TNF drives Alzheimer's disease-related neuronal cycle events

October 17, 2013:

Further experimental evidence implicating excess TNF (tumor necrosis factor-alpha) as centrally involved in the pathogenesis of Alzheimer’s disease has published. The article is entitled “Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cycle events“.  The new study, from scientists at the Department of Molecular Genetics and Microbiology, University of New Mexico, provides further support for the scientific rationale proposed by Edward Tobinick M.D in 1999 (U.S. patent 6,177,077)  and later elaborated in subsequent publications (for published reviews, please see Edward Tobinick, Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs, 2009. 23(9): p. 713-25; Clark, I.A., L.M. Alleva, and B. Vissel, The roles of TNF in brain dysfunction and disease. Pharmacol Ther, 2010. 128(3): p. 519-48; and Tobinick, E., Current Alzheimer Research, 2012. 9(1): p. 99-109.

The abstract of the new article concludes “….. Together our data suggest a cell-autonomous role of microglia, and identify TNF-alpha as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD”.

This new data joins data published in September 2013 from UCSF implicating excess TNF in the pathogenesis of another form of dementia, semantic variant Primary Progressive Aphasia (PPA). Dr. Tobinick reported the rapid clinical response of a patient with PPA to TNF inhibition in 2008 (Tobinick, E., …..rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med, 2008. 10(6): p. 135). TNF modulation is utilized at the INR off-label. Individual results can vary. Please see the Terms of Use.

Charlie and Cheryll reunite with Dr. Tobinick at the INR Los Angeles July 2013

Charlie and Cheryll at the INR 100 UCLA Medical Plaza Los Angeles July 2013
Charlie and Cheryll at the INR 100 UCLA Medical Plaza Los Angeles July 2013

3 years after filming the 60 Minutes Australia documentary, entitled “A New Shot at Life” Charlie and Cheryll reunite with Dr. Tobinick at the INR in Los Angeles. To view the 60 Minutes documentary, click here or here.

New data points to excess TNF as a potential therapeutic target for certain forms of dementia

On March 30, 2013, new data from the UCSF Memory and Aging Center published pointing to excess TNF as a potential therapeutic target for certain forms of dementia. In particular, elevated TNF levels were observed in the cohort of individuals examined with semantic variant PPA (primary progressive aphasia) (see Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, Criswell LA, Jaeger PA, Stan T, Heggeli KA, et al: TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 2013).

We note that this UCSF study follows by more than four years the initial report of rapid clinical improvement in an individual with PPA following the off-label use of perispinal etanercept (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, 10:135).

Basic Science News: TNF inhibition reduces neurovascular injury after Intracerebral Hemorrhage

TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice

Melanie D. King,
Cargill H. Alleyne Jr.,
Krishnan M. Dhandapani
Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2 h post-injury administration of R-7050 significantly reduced blood–brain barrier opening and attenuated edema development at 24 h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.

Science News: New pathology study: Inflammation persists for years after a single traumatic brain injury

Brain. 2013 Jan;136(Pt 1):28-42. doi: 10.1093/brain/aws322.
Inflammation and white matter degeneration persist for years after a single traumatic brain injury.

Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W.

Penn Centre for Brain Injury and Repair and Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.


A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer’s disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer’s disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ?3 months from injury, cases withtraumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, withtraumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.

INR on 60 Minutes New Zealand

March 11, 2012

Pleased to report that the featured news story, “A Shot at Life”, was shown tonight on 60 Minutes New Zealand. We welcome correspondence and inquiries from our friends in New Zealand . The story can be seen on the 60 Minutes New Zealand website at the following link:—A-Shot-At-Life/tabid/2059/articleID/76134/Default.aspx

We thank 60 Minutes Australia and our wonderful patients and their families to making this possible.

Best wishes to all,

The INR staff

60 Minutes Australia lead story on November 6, 2011 features INR's Alzheimer treatment

Pleased to report that the lead story on 60 Minutes Australia tonight (November 6, 2011), in both the Sydney and Melbourne metropolitan areas, is their feature story about our work.

The transcript and full-story can be viewed here:

Many thanks to all our patients, friends, and staff that have helped to make this happen and bring this forward.

Validity of INR's pioneering work re-confirmed

A newly published randomized study from Chiba University in Japan provides robust scientific support for our pioneering work utilizing novel methods of delivery and indications for etanercept. The new study, published ahead-of-print in the leading journal Spine demonstrated the superiority of epidural administration of etanercept over an epidural steroid injection for treatment of sciatica associated with spinal stenosis. This method of treatment was invented at the INR (U.S. patent 6419944, issued to Edward Tobinick M.D.) a decade ago. When the INR first published our work with etanercept for sciatica in 2003 and 2004 there were many who were [incorrectly] skeptical. This new study joins a favorable randomized, placebo-controlled study conducted by the U.S. Army in conjunction with Johns Hopkins researchers published in 2009 after their [uncredited] consultation with us several years before. Pleased that the truth has again been confirmed.

Lead story on 60 Minutes Australia is their report on perispinal etanercept for Alzheimer’s at the INR

The INR is pleased to announce that the lead story on 60 Minutes Australia on their October 16, 2011 national broadcast is their in-depth report about the results of our Alzheimer treatment program.

The transcript and full-story can be viewed here:

Many thanks to all our patients, friends, and staff that have helped to make this happen and bring this forward.

New genetic data implicates inflammatory mechanisms in Alzheimer's disease

A front-page article today (April 3, 2011) on the New York Times website reports a new discovery that again implicates inflammatory mechanisms in the pathogenesis of Alzheimer’s disease.

The link is here:…/04alzheimer.html?hp

The article begins:

“New Studies on Alzheimer’s Uncover Genetic Links
Published: April 3, 2011

The two largest studies of Alzheimer’s disease, an international analysis of genes of more than 50,000 people, have led to the discovery of five new genes that make the disease more likely in the elderly and provide tantalizing clues about what might start Alzheimer’s going and fuel its progress in a person’s brain.

The new genes add to a possible theme: so far genes that increase Alzheimer’s risk in the elderly tend to be involved with cholesterol and with inflammation. They also may be used to transport molecules inside cells.

For years, there have been unproven but persistent hints that cholesterol and inflammation are part of the disease process. People with high cholesterol were more likely to get Alzheimer’s disease. In addition, strokes and head injuries, which make Alzheimer’s more likely, also cause brain inflammation….”

The article continues with more discussion. For further background, please consider what is generally known about inflammation and TNF, an immune signaling molecule that is the master regulator of the inflammatory immune response in the human body.

TNF initiates, amplifies, and prolongs the inflammatory response. See the Wikipedia entry:

“Tumor necrosis factor promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor.”

The NY Times story reports the association of both AD and stroke with inflammatory mechanisms. This association was previously reported in the INR’s recent article in the journal CNS Drugs. In the CNS Drugs article Edward Tobinick MD, Founder of the INR, documented rapid improvement in neurological deficits produced by stroke following the use of the INR’s patented local method of administration of etanercept. Etanercept is a potent biologic antagonist of TNF.

The new Nature Genetics article provides strong new evidence generated by collaborative research from leading Alzheimer research centers that supports the role of inflammatory mechanisms in AD and points to a direction for future research.