The data from this six month Phase 2 clinical trial in 12 patients with Alzheimer's disease suggest notable improvements in verbal learning, memory, and fluency in this cohort treated with perispinal etanercept. This data is consistent with the preliminary evidence from the two case reports included herein, and with the case study most recently reported by the authors [3
]. The data reported here, along with confirmatory clinical experience of more than three years duration in Alzheimer's disease, suggest that perispinal etanercept treatment of patients with TNF-alpha mediated dementias may result in improvement in verbal fluency and related language functions [1
]. In addition, these data, combined with those from previous reports, suggest that positive clinical effects may begin rapidly, within minutes, and may be durable with ongoing maintenance dosing [1
]. Perispinal etanercept may result in improvement in behavior, frontal lobe and executive function, conversational abilities, naming abilities, and ability to comprehend and follow spoken commands [1
]. The clinical effects suggest that this treatment approach, in addition to its utility for other forms of Alzheimer's disease, may be useful for patients with frontotemporal dementia and frontal variant Alzheimer's disease [46
]. Further study will be necessary to characterize response rates, dosing schedules, and duration of response in the non-Alzheimer dementias.
The family and clinician observations of improvements in the patients' cognition, verbal ability, and behavior, suggest the possibility that perispinal etanercept may have the ability to reduce the caregiver burden in selected patients with severe dementia. One may argue that these are observations in only a small number of patients. But rather than dismissing the potential scientific significance of these observations, it would be more scientifically appropriate to view these results as observations which merit further investigation [47
]. Small studies and case reports lend themselves to examination of individual treatment responses, particularly with diseases which are well-studied and characterized [47
]. In a study such as this, the first objective is often to establish the likelihood of a biological effect beyond the chance of a type I error, i.e., whether any individual experienced a significant treatment effect [47
]. Further study will be necessary to characterize response rates, dosing schedules, and duration of response.
As previously hypothesized, the current results suggest that perispinal etanercept may have the ability to influence brain function, perhaps through delivery via the cerebrospinal venous system [1
]. This form of delivery may be facilitated by the large surface area of the choroid plexus (which may be as much as one-half the size of the entire surface area of the cerebral capillaries) and by the decreased barrier characteristics of the choroid plexus [48
]. Etanercept reaching the choroid plexus could have widespread neuronal effects due to its effect on glia, even in the absence of deeper brain delivery, due to the widespread effects exerted on the multiple synapses even a single glial cell can control, through their extensive projections [3
As previously discussed, the rapid clinical improvements seen following perispinal etanercept may be due to synaptic effects related to the role of TNF-alpha as a gliotransmitter [3
]. Other molecules which function as gliotransmitters are adenosine, glutamate, ATP, and D-serine [50
]. Because of the related pro-inflammatory effects of TNF-alpha and IL-1, initially one might be tempted to speculate that IL-1 might have synaptic effects similar to those of TNF-alpha. Caution, however, may be in order, because these cytokines may have quite divergent clinical effects [53
]. Indeed, it is quite likely that the effects of different cytokines may vary across the different dementias, and even within the spectrum of diseases which we currently classify together as different forms of Alzheimer's disease [54
In addition to synaptic effects, etanercept may have vascular effects which may contribute to both the rapid and sustained clinical improvement noted. Etanercept may have the potential to improve endothelial dysfunction and thereby have a vasculoprotective role [8
]. In addition, etanercept may have the potential to improve microvascular function, particularly in a clinical disorder associated with TNF excess [55
]. This may be of particular importance in patients treated with perispinal etanercept who have a vascular component to their dementia, such as patients with mixed dementia consisting of Alzheimer's disease and vascular dementia.
Anatomically targeted delivery of etanercept, tailored to the disease target, may be critically important to ensure the success of the intervention [1
]. Delivery of etanercept into an anatomic structure where it would not have access to the primary site of pathology, such as intradiscal administration for treatment of radiculopathy, may doom such an intervention to failure [57
]. This highlights the concern of the authors that physicians inexperienced with perispinal administration of etanercept may attempt to initiate etanercept treatment in patients with dementia utilizing the routes normally used to treat rheumatoid arthritis and psoriasis patients i.e. subcutaneous administration in the abdomen, arms, or thighs. Published data do not support the concept that etanercept can reach the cerebrospinal fluid in therapeutic concentration if given by its usual method of subcutaneous administration in the abdomen [59
]. Etanercept does not cross the blood-brain barrier when administered systemically [59
]. Conversely, when delivered via perispinal administration into Batson's plexus, large molecules may have the ability to reach the brain via retrograde delivery through the cerebrospinal venous system, a potential anatomic route first demonstrated by Batson in cadavers [1
In addition to concerns regarding drug delivery, dosage and dosing intervals may need to be individualized for each patient. This requires experience with the use of perispinal etanercept in the treatment of patients with dementia. Potential side effects of the use of perispinal etanercept for the treatment of dementia, an off-label use, include all of the risks inherent with the use of etanercept for its labeled indications, which may include rare instances of death, infection, decreased blood counts, congestive heart failure, lymphoma, demyelinating disease, and reactivation of tuberculosis [62
]. PPD skin testing prior to initiation of etanercept treatment is mandatory, and a black box warning highlighting the risk of tuberculosis, sepsis, and severe infection has been added to the package insert [62
There are limitations to the data presented. The clinical trial was open-label, and not controlled. The data is limited. These caveats notwithstanding, the scientific rationale for the further investigation of anti-TNF-alpha treatment of Alzheimer's disease is compelling, with supporting genetic, epidemiologic, clinical, and basic science evidence [1
]. In addition, family members, independent neurologists, and other independent observers have confirmed the clinical, cognitive, and behavioral improvement noted [1
]. Nevertheless there is, as yet, no double-blind, placebo-controlled data, the availability of which would further strengthen the reported results. These additional clinical trial results in this 12 patient cohort, together with these case study results, further support the initiation of larger scale studies of this therapeutic intervention, including Phase 3 trials. 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 both Alzheimer's disease and semantic dementia which are worthy of further investigation.