Perispinal Etanercept Produces Rapid Improvement in Primary Progressive Aphasia: Identification of a Novel, Rapidly Reversible TNF-Mediated Pathophysiologic Mechanism

Edward Tobinick, MD

Disclosures

June 10, 2008

Abstract

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.

Introduction

Primary progressive aphasia (PPA) is an uncommon form of progressive dementia without established treatment. One third of these patients have underlying Alzheimer's disease pathology, and two thirds have pathology characteristic of frontotemporal dementia.[1] These patients characteristically present with progressive difficulty with language as the most prominent initial manifestation of the disease, which advances in an unrelenting fashion until all language abilities are lost.[2] No effective treatment has been established.[1,2]

Basic science and genetic, epidemiologic, and clinical evidence suggest that excess tumor necrosis factor-alpha (TNF-alpha) may play a central role in the pathogenesis of Alzheimer's disease.[3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23] In addition, excess TNF has been documented in the cerebrospinal fluid of patients with frontotemporal dementia.[24] Excess TNF may, therefore, represent a therapeutic target in PPA. Etanercept, a recombinant dimeric anti-TNF fusion protein, binds to TNF and blocks its interaction with cell-surface TNF receptors, thereby reducing the biologic effect of excess TNF. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy in Alzheimer's disease.[25,26,27,28,29] This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA.

 


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