| |
Report on Enbrel Study
By Dr. Jack Diamond, Scientific Director, Alzheimer Society of Canada
The news
A recent widely publicized report is causing great excitement among both Alzheimer researchers and Alzheimer caregivers. A single drug treatment of an 81 year old man with moderately advanced Alzheimer's disease appeared to produce a significant recovery of cognitive function and of memory capability within about 10 minutes of administering the treatment. What are we to make of this?
What's going on in the Alzheimer brain
The major event which underlies the entire disorder is the progressive death of nerve cells. This is irreversible. However, cell death does not happen instantaneously. First the nerve cells become sick (rescuing sick nerve cells before they die is a major objective of researchers). That individual nerve cells have a long sickness period is consistent with the many years over which Alzheimer's disease progresses, but the best evidence is that cholinesterase inhibitors can help maintain key functions of surviving but sick nerve cells for periods of up to three years or more after the disease is diagnosed.
The first regions of the nerve cells to be affected in Alzheimer's disease are the most distant, and therefore the most vulnerable, parts of the cell; these are the endings of the nerve fibres which contact the next cells in the circuit. These junctional regions across which the nerve messages are transmitted from one nerve cell to another are called "synapses" (the Greek word for the Latin "contacts"). Synaptic functions (involved in the "synaptic transmission" of messages) are the first victims of Alzheimer's disease. Impaired synapses means impaired communication between nerve cells; it happens long before nerve cells die, and is now recognized as being responsible for the first signs of Alzheimer's disease. The new report actually focuses on synapses.
What is causing the nerve cells to become sick in the first place?
This question is what guides researchers in their quest for a cure. What we do know is first, the sickness is initiated when the levels in the brain of a number of key substances increase, and second, that these increases are triggered by aging and exposure to the various other risk factors for Alzheimer's disease. The most important of these threatening substances is a protein called beta-amyloid or "A-beta" for short. The individual A-beta molecules rapidly begin to stick together first to form the small highly toxic fibrils called "oligomers" and eventually the much bigger but still microscopic "senile plaques" which are scattered throughout the brain. The oligomers and plaques also help promote the appearance of the other major abnormality, namely the fibrous tangles which develop inside nerve cells and in a sense choke them to death (they are made largely of a protein called "tau", not A-beta).
Along with the plaques and tangles, the third major adverse event that is responsible for some of the threatening substances in the Alzheimer brain is neuroinflammation, and is the theme of the new report. Inflammatory processes are actually normal protective responses of the immune system to disease or trauma, and they involve the release from special immune cells of protective substances known as "cytokines". The immune cells of the brain are part of its "glial cell" population; glial cells far outnumber the nerve cells, and are a sort of "caregiver" community. Unfortunately, as the Alzheimer's disease progresses, the levels of the protective inflammatory cytokines released from glial cells rise to toxic values, contributing to nerve cell death.
The new report
What the authors of the new report did was test the effects of a drug called Etanercept (Enbrel). Etanercept is used especially to treat rheumatoid arthritis and also a skin disorder called psoriasis, and works by binding to a member of the inflammatory cytokines mentioned above, specifically the one known as TNF alpha. The rationale for testing Etanercept was that high levels of TNF alpha are reported to develop in Alzheimer's disease, enough not only to have direct toxic actions on nerve cells, but also to promote the production both of the threatening A-beta protein and of other cytokines which can induce the appearance of A-beta. And to cap it all, as A-beta levels increase they cause yet more production of TNF alpha (this is called a "positive feedback loop"). In this instance, a dose of Etanercept was injected through a needle inserted into the spine at the back of the neck to achieve an "extrathecal" delivery, i.e. outside the membranes surrounding the spinal cord, the assumption being that the numerous veins in the vicinity would convey the drug to the brain, where it would do its job. There had already been a preliminary study in 2006 of 15 Alzheimer patients who received Etanercept weekly and after 6 months some cognitive improvement was noted. In the new study an improvement was noted within 10 minutes of the first injection, and the improvement lasted seven weeks, the injections being given for the first five of these weeks.
Problems with the new report
The ten minute issue. First, it's important to understand that even if a drug were to totally prevent all of the causes of nerve cell sickness described above, it would at best stop progression of the disease (though let's not ignore the fact that this would be a huge achievement). To cure the person, however, requires that there also be at least some reversal of cognitive and memory defects. Given the moderately advanced stage of Alzheimer's disease in the person studied in the new report, a significant degree of cell death must already have occurred in the brain. Our present understanding of how recovery of cognition and memory could occur after significant nerve cell death requires that new connections become established in the brain and/or that old connections become reestablished. These nerve growth-related mechanisms take time, however, at the very least days, but more likely weeks or months. Obviously 10 minutes is hopelessly inadequate for significant circuitry repair to occur. As for sick but still surviving nerve cells, it seems very unlikely that that their impaired synaptic functions could be restored to anything like normal levels in 10 minutes.
How do the authors of the new report deal with these concerns?
They cite evidence that one of the normal beneficial roles of TNF alpha secreted from glial cells might be a regulatory one; it's been suggested that TNF alpha somehow helps orchestrate the thousands of synapses involved in even the tiniest activity under brain control, to work in harmony, thereby (it's suggested) enhancing the brain's efficiency (this summary is that of the present reviewer). The authors postulate that this suggested regulatory role of TNF alpha is jeopardized when TNF alpha levels increase, as happens in Alzheimer's disease, the consequent "synaptic dis-harmony" (reviewer's wording) resulting in impairments of cognition and memory. The improvement observed a mere 10 minutes after injection of a single dose of Etanercept is suggested as due to the TNF alpha actions now being reduced to normal values, allowing the normal regulatory role of this cytokine at the synapses to be exercised. This explanation then is independent of conventional nerve cell sickness. It's hard, however, to see how it could account for recoveries of cognitive impairments due to the death of nerve cells. Neuroscientists might find these speculations more appealing if some solid evidence existed to support them.
Where do we stand?
There has to be some explanation of the authors' observations of apparent recovery of missing or reduced cognitive and memory functions. The solution to this conundrum, however, might emerge from quite different considerations.
The major problems with the report relate to the absence from it of the conventional procedures expected of a clinical or scientific study, especially anticipated when the reported results are unusually challenging or controversial. The study was done on a single person. Even three or four would have helped make the findings more acceptable, but what is required are much larger numbers than these, including "controls", equivalent subjects in which the therapeutic procedure was carried out but with the drug in question replaced by a sterile saline solution, a "placebo". This crying need for "control" studies tests the ability of the procedure itself to produce the observed result, rather than the drug under study (admittedly this is not always possible to do for ethical reasons). Alzheimer patients are known to be very susceptible to placebo effects, and also to be unusually variable over time, their responses going up or down as the conditions change (altered domestic conditions, eating schedules, presence of different people, any kind of stress, and so on). In this instance, to help the drug reach the brain the patient was positioned for a brief while with head down and feet raised. Overall the entire injection procedure requires the involvement of anaesthesiologists or neurosurgeons to be carried out successfully and non-traumatically. It's impossible to imagine it becoming a routine therapeutic approach in Alzheimer's disease, but it's not difficult to see it as an unusually stressful event. And there are particular scientific concerns. TNF alpha levels don't always rise in Alzheimer patients, and there is no consistent evidence that extrathecally-delivered drugs do travel via veins to reach the brain.
We especially need the study to be repeated in other clinics, and by researchers who have no vested interest in the results (the lead investigator in the present report has stock in the company which makes Etanercept). Incidentally, TNF alpha inhibitors like Etanercept can induce a number of important side effects, which include uveitis (inflammation of the eye), reactivation of tuberculosis, autoimmune hepatitis (a liver disorder), aplastic anaemia (a blood disorder), peripheral neuropathy (painful condition of nerves), optic neuropathy (optic nerve disorder), septic arthritis (joint infections) and systemic lupus (an autoimmune disease that can attack many of the body's organs or tissues such as skin, muscles, joints, lungs and heart). Not a drug to be taken lightly!
And finally, although this patient has Alzheimer's disease, could a part of the cognitive and memory impairments be attributable to inflammatory swelling in the vicinity of the brain and cervical spinal cord, the observed improvements then being explained by a rapid reduction of the swelling due to the combination of altered body position and pharmacological inhibition of the inflammatory cytokine, TNF alpha? An explanation along these lines is much more plausible to this reviewer than the one presented by the authors of the report.
Conclusion
The reasons given above indicate that this new report is seriously flawed. As presented it cannot be accepted as offering support for the use of TNF alpha inhibitors like Etanercept in Alzheimer's disease. Reports such as this actually do damage to the cause; they raise false hopes in those with the disease and in their caregivers, and they give false impressions to non-researchers as to how research is actually done.
|
