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).
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.
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.
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:
We thank 60 Minutes Australia and our wonderful patients and their families to making this possible.
Best wishes to all,
The INR staff
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.