The mental deterioration that comes with Alzheimer's disease is often viewed as a mercy to the afflicted. Unfortunately, what is merciful for the patient often extracts a devastating toll on familY and friends. For everyone, this preliminary report is a ray of hope in an otherwise bleak picture. If these initial case reports are true this could be a landmark moment in the effort to improve our understanding and treatment of Alzheimer's Disease.
DISCLAIMER: No one suggests this is a cure.
At best, this new therapy may only treat the symptoms of Alzheimer's Disease. However, treatment without cure does not diminish the potential value of this recently reported therapy. Millions of diabetics live active and productive lives thanks to therapies that treat symptoms. They are not cured by any stretch of the imagination, but who can argue with the benefits of self-administered insulin? Similarly, people suffering from Parkinson's Disease can improve their quality of life by treating the disease's characteristic motor symptoms with drugs like L-dopa. It is worth noting the people who demonstrated the importance of insulin and L-dopa were awarded Nobel prizes. This finding could be every bit as huge.
DISCLAIMER:
I have no economic interest in this story. I just think it's cool.
Intro:
Here's a nontechnical rendition of what this report means. I'm glossing over details and trying to keep the technical terms to a minimum so people can get a general understanding of this because I think it will be a big story for some time to come. For those interested in following this, I put the links at the end.
Case Studies:
The report covers a single case, although other cases do exist. In clinical research this type of report is usually considered a case report. You can think of case reports as anecdotes with reliable reporting. In fact, the first report of Alzheimer's Disease appeared as a case study in the British medical journal called The Lancet about 100 years ago. He reported on the case of a patient who Alzheimer followed for several years until her death. Identifying the characteristics of the disease led to several other cases being identified in the next few years.
There is nothing wrong with case reports as long as you keep them in context. When you are dealing with something a doctor might see once in their lifetime, if at all, it's a perfectly reasonable way to raise awareness so that others can keep an eye out for their once in a lifetime patient.
If the reports are reliable, over time we develop a body of literature that informs our understanding of a particular disease. Over the last 100 years, the understanding of Alzheimer's disease has advanced significantly. We know it's in the brain. We know there are specific derangements of cell structures. We know there are specific symptoms. We know it is a degenerative disease. It is suspected this may be related to inflammatory processes mediated by a molecule called Tumor Necrosis Factor-alpha (TNF-alpha).
Inflammation:
Inflammation is a normal response to injury. You get hurt and the immune system kicks in. A lot of stuff is going on in the injured area to repair the damage. Cells and molecules have to get in there to fix the damage. It gets crowded in there and things swell up. TNF-alpha is part of the signalling pathway that stimulates inflammtion.
Normally, things go back to normal after the damage is repaired. The immune response dissapears and the swelling goes down. When they don't you have a problem. A good example of a constantly turned on immune reponse would be rheumatoid arthritis. That is a case of an auto-immune disease where the body keeps attacking itself. The immune system is working overtime and damaging otherwise good material. There is reason to believe that is what is happening with Alzheimer's disease. For some reason, the immune system is attacking parts of the brain, specifically glial cells. The "plaques and tangles" seen in brains of patients with Alzheimer's are probably the aftermath of a specific type of cell damage.
The plaques and tangles are important, because that is the definitive way of identifying Alzheimer's disease. Unfortunately, you can only get that information by autopsy. Not so helpful if the patient is still alive. This means any treatment is carried out on a suspected Alzheimer's patient. Keep that important piece of information in mind as you read through this stuff.
The treatment:
The study takes a molecule that blocks TNF-alpha receptors and injects it into the central nervous system of an Alzheimer patient. This isn't as creepy as it sounds. Anyone who has had an epidural during delivery has had stuff injected directly into their central nervous system. They probably thanked the doctor for that too.
The drug is called Etanercept. Here's a formal description for anyone interested in pursuing this:
Etanercept is a recombinant dimeric fusion protein consisting of the extracellular ligand-binding portions of two human p75 TNF-alpha
receptors linked to the Fc fragment of human IgG1.
Patient summary:
The patient is an 81 y.o. physician who was referred in October 2007 for consideration of perispinal etanercept treatment by his internist. The patient had been in good general health until about two years before presentation, at which time his wife noted progressive memory difficulties and difficulties with mathematical calculation.
The patient used to be a doctor himself. Obviously, he was of above average intellect and functioned very well until things deteriorated. He had a history of high blood pressure and elevated cholesterol but nothing outstanding:
the past medical history was unremarkable, with no history of diabetes, stroke, transient ischemic attack, head trauma, epilepsy, loss of consciousness, hallucinations, recent infection, demyelinating disease, or blood or bleeding disorders, lymphoma, congestive heart failure, autoimmune disease, immunosuppression, tuberculosis or visual disturbance. Purified protein derivative testing was negative. Family history of dementia or neurodegenerative disease was negative.
Remember, the definitive diagnosis for Alzheimer's is done at autopsy,so you have to rule out all the other possible causes before tagging someone with that diagnosis. I've highlighted the important points about his mental abilities below:
Mental status examination performed one day prior to etanercept administration revealed a dignified appearing man who appeared
younger than his stated age, neatly groomed and socially outgoing in a
superficial engaging fashion. There was no agitation, suspiciousness,
or hostility. He appeared at times to be inappropriately euphoric.
He had difficulty recalling personal autobiographical information such as birthday or his father’s occupation. He could not recall the names of any of the physicians who treated him. He was not oriented to the calendar date, day of the week, year, place, city, or state.
His spontaneous speech appeared fluent with normal prosody, articulation, and rate of speech production without any dysarthria.
On detailed examination he had marked anomic aphasia, i.e., when shown the first ten pictures of the Boston Naming Test the patient could not name nine out of ten, but used marked circumlocution. He was able to repeat complex sentences without difficulty. On a verbal fluency task, i.e., when asked to list all of the words that start with the letter F in 60 seconds he listed five words with five perseveratory responses and one neologism. When given a semantic task, i.e. asked to list all the animals he could in 60 seconds he could only list two, dog and cat.
That's pretty severe for someone who used to be a doctor. That would be pretty severe for a third grader.
On memory testing the patient could not recall the name of physician HG after 90 seconds despite repetitive introductions on at least four occasions throughout the examination. It took three trials for the patient to register five words and 90 seconds later the patient could not retrieve any of the words even with categorical cueing. When given multiple choice cueing he was able to retrieve two words. On an A vigilance task, screening for sustained attention, the patient made four errors of omission. He was able to list five digits in a forward fashion, but could not list three digits in a reverse fashion.
Clearly the short-term memory is not working in this patient.
The patient could not perform simple calculations and could not do
serial sevens. When asked to add 29 plus 11 after a marked latency he said 31. Abstract concepts such as a how a train and a bicycle, a watch and a ruler, or music and painting were similar could not be expressed by the patient.
On the Montreal Cognitive Assessment test (MOCA) the patient scored seven out of 30 possible points, consistent with a moderate to severe cortical dementia.
The patient met the NINCDS-ADRDA Criteria for probable AD, and, in addition, met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for AD.
That is important because it establishes an ethical basis for using a drug normally prescribed for rheumatoid arthritis in an experimental way. If you are going to do this kind of work, it is important to do it in an ethically defensible way.
Immediately prior to etanercept administration the patient was
questioned by author ET. He could not state the year nor could he
name the state.
Twenty-five mg of etanercept in 1 cc of sterile water was administered
by posterior cervical interspinous injection in the midline with a 27
gauge needle at the C6-7 interspace followed by Trendelenburg
positioning with the head dependent for five minutes, as previously
described, to effect entry of etanercept into the cerebrospinal venous
system. The patient had no difficulty with this positioning and
resumed sitting posture without incident.
(In other words, they put a really fine needle into his spinal column near the base of his neck and pumped in a small amount of the drug.)
Ten minutes after dosing the patient was reexamined. He was noticeably calmer, less frustrated, and more attentive. He was able to correctly identify the state as California, and he identified the year as 2006. His responses to questioning seemed less effortful and more rapid, with less latency. He left for author HG’s office for further testing.
Neurologic examination two hours after etanercept treatment:
The patient was retested by author HG two hours after etanercept administration. He could not recall being in author ET’s office earlier in the day, but could recall HG’s name. He was now oriented to month, day of week, and place, and could again correctly name the state as California, which he could not do prior to perispinal etanercept administration. He was off on the calendar date by two days, and year by one year. Throughout testing he appeared more aware of his deficient performance.
The patient’s ability to name pictures was markedly improved, correctly naming nine out of the first ten pictures on the Boston Naming Test short form, requiring phonemic cueing for three of the items (squid, bench, and hammock), a marked improvement from the day prior when he could only name one of the ten presented pictures and used marked circumlocution. On the verbal fluency FAS test he was able to list eight words that started with the letter F in 60 seconds and made only one perseveratory response. On a categories semantic task he was able to list five animals in 60 seconds.
On attentional testing, the patient could accurately list five digits in a
forward fashion and three digits in a reverse sequence fashion. On an
A vigilance task he made no errors of omission or commission.
On calculations, he could subtract seven from one hundred correctly, but could not perform serial sevens. He could not divide 58 by two, nor could he add 29 plus 11. He could not tell physician HG how many nickels were in a dollar.
On ability to abstract concepts he was able to relate how a train and bicycle were similar in that they both can be used for transportation. When asked how a watch and a ruler were similar he related that they both give information. When asked how music and painting were similar he stated "you draw your painting, however music you hear".
Montreal Cognitive Assessment performed two hours following the
single dose of perispinal etanercept yielded a score of 15 out of 30
points.
That is not a complete reversal by any means, but it is stunning how much of a reversal is seen so quickly after treatment. That suggests the cognitive symptoms commonly associated with Alzheimer's Disease may be due in part to a chronic inflammation. I want to be careful about drawing causalities here, but that is a big deal if you consider the alternative hypothesis: that the symptoms are due to the destruction of parts of the brain. Think of it this way: If you have water in your fuel line, you can bleed the line and get things working again. If you have a blown fuel pump, you have to replace it. That's a big difference when you have a custom engine and they don't make extra fuel pumps.
Here's the follow up:
Upon returning to the clinic one week following perispinal etanercept administration for his weekly dose the patient’s wife and son confirmed that he had remained markedly clinically improved throughout the week, a fact which was remarked upon by the family.
On re-examination by author ET prior to repeat dosing one week after the initial dose, the patient correctly identified the year, month, season, day of week and state. He appeared to answer with less frustration,and the examiner’s impression was that there was reduced latency of response, and his affect seemed improved. On the FAS test for verbal fluency when asked to list all of the words that start with the letter F in 60 seconds he listed 8 words, and named 5 animals in 60 seconds. The patient received a single dose of perispinal etanercept for each of the first five weeks; the next dose was omitted, and the patient returned after seven weeks and was retested. At seven weeks, fourteen days after receiving his last dose of perispinal etanercept, his Montreal Cognitive Assessment score was 14 out of 30.
That is pretty stunning. The Montreal Cognitive Assessment score change is more than 3 standard deviations. That is not a coincidental result.
The Million Dollar Question
Is this going to stay the same or will he relapse? Does he really have Alzheimer's disease in the first place? Is the rapid response the result of inhibiting an inflammatory response, or is TNF-alpha (as the authors suggest) playing a role in signalling between nerves? The last question is important because it raises the possibility that they may not have reversed a problem so much as found a work around.
As the authors note in their discussion:
When TNF-alpha is overexpressed, due to glial activation,(consider this inflammation) it is postulated that the synaptic regulatory activities of TNF-alpha are disturbed. Synaptic dysfunction is hypothesized to result from this dysregulation, which may provide a basis for reduced functional connectivity between brain regions in Alzheimer’s disease. The rapid effects of perispinal etanercept are hypothesized to be the result of rapid neutralization of excess TNFalpha, which thereby ameliorates this synaptic dysregulation, allowing normal cross talk between different regions of the brain.
In other words, think of TNF-alpha like blood sugar. If your blood sugar is way out of whack (too high or too low) you can be disoriented, or even comatose. This is the problem diabetics run into when their blood sugar is poorly regulated. Insulin controls the levels of blood sugar, keeping it in a normal range so you don't wind up having to pee all the time, or get dizzy, or slip into a coma. Obviously, it is more complicated than that, but that analogy gives a basic flavor of what the authors are suggesting here.
In any event, if you are interested in following this here are some useful links:
The original report(Abstract with link to PDF.)
TNF-alpha inhibition as Alzheimer's treatment (Mayo Clinic)
Earlier Clinical trials of anti-TNF-alpha with Alzheimer's
General read of the study
TNF-alpha (Wikipedia intro with references)
TNF-alpha and TNF-alpha inhibitors (general reference)