Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism.

Primary progressive aphasia (PPA) is an uncommon form of progressive dementia for which there exists no established treatment. The underlying pathology may be that of either frontotemporal dementia or Alzheimer's disease. Increasing evidence suggests that excess tumor necrosis factor (TNF) may play a central role in Alzheimer's disease. Additionally, excess TNF has been documented in patients with frontotemporal dementia. Excess TNF may therefore represent a therapeutic target in PPA. Etanercept, an anti-TNF fusion protein, binds to TNF, thereby reducing its biologic effect. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy for Alzheimer's disease. This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA. This report documents rapid improvement in verbal abilities, beginning within 20 minutes of perispinal etanercept, in a patient with severe PPA. With repeated weekly dosing, sustained improvement at 1 month is documented, with a more than 10-point improvement in the patient's abilities to perform activities of daily living as measured by a standardized instrument, the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory. Rapid clinical improvement in PPA following perispinal etanercept administration may be related to TNF's role as a gliotransmitter and modulator of synaptic communication in the brain. These results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease. Further study of this therapeutic method is indicated.