Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease

Edward L Tobinick, Hyman Gross, Edward L Tobinick, Hyman Gross

Abstract

Background: Recent clinical studies point to rapid and sustained clinical, cognitive, and behavioral improvement in both Alzheimer's disease and primary progressive aphasia following weekly perispinal administration of etanercept, a TNF-alpha inhibitor that acts by blocking the binding of this cytokine to its receptors. This outcome is concordant with recent basic science studies suggesting that TNF-alpha functions in vivo as a gliotransmitter that regulates synaptic function in the brain. We hypothesized that perispinal etanercept had the potential to improve verbal function in Alzheimer's disease, so we included several standarized measures of verbal ability to evaluate language skills in a clinical trial of perispinal etanercept for Alzheimer's disease.

Methods: This was a prospective, single-center, open-label, pilot study, in which 12 patients with mild-to-severe Alzheimer's disease were administered etanercept, 25-50 mg, weekly by perispinal administration for six months. Two additional case studies are presented.

Results: Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Test batteries included the California Verbal Learning Test-Second Edition, Adult Version; Logical Memory I and II(WMS-LM-II) from the Wechsler Memory Scale-Abbreviated; the Comprehensive Trail Making Test (TMT); Boston Naming Test; and letter(FAS) and category verbal fluency. All measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency was most highly significant with a p < 0.0007. In addition, rapid improvement in verbal fluency and aphasia in two patients with dementia, beginning minutes after perispinal etanercept administration, is documented.

Conclusion: In combination with the previously reported results of perispinal etanercept in Alzheimer's disease and primary progressive aphasia, these results further argue that larger scale studies of this therapeutic intervention, including Phase 3 trials, are warranted in dementias. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying Alzheimer's disease and related forms of dementia, and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in Alzheimer's disease which are worthy of further investigation.

Figures

Figure 1
Figure 1
Changes in verbal fluency, learning, and memory over 6 months during maintenance treatment with perispinal etanercept in a 12 subject pilot study, as reflected by T-score change from baseline to 6 months. Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. Abbreviations: California Verbal Learning Test-Second Edition, Adult Version (CVLT-II), including tests 1–5 and slope of change; Logical Memory I (LMI), and II (LMII) from the Wechsler Memory Scale-Abbreviated (WMS-a); the Comprehensive Trail Making Test (TMT), including tests 1 (TMT-1) and 4 (more difficult) (TMT-4); Boston Naming Test; and letter(FAS) and category(animal) verbal fluency.
Figure 2
Figure 2
FDG-PET brain scan of a patient with non-fluent aphasia secondary to Alzheimer's disease (case report 2), prior to treatment, demonstrating decreased glucose metabolism in the left parietal, bilateral temporal, and left frontal lobe.

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