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The Tobinick Method™ for treatment of Alzheimer's Disease at the INR®: outline of the scientific rationale

The most promising new therapeutic approach involves intervention in the neuroinflammatory processes which are central to the pathogenesis of Alzheimer's Disease[1-3]. It is now becoming increasing clear that glial activation leads to an excess of pro-inflammatory cytokines in the Alzheimer brain, and that this presents a therapeutic opportunity[4, 5]. Accumulating evidence supports the concept of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) as a key therapeutic target[6,7,10-29]. Excess TNF interferes with memory processes, such as long-term potentiation, and interrupts synaptic processes[7-11]. Excess TNF potentiates glutamate neurotoxicity and interferes in multiple additional brain pathways[12-16]. In particular, excess TNF is involved in a feedback loop with amyloid, both inducing amyloid production and being induced by amyloid[17-20].

The evidence implicating excess TNF in Alzheimer pathogenesis has been cascading in recent years. Multiple studies have now implicated excess TNF production, including specific genetic polymorphisms which result in increased TNF production, with AD risk[21-27].

The INR®, having invented a specific anti-TNF treatment approach, now has continuing positive clinical experience utilizing this novel route of administration of a potent biologic antagonist of TNF-alpha for the treatment of Alzheimer's Disease[28]. This patented approach[29] is now supported by citations from multiple academic centers[4, 6, 30, 31], by the scientific evidence discussed above, and by the potential vasculoprotective effects which have been suggested may accompany the use of specific biologic anti-TNF intervention in aging[32]. For families with a family member whose dementia or Alzheimer's has failed to adequately respond to any form of approved treatment, the INR® has a limited capacity to accept new patients for initiation of anti-TNF treatment. In addition the INR is actively involved in collaborative research with multiple academic partners and encourages inquiry by academic centers wishing to collaborate in investigating mechanisms of TNF inhibition in AD and other forms of dementia and CNS disease.

1. Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. [download full-text PDF].
2. Mrak, R.E. and W.S. Griffin, Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging, 2005. 26(3): p. 349-54.
3. Rosenberg, P.B., Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry, 2005. 17(6): p. 503-14.
4. Van Eldik, L.J., et al., Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol, 2007. 82: p. 277-96.
5. 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.
6. 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.
7. Pickering, M. and J. O'Connor J, Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res, 2007. 163: p. 339-54.
8. Goddard, C.A., D.A. Butts, and C.J. Shatz, Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A, 2007. 104(16): p. 6828-33.
9. Stellwagen, D. and R.C. Malenka, Synaptic scaling mediated by glial TNF-alpha. Nature, 2006. 440(7087): p. 1054-9.
10. Wang, Q., et al., Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor. Eur J Neurosci, 2005. 22(11): p. 2827-32.
11. 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.
12. 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.
13. Chiarini, A., et al., The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol, 2006. 111(4): p. 221-46.
14. Takeuchi, H., et al., 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.
15. 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.
16. Floden, A.M., S. Li, and C.K. Combs, Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci, 2005. 25(10): p. 2566-75.
17. Jekabsone, A., et al., 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.
18. Medeiros, R., et al., 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.
19. Yamamoto, M., et al., Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Regulate Amyloid-{beta} Plaque Deposition and {beta}-Secretase Expression in Swedish Mutant APP Transgenic Mice. Am J Pathol, 2007. 170(2): p. 680-92.
20. Patel, N.S., et al., Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J Neuroinflammation, 2005. 2(1): p. 9.
21. Guerreiro, R.J., et al., Peripheral inflammatory cytokines as biomarkers in Alzheimer's disease and mild cognitive impairment. Neurodegener Dis, 2007. 4(6): p. 406-12.
22. Tan, Z.S., et al., Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology, 2007. 68(19): p. 1902-1908.
23. 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.
24. 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.
25. Alvarez, A., et al., Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging, 2006.
26. Zuliani, G., et al., Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2007 Oct; 41(8):686-93. Epub 2006 Apr 4.
27. Lio, D., et al., Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease. Mech Ageing Dev, 2006. 127(6): p. 567-71.
28. Tobinick, E., Gross, H., Cohen, H., Weinberger, A., TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. Medscape General Medicine, 2006. 8(2): p. 25f.
29. Tobinick, E., Tumor necrosis factor antagonists for the treatment of neurological disorders. US patent 6,015,557. Also U.S. patents 6177077, 6419944, 6537549, 6982089, 7214528, and additional issued and pending U.S. and foreign patents.
30. Munoz, L., et al., A novel p38 alpha 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: p. 21.
31. Hu, W., 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): p. 414-8.
32. Csiszar, A., et al., Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol, 2007. 170(1): p. 388-98.

1. 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.
2. 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.
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. 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.
5. Mrak, R.E. and W.S. Griffin, Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging, 2005. 26(3): p. 349-54.
6. McGeer, P.L. and E.G. McGeer, Local neuroinflammation and the progression of Alzheimer's disease. J Neurovirol, 2002. 8(6): p. 529-38.
7. 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.
8. Bains, J.S. and S.H. Oliet, Glia: they make your memories stick! Trends Neurosci, 2007. 30(8): p. 417-24.
9. Oliet, S.H., R. Piet, D.A. Poulain, and D.T. Theodosis, Glial modulation of synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus. Glia, 2004. 47(3): p. 258-67.
10. Goddard, C.A., D.A. Butts, and C.J. Shatz, Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A, 2007. 104(16): p. 6828-33.
11. Stellwagen, D. and R.C. Malenka, Synaptic scaling mediated by glial TNF-alpha. Nature, 2006. 440(7087): p. 1054-9.
12. Beattie, E.C., et al., Control of synaptic strength by glial TNFalpha. Science, 2002. 295(5563): p. 2282-5.
13. 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.
14. 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.

15. Tobinick, E., H. Gross, A. Weinberger, and H. Cohen, TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. Medscape General Medicine, 2006. 8(2): p. 25f.
16. 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.
17. 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.
18. Tweedie D, Sambamurti K, Greig NH, TNF-alpha Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets. Curr Alzheimer Res 2007 Sep; 4(4):375-8.

19. Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. [download full-text pdf].

20. Tobinick E, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008 Jan 9; 5(1):2. [download full-text pdf].

Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D, Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol 2007.:277-96.

Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.

Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, Campos MM, Calixto JB 
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 May 16; 27(20):5394-404.

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.

Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R 
Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction.
Biochem Soc Trans 2007 Oct; 35(Pt 5):1219-23.

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta. Protection against the synaptic plasticity-disruptive effects of soluble Abeta was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Abeta oligomers in preclinical AD.

Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW 
Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease.
Arch Neurol 2006 Aug; 63(8):1165-9.

Background: Functional polymorphisms in tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) can affect immune response, inflammation, tissue injury, and possibly the susceptibility to Alzheimer disease (AD).
Results: The TNF-alpha -863 A allele was associated with reduced odds of developing AD, and the test for trend suggested that having 2 copies of the A allele further reduces the risk (odds ratios [C/C, reference], 0.66 for C/A and 0.58 for A/A; P = .04). Because of linkage disequilibrium in the TNF-alpha region, we constructed promoter region haplotypes as defined by single nucleotide polymorphisms at positions -863 and -308. Based on knowledge of TNF-alpha protein production, we ordered the haplotypes based on apparent increasing transcriptional activity. After adjusting for age, education, and the presence of the APOE epsilon4 genotype, the test for trend showed increasing odds of AD with increasing transcriptional activity (P = .02). The IL-10 -1082 and IL-10 -592 allele and genotype frequencies were not significantly different between cases and controls.
Conclusion: Variation in the TNF-alpha promoter region, or possibly polymorphisms in nearby genes, could affect cerebral inflammatory response and the risk of late-onset AD.

Mrak RE, Griffin WS 
Glia and their cytokines in progression of neurodegeneration.
Neurobiol Aging 2005 Mar; 26(3):349-54.

A glia-mediated, inflammatory immune response is an important component of the neuropathophysiology of Alzheimer's disease, of the midlife neurodegeneration of Down's syndrome, and of other age-related neurodegenerative conditions. All of these conditions are associated with early and often dramatic activation of, and cytokine overexpression in, microglia and astrocytes, sometimes decades before pathological changes consistent with a diagnosis of Alzheimer's disease are apparent, as in patients with Down's syndrome or head injury. Brains of normal elderly individuals also often show Alzheimer-type neuropathological changes, although to a lesser degree than those seen in Alzheimer's disease itself. These normal age-related glial changes, likely a response to the normal wear and tear of the aging process, raise the threshold of glial activation and thus may explain the fact that even genetically determined Alzheimer's disease, resulting from genetic mutations such as those in beta-amyloid precursor protein and presenilins or from genetic duplication such as of chromosome 21, only shows the full manifestation of the disease decades after birth. In the more common sporadic form of Alzheimer's disease, age-related increases in glial activation and expression of cytokines may act in synergy with other genetic and acquired environmental risks to culminate in the development of disease.

Wang Q, Wu J, Rowan MJ, Anwyl R 
Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor.
Eur J Neurosci 2005 Dec; 22(11):2827-32.

A number of recent studies have shown that beta-amyloid (Abeta) inhibits the induction of long-term potentiation (LTP) in the hippocampus. However, little is known about the mechanisms underlying such inhibition of LTP. In the present study, we present evidence that the cytokine tumor necrosis factor (TNF) alpha has a key role in the Abeta inhibition of LTP. The suppression of LTP by Abeta was absent in mutant mice null for TNF receptor type 1 (TNF-R1) and was prevented by the inhibitors of TNFalpha, infliximab and TNF peptide antagonist, and by the inhibitor of TNFalpha production, thalidomide. In addition, exogenous TNFalpha inhibited LTP induction, an action mediated via TNF-R1 as such inhibition was absent in mutant mice null for TNF-R1. The inhibition of LTP by TNFalpha involved activation of group I metabotropic glutamate receptor and p38 MAP kinase, identical to that for the Abeta-mediated inhibition of LTP induction.