. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2. PubMed.

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  1. The role of TNFα in the brain is complex. Although there is a lot of indirect evidence that TNFα is detrimental in AD, this protein can be neuroprotective and has been shown to mediate synaptic scaling, a process that helps cells to readjust synaptic strength after prolonged activity (Stellwagen and Malenka, 2006). Given these diverse functions, we cannot yet say what increased or decreased levels in plasma or CSF mean for this disease.

    I think we should be cautious with inhibiting TNFα in AD, as AD is not an acute inflammatory disease.

    References:

    . Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. PubMed.

  2. Dr. Ed Tobinick reports clinical improvement in AD patients administered etanercept, a macromolecular drug that interferes with TNFα activity. His recent Journal of Neuroinflammation paper reports the unexpected and intriguing finding that perispinal administration of etanercept leads to observable clinical improvement in AD patients within minutes. This case report of one patient follows up an earlier 2006 report in Medscape General Medicine. In that pilot study, 15 patients with mild to severe AD were treated once weekly with etanercept by perispinal administration for 6 months, and showed significant and sustained improvement in three different cognitive tests. Dr. Tobinick himself has raised several caveats related to the study, such as the possibility that the rapid effects are related to mood elevation or improved alertness, the lack of a control group treated with placebo, and the unconventional drug delivery method. The clinical observations are sufficiently intriguing to warrant analysis in a randomized, double-blind, placebo-controlled clinical trial.

    These initial clinical observations from a feasibility study are consistent with the hypothesis that cytokine levels and activity need to be tightly regulated in the brain, and that cytokine dysregulation might be a pathophysiology progression mechanism that can be targeted in new therapeutic development. The mechanisms behind how etanercept treatment influences cognition, especially the rapidity of the effects in the recent study, are not known and are one of many parameters that need to be studied in more detail. However, a number of testable hypotheses can be proposed and rapidly tested in preclinical animal models in parallel with planning for future clinical trials.
    The clinical observations also indicate the critical need for small molecule therapeutics that modulate cytokine production. This critical need is amplified when one realizes that current cytokine-modulating drugs are macromolecules, and using macromolecules as a therapeutic approach has a number of disadvantages for clinical use in chronic CNS disorders, such as high cost and inconvenient dosing regimens. Clearly, there is an unmet need for small molecule, orally active, brain-penetrant, anti-cytokine compounds to test as potential new classes of AD therapeutics.