.H. Tseng, K.L. Edwards, G.D. Schellenberg, J.A. Hansen, W.A. Kukull, and L.W. Jin, 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.
20. Csiszar, A., N. Labinskyy, K. Smith, A. Rivera, Z. Orosz, and Z. Ungvari, Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol, 2007. 170(1): p. 388-98.
21. 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.
22. De, A., J.M. Krueger, and S.M. Simasko, Glutamate induces the expression and release of tumor necrosis factor-alpha in cultured hypothalamic cells. Brain Res, 2005. 1053(1-2): p. 54-61.
23. Edwards, M.M. and S.R. Robinson, TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease. J Neural Transm, 2006.
24. Janelsins, M.C., M.A. Mastrangelo, S. Oddo, F.M. LaFerla, H.J. Federoff, and W.J. Bowers, Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J Neuroinflammation, 2005. 2: p. 23.
25. Jekabsone, A., P.K. Mander, A. Tickler, M. Sharpe, and G.C. Brown, Fibrillar beta-amyloid peptide Abeta1-40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflammation, 2006. 3: p. 24.
26. Medeiros, R., R.D. Prediger, G.F. Passos, P. Pandolfo, F.S. Duarte, J.L. Franco, A.L. Dafre, G. Di Giunta, C.P. Figueiredo, R.N. Takahashi, M.M. Campos, and J.B. Calixto, Connecting TNF-{alpha} Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer’s Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid {beta} Protein. J Neurosci, 2007. 27(20): p. 5394-5404.
27. Meme, W., C.F. Calvo, N. Froger, P. Ezan, E. Amigou, A. Koulakoff, and C. Giaume, Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid. Faseb J, 2006. 20(3): p. 494-6.
28. Mrak, R.E. and W.S. Griffin, Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging, 2005. 26(3): p. 349-54.
29. Ralay Ranaivo, H., J.M. Craft, W. Hu, L. Guo, L.K. Wing, L.J. Van Eldik, and D.M. Watterson, 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.
30. Takeuchi, H., S. Jin, J. Wang, G. Zhang, J. Kawanokuchi, R. Kuno, Y. Sonobe, T. Mizuno, and A. Suzumura, Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem, 2006. 281(30): p. 21362-8.
31. Tan, Z.S., A.S. Beiser, R.S. Vasan, and e. al., Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology, 2007. 68(19): p. 1902-1908.
32. Zou, J.Y. and F.T. Crews, TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res, 2005. 1034(1-2): p. 11-24.
33. Zuliani, G., M. Ranzini, G. Guerra, L. Rossi, M.R. Munari, A. Zurlo, S. Volpato, A.R. Atti, A. Ble, and R. Fellin, Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res, 2006.
34. Cohen, S.P., N. Bogduk, A. Dragovich, C.C. Buckenmaier, 3rd, S. Griffith, C. Kurihara, J. Raymond, P.J. Richter, N. Williams, and T.L. Yaksh, Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology, 2009. 110(5): p. 1116-26.
35. Kato, K., S. Kikuchi, V.I. Shubayev, and R.R. Myers, Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience, 2009. 160(2): p. 492-500.
The following are selected publications that have cited scientific publications of Edward Tobinick MD, Director of the INR®:
Scientific Articles:
1. Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. [download free full-text PDF].
2. Misra, Ambikanandan; Jogani, Viral; Jinturkar, Kaustubh; Vyas, Tushar. Recent Patents Review on Intranasal Administration for CNS Drug Delivery. Recent Patents on Drug Delivery & Formulation, Volume 2, Number 1, January 2008 , pp. 25-40(16).
3. Zanella, John M. MS; Burright, Eric N. PhD; Hildebrand, Keith DVM, PhD; Hobot, Chris BS; Cox, Mark BS; Christoferson, Laura BS; McKay, William F. MS. Effect of Etanercept, a Tumor Necrosis Factor-Alpha Inhibitor, on Neuropathic Pain in the Rat Chronic Constriction Injury Model. Spine 33(3):227-234, February 1, 2008.
4. Sonya Vasto, Giuseppina Candore, Giovanni Duro, Domenico Lio, Maria Paola Grimaldi, Calogero Caruso. Alzheimer’s disease and genetics of inflammation: a pharmacogenomic vision. Pharmacogenomics December 2007, Vol. 8, No. 12, Pages 1735-1745.
5. Tweedie D, Sambamurti K, Greig NH. Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, US. TNF-alpha Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets. Curr Alzheimer Res. 2007 Sep;4(4):375-8.
6. Van Eldik, L. J. Thompson, W. L. Ranaivo, H. R. Behanna, H. A. Watterson, D. M. Glia Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases: Function-Based and Target-Based Discovery Approaches, International Review of Neurobiology 2007, 82:278-297.
7. Uceyler N, Sommer C. Cytokine-induced Pain: Basic Science and Clinical Implications. Reviews in Analgesia 2007;9(2):87-103.
8. Tubbs RS, Hansasuta A, Loukas M, Louis RG, Jr., Shoja MM, Salter EG, et al. The basilar venous plexus. Clin Anat 2007.
9. Saxena AK, Kumar S. Management strategies for pain in breast carcinoma patients: current opinions and future perspectives. Pain Pract 2007;7(2):163-77.
10. Owlia MB, Salimzadeh A, Alishiri G, Haghighi A. Comparison of two doses of corticosteroid in epidural steroid injection for lumbar radicular pain. Singapore Med J 2007;48(3):241-5.
11. Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, et al. A novel p38alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation 2007;4(1):21.
12. Hu W, Ranaivo HR, Roy SM, Behanna HA, Wing LK, Munoz L, et al. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett 2007;17(2):414-8.
13. Le Maitre CL, Hoyland JA, Freemont AJ. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. Arthritis Res Ther. 2007 Aug 9;9(4):R77.
14. Kenneth M. Kulmatycki1, Fakhreddin Jamali. Drug Disease Interactions: Role of Inflammatory Mediators in Pain and Variability in Analgesic Drug Response. J Pharm Pharm Sci, 10 (4): 554-566, 2007.
15. Schäfers, Maria; Sommer, Claudia. Anticytokine therapy in neuropathic pain management. Expert Review of Neurotherapeutics, Volume 7, Number 11, November 2007 , pp. 1613-1627(15).
16. van Marum, R.J., Current and future therapy in Alzheimer’s disease. Fundam Clin Pharmacol, 2008. 22(3): p. 265-74.
17. Schwab, C. and P.L. McGeer, Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis, 2008. 13(4): p. 359-69.
18. Maczurek, A., K. Shanmugam, and G. Munch, Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer’s disease. Ann N Y Acad Sci, 2008. 1126: p. 147-51.
19. Berbaum, K., K. Shanmugam, G. Stuchbury, F. Wiede, H. Korner, and G. Munch, Induction of novel cytokines and chemokines by advanced glycation endproducts determined with a cytometric bead array. Cytokine, 2008. 41(3): p. 198-203.
Hardcover/ Bound Texts:
1. Neuroinflammation in Neuronal Death and Repair, Volume 82 (International Review of Neurobiology.) G. Bagetta, editor (Hardcover – Jul 16, 2007) Amsterdam ; Boston : Elsevier Academic Press ©2007. ISBN: 9780123739896 0123739896.
2. Interactions Between Neurons and Glia in Aging and Disease by Joao Malva, Ana Cristina Rego, Rodrigo Cunha, and Catarina Oliveira (Eds.) (Hardcover – Aug 22, 2007). 2007, Approx. 535 p., Hardcover ISBN: 978-0-387-70829-4 New York ; London : Springer, 2007.
3. Cytokines in the Genesis and Treatment of Cancer (Cancer Drug Discovery and Development) by Michael A. Caligiuri and Michael T. Lotze (Hardcover – April 20, 2007) Totowa, N.J. : Humana Press ©2007. ISBN: 9780896038202 0896038203 9781597454551 1597454559.
4. Chapter 10: Anti-TNF-alpha antibody and cancer cachexia, The ASCRS Textbook of Colon and Rectal Surgery by J.M. Church, J. Garcia-Aguilar, P.L. Roberts, and T.J. Saclarides; New York : Springer ©2007. ISBN: 9780387248462 0387248463.
5. Spinal Reconstruction: Clinical Examples of Applied Basic Science, Biomechanics and Engineering by Kai-Uwe Lewandrowski, Michael J. Yaszemski, Iain Kalfas, and Paul Park (Hardcover – Feb 12, 2007) New York : Informa Healthcare ©2007. ISBN: 9780849398155 0849398150.
6. Olesen J, Jensen T. From Basic Pain Mechanisms to Headache. Oxford University Press 2007.
7. Neuroimmunology: The Immune System and Alzheimers, in the 2007 Progress Report on Brain Research, Dana Alliance for Brain Initiatives, Dana Press, New York ©2007.