Alzheimer’s

New Insights into the Pathobiology of Alzheimer’s Disease

There is widespread consensus within the Alzheimer research community that neuroinflammation occurs in the Alzheimer brain[1-4]. Edward Tobinick M.D., founder of the INR, in 2004 developed a unique, off-label, method designed to target neuroinflammation in Alzheimer’s [4-7, 9-12]. This treatment method, called perispinal etanercept, has been used successfully for patients with Alzheimer’s at the Institute of Neurological Recovery for more than 20 years (see the scientific references below).

 

Neuroinflammation and Alzheimer’s disease

Neuroinflammation in the brain in Alzheimer’s Disease may involve elevation of an inflammatory molecule called TNF.  A previous study has found that TNF is present in the fluid surrounding the brain(the cerebrospinal fluid) in Alzheimer’s Disease at a level 25 times normal[3]. It is known that elevated TNF can interfere with neuronal function, a process that could interfere with normal communication (synaptic transmission) between brain cells[4-15].

 

Edward Tobinick M.D., founder of the INR, has advanced scientific investigation of a new therapeutic target for Alzheimer’s disease

Dr. Tobinick was the principal investigator and lead author of the first clinical trial to demonstrate the potential of TNF inhibition utilizing etanercept as an Alzheimer’s disease therapeutic, entitled “TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study” (article here) that published in 2006. Dr. Tobinick and his colleagues subsequently published multiple articles detailing the clinical effects of etanercept for Alzheimer’s disease, as follows:

Disclaimer: Results vary. Patients may not respond. Etanercept for this indication is off-label. Please see the Terms of Use.

Please see the published, peer-reviewed scientific articles for a more complete scientific explanation of the role of inflammation, and excess TNF, in the pathobiology of Alzheimer’s disease and related forms of dementia, and the role Dr. Tobinick and his colleagues have played in advancing this new scientific paradigm[1-18].  Pharmacologic interference with the biological activity of TNF represents an emerging off-label treatment approach[21-22]. Breakthroughs in medicine that challenge existing paradigms often take years to be recognized[19, 20]. It would therefore seem fair to say that the average physician or neurologist would likely not be aware of the scientific basis of TNF inhibition as an emerging treatment strategy for AD. Cutting edge science takes many years to be accepted, and even longer to become widely known(an average of 17 years, according to the National Institute of Medicine)[19, 20). Nevertheless, scientists around the world are aware of this emerging treatment paradigm; see the article in New Scientist entitled “Arthritis drug shows potential to stall Alzheimer’s” (news story here).

References

  1. Inflammation and anti-inflammatory strategies for Alzheimer’s disease–a mini-review. McNaull BB, Todd S, McGuinness B, Passmore AP. Gerontology. 2010;56(1):3-14.
  2. Systemic inflammation and disease progression in Alzheimer disease. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Neurology. 2009 Sep 8;73(10):768-74.
  3. Intrathecal inflammation precedes development of Alzheimer’s disease. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1200-5.
  4. Perispinal etanercept: a new therapeutic paradigm in neurology. Edward Tobinick MD. Expert Rev Neurother. 2010 Jun;10(6):985-1002.
  5. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. Edward Tobinick MD. CNS Drugs. 2009 Sep 1;23(9):713-25.
  6. Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. Edward Tobinick MD, K Chen PhD, X Chen PhD. BMC Res Notes. 2009 Feb 27;2:28.
  7. Perispinal etanercept for neuroinflammatory disorders. Edward Tobinick MD. Drug Discov Today. 2009 Feb;14(3-4):168-77.
  8. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Edward Tobinick MD. Medscape J Med. 2008 Jun 10;10(6):135.
  9. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. Edward Tobinick MD, Hyman Gross MD. BMC Neurol. 2008 Jul 21;8:27.
  10. Perispinal etanercept for treatment of Alzheimer’s disease. Edward Tobinick MD. Curr Alzheimer Res. 2007 Dec;4(5):550-2.
  11. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. Edward Tobinick MD, Hyman Gross MD. J Neuroinflammation. 2008 Jan 9;5:2.
  12. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. Edward Tobinick MD, Hyman Gross MD, Alan Weinberger MD, Hart Cohen MD. MedGenMed. 2006 Apr 26;8(2):25.
  13. Perispinal etanercept: potential as an Alzheimer therapeutic.Griffin WS. J Neuroinflammation. 2008 Jan 10;5:3. (FULL-TEXT HERE).
  14. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Park KM, Bowers WJ. Cell Signal. 2010 Jul;22(7):977-83.
  15. The roles of TNF in brain dysfunction and disease. Clark IA, Alleva LM, Vissel B. Pharmacol Ther. 2010 Sep 8, in press.
  16. An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. Sarajärvi T, Helisalmi S, Antikainen L, et. al. J Alzheimers Dis. 2010;21(3):763-7.
  17. The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide. Medeiros R, Figueiredo CP, Pandolfo P, et. al. Behav Brain Res. 2010 May 1;209(1):165-73.
  18. Soluble TNF receptors are associated with ABeta metabolism and conversion to dementia in subjects with mild cognitive impairment. Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S, Hansson O. Neurobiol Aging. 2010 Nov;31(11):1877-84.
  19. The U.S. National Institute of Medicine has established the lengthy time that it takes for a new treatment paradigm to be established, and this is codified in California law. See California B&P 2234.1(4c): “Since the National Institute of Medicine has reported that it can take up to 17 years for a new best practice to reach the average physician and surgeon, it is prudent to give attention to new developments not only in general medical care but in the actual treatment of specific diseases, particularly those that are not yet broadly recognized in California”.
  20. Paths to acceptance. The advancement of scientific knowledge is an uphill struggle against ‘accepted wisdom’. Wolinsky H. EMBO Rep. 2008 May;9(5):416-8.
  21. The off-label use of FDA-approved medications is both legal and a common occurrence in daily medical practice. Although drug manufacturers are prohibited from promoting off-label uses, physicians may and commonly use medications for off-label indications if there is an established scientific rationale. The scientific rationale for targeting TNF to treat Alzheimer’s disease is supported by studies performed by scientists at academic institutions around the world [see References 1-18 above].
  22. FDA, off-label use, and informed consent: debunking myths and misconceptions. Beck JM, Azari ED. Food Drug Law J. 1998;53(1):71-104.
  23. U.S. patents 6982089, 7214658, 7629311; Australian patent 758523; and additional pending and issued U.S. patents. These patents are assigned to TACT IP, LLC.