Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.

OBJECTIVE: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib. METHODS: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline. RESULTS: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances. CONCLUSIONS: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.

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

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.

Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.

Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha (TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal administration, for treatment of Alzheimer's disease over a period of six months has been previously reported in a pilot study. This report details rapid cognitive improvement, beginning within minutes, using this same anti-TNF treatment modality, in a patient with late-onset Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease and provides a promising area for additional investigation and therapeutic intervention.

TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study.

CONTEXT: Current pharmacologic treatments for Alzheimer's disease (AD) do not prevent long-term clinical deterioration. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, has been implicated in the pathogenesis of AD. OBJECTIVE: To investigate the use of a biologic TNF-alpha inhibitor, etanercept was given by perispinal extrathecal administration for the treatment of AD. METHODS: This was a prospective, single-center, open-label, pilot (proof-of-concept) study, in which 15 patients with mild-to-severe AD were treated for 6 months. We administered etanercept, 25-50 mg, once weekly by perispinal administration. Main outcome measures included the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Severe Impairment Battery (SIB). RESULTS: The average age of our patient population was 76.7. The mean baseline MMSE was 18.2 (n = 15); the mean baseline ADAS-Cog was 20.8 (n = 11); and the mean baseline SIB was 62.5 (n = 5). There was significant improvement with treatment, as measured by all of the primary efficacy variables, through 6 months: MMSE increased by 2.13 -/+ 2.23, ADAS-Cog improved (decreased) by 5.48 -/+ 5.08, and SIB increased by 16.6 -/+ 14.52. CONCLUSION: An increasing amount of basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of AD. This small, open-label pilot study suggests that inhibition of the inflammatory cytokine TNF-alpha may hold promise as a potential approach to AD treatment. Further study in randomized, placebo-controlled clinical trials is merited.