Lecanemab killing people??

There has been a great deal of enthusiasm for lecanemab following the seemingly positive results of Biogen's phase 3 clinical trial.  Only one problem ... two test subjects died during the trial.  Biogen and their partner, Esai, made a statement claiming the deaths were not a consequence of the use of lecanemab, but rather significant comorbidities in the subjects.  But now there has been a third death.  Neuroscientists recruited by Science.org (publication of American Association for the Advancement of Science) reviewed the medical records of the Florida woman who died in the third case and concluded her death was most likely caused by lecanemab.

All of the "mabs" (monoclonal antibodies) cause brain swelling and microhemorrhaging  But, until lecanemab, none of these led to any deaths.  If you take Aduhelm, the first mab treatment to be approved by the FDA, you must get regular MRIs to check for swelling and microhemorrhaging.  And while there were no deaths during the clinical trials for aducanumab (now marketed as Aduhelm) at least one patient being treated with Aduhelm has now died.  This was apparently a consequence of using the mab.

So what do Biogen and Esai have to say about the new death?  I don't know.  I've visited the press rooms of both companies, and I can't find anything they've said yet.

There is nothing new about patients dying during clinical trials or even from drugs that have been approved by the FDA.  Of course, the diseases they hope to treat are themselves even more deadly.  The hope is that the inevitable risks are well understood and weighed before beginning a course of treatment.  And one purpose of drug trials is to measure previously unknown risks and effects of taking an experimental drug.  I'm waiting to see what Esai, Biogen, and the scientists engaged in testing and understanding the risks and rewards associated with mab treatments have to say about the safe testing and and use of lecanemab and other mabs.

Education -- or occupation? What helps resist Alzheimer's disease?

A well-established concept in Alzheimer's disease research is cognitive reserve.  For whatever reason, people with more education are less likely to develop Alzheimer's disease.  They call it "cognitive reserve," suggesting that a better educated brain has something in reserve to compensate for the deterioration that comes with disease.  This isn't by way of storing up information, but rather the process of learning causes changes in the structure of the brain that strengthen it.

We discussed cognitive reserve in Beating the Dementia Monster, pairing education with intellectually stimulating occupations.  We left the question open as to whether this reflected a) learning activities strengthening the brain, b) a likely higher IQ among the better educated, or c) better education leading to more stimulating occupations. So part of the question is, were you simply born with that reserve (nature), or did it develop as a consequence of life experiences (nurture)?  If life experiences, was that due to learning activities when you were younger or to a mentally stimulating career?

The question of why education would correlate with cognitive reserve has been investigated in the United States and in some other countries where most of the population is better educated.  My sense is that the evolving consensus is that the mental activities associated with learning build cognitive reserve.  But the question is still open regarding the role of the mentally stimulating occupations better-educated people are likely to occupy.  Would doing this research in a population biased toward lower education reveal anything different from the research conducted in generally well-educated countries?

I came across an interesting article in the November issue of Alzheimer's and Dementia; the journal of the Alzheimer's Association.  It was entitled, "Education, but not occupation, is associated with cognitive impairment: The role of cognitive reserve in a sample from a low-to-middle-income country."  I don't subscribe to Alzheimer's and Dementia, so I had to infer the content of the research from the abstract.

From the title of the article, we see the researchers concluded that the activity of learning contributed to the development of cognitive reserve.  Stimulating occupation ... not so much.

So, in what country did they do the research?  The abstract didn't say, but the researchers were from Brazil.  So I'm guessing that's where they did their work.  The researchers studied mental capacity of 1,023 subjects.  Seventy-seven per cent had less than five years of education, and 56% were in unskilled occupations.  They found that occupation complexity and demands were unrelated to cognition.  

They concluded that, "Education, but not occupation, was related to better cognitive abilities independent of the presence of neuropathological insults."  They used the established "Clinical Dementia Rating Scale" to relate their findings to what would likely be the presence or absence of neurodegenerative disease.

I'm left wondering a bit as to whether they tied all of the pieces together to get to their conclusions.  Do their results establish a distinctive relationships between learning and occupation in the context of disease?  I'm not so sure. But it does appear that they have reinforced the belief that educating people, especially young people, builds resistance to Alzheimer's disease.

How it all went

As advertised, I had my lumbar puncture/spinal tap on Monday, and the kidney stone treatment on Wednesday.  All went fine.  The spinal tap was significant, because it probed what was going wrong in my brain to cause my balance problems.  The kidney stone seems to be a consequence of the way I have implemented the MIND diet -- too much spinach and almonds.  So I should rely more on kale and broccoli instead of spinach, as well as peanuts and walnuts instead of almonds.  These have less oxalate, but have similar benefits for brain health.

We arrived at the hospital in time for my appointment at 5:55 a.m.  Really early.  I was in general anesthesia when they inserted the stent in my right ureter and then hit the stone with shock waves.  When I woke up, I was back in the recovery room for a couple of hours, and then we went home.  That was a little after 11:00 a.m.  

So far I've had very little pain but a certain amount of blood in my urine.  With the stent still in, they don't want me to go back to the gym for a while.  They want to give the fragments a couple of weeks to pass, and then they'll do a CT scan to see if any are left too big to pass through the stent.  If there are, we go back for another shock wave treatment.  I may still need general anesthesia to remove the stent, but I'm not sure.

So this wasn't too terrible, at least no so far.  I always feel kind of crummy the day after general anesthesia, and today is no exception.  But I'll be fine.

I'll be seeing the urologist in early January.  He should have results of chemical analysis of the stone to determine how I should modify my diet.  But the situation looks clear to me.  I read that about 80% of kidney stones are oxalate, and that correlates with me increasing my intake of foods high in oxalate for the MIND diet.  But there are plenty of ways to implement the MIND diet without overdoing it on oxalate.

More skeptisicm of the amyloid hypothesis

In Beating the Dementia Monster, we expressed some skepticism about the amyloid hypothesis and the current ideas about the role beta amyloids play in Alzheimer's disease.  The concept is that malformed proteins (actually, peptides) are excreted from the cells and form plaques in the brain.  The plaques stick to brain cells and kill them.  So the driving idea in research and the search for effective treatments was to find ways of removing the plaques and cure, or at least impede the disease.

This hasn't worked out very well.  I was skeptical of the hypothesis, although I toned down my approach following comments by reviewers of the manuscript prior to publication.  Researchers have found they can remove the plaques without curing the disease.  So this hasn't worked out very well.  Aduhelm removes the plaques, but no one is satisfied with how well it alters the course of the disease.  Lecanemab may be a little better, but it's not a cure.  And it might have killed some of the test subjects.  If repeated failures of experimental treatments wasn't enough, we found that fraud had reinforced faith in the amyloid hypothesis.  

In Beating the Dementia Monster, we discussed several alternatives to the amyloid hypothesis.  These included the propagation of gum disease bacteria into the brain as well as infection with the herpes virus.  Environmental considerations, such as air pollution, correlate with increased incidence of the disease.

Science is coming to terms with the fact that this is an extremely complex disease, and there may be far more moving parts than have been anticipated.

I read this fascinating but long article that traces the history of Alzheimer's research up to the present conundrum.  It's main focus is on the amyloid hypothesis and how it may have led researchers astray for many years.  Research was so focused on it as the explanation for Alzheimer's disease, that researchers pursuing other paths were marginalized.  Research money was scarce for anything outside of the amyloid bubble.

The author of the article is a bit biased, and she follows the story of a few iconoclast researchers.  In so doing, she focuses on one particular alternate explanation, the "endosomal-lysosomal hypothesis."  

One appeal of the amyloid hypothesis was that it was simple.  These plaques are forming and killing cells, so just get rid of them.  What could be easier.  Except that it hasn't been working out.

The endosomal-lysosomal hypothesis is a lot more complicated.  It involves autophagy, or how cells reach the end of their lives and recycle their constituent parts.  Aficionados of the Keto diet and the more extreme forms of intermittent fasting will know about promoting autophagy and its benefits. 

One distinction between the two hypotheses is the role of beta amyloid.  In the original amyloid hypothesis, amyloid is excreted from the cell, forms plaques, and the plaques kill cells from outside.  In the endosomal-lysosomal hypothesis, the amyloids kill the cells before they leave.  So cleaning out the amyloid from the brain is like removing the gravestones from the graveyard.  It doesn't make the people come back to life.  

The endosomal-lysosomal hypothesis posits that there is a complex disruption in how the cells die and recycle their constituents.  It's too complicated for this blog, but you can read the article.  And the author says something that I've been hearing for a while.  None of these hypotheses fully explains this incredibly complex disease.  Perhaps they are all playing different roles in a bigger story.  The author subtly recalls the Hindu parable of the blind men and the elephant. 

One down, one to go

Yesterday, I went for my lumbar puncture / spinal tap experiment.  I showed up at the hospital an hour before the procedure and met with a physical therapist.  She administered a number of tests of my balance and gait, finding that I was a "severe" fall risk, at least by one of her measures.  After that, they drained 30ml of cerebrospinal fluid from the lumbar region of my spine to relieve pressure in my brain.  They repeated the tests one hour after the procedure and then two hours later.

When I arrived in the hospital gym to perform the second set of tests, I didn't feel better balanced and didn't notice improvement in my gait.  So I was initially disappointed.  But Amy did notice improvement, and the physical therapist's tests found distinct improvement.  She pointed out to me that, when I walked, the leading foot would now go out significantly farther than the other, and I moved more quickly.  This was whether I was walking normally or as fast as I could.  Her protocol found that I was now on the low end of "moderate" fall risk.

These results indicate that normal pressure hydrocephalus may be complicating my scenario. 

So, at the time I was being tested, I didn't perceive the improvement, but that evening I very much did.  It was exhilarating to recognize how well I could walk.

According to the surgeon, about 20% of procedures lead to headaches after the supply of cerebrospinal fluid (CSF) in the brain is depleted.  In this case, they would be removing 3X the volume of CSF that they normally drain, so the probability of headache was much higher.  My sister-in-law reported that she had an extremely severe headache after a lumbar puncture she once had.  I very definitely developed a headache, and I still feel it a day later.  And because of tomorrow's kidney stone surgery, I'm not allowed to take aspirin. acetaminophen, or any other anti-inflammatory medication.   

Of course, right after the lumbar puncture, my body went right to work replenishing the CSF, and my balance has returned to where it was before the procedure.  I will see my neurologist in a few weeks to consider the possibility of a shunt as a more durable solution.

My mother has a warning for me.  At 93, she was tested like I was and found not to be a fall risk.  She was so happy with the that result, that she went out to her garden to work, fell, and broke her wrist.  I believe that was this past spring.  (I saw her in mid-November, and she seemed to be doing OK with it.)

Tomorrow morning, we're to show up for surgery at 5:50 a.m.  That's for the kidney stone.  Hopefully, this will also go well.  I remain anxious about the effect of general anesthesia on the condition of my brain.

My challenges this week

As I mentioned before, my implementation of the MIND diet may have contributed to the formation of a good-sized kidney stone in my right kidney.  It's apparently too big to pass on its own, so they want to break it up with shock waves.  That's supposed to happen on Wednesday.  I'm told the process is unpleasant and protracted.

Also, I have a new (additional) neurologist who wants to further explore the possibility that my balance problems are actually caused by hydrocephalus rather than (or in addition to) Alzheimer's disease.  About a year ago I saw a neurologist in Seattle known for his work on hydrocephalus, and he concluded hydrocephalus was not my problem.  But he didn't do the standard test for this, which is to drain about 30ml of spinal fluid and see if that improves balance and gait.  Draining spinal fluid drains fluid from the brain, which may relieve excess pressure on the part of the brain that controls balance.  Tomorrow, the new neurologist will drain that 30ml of fluid, and we'll see what happens.

So this looks to be an exciting week.  Monday (today) for the spinal tap (more properly called a lumbar puncture), and Wednesday for the kidney stone procedure.

As we discussed in Beating the Dementia Monster, I had a spinal tap for the SNIFF study.  I didn't find it terribly onerous, despite its reputation.  The kidney stone procedure is another matter.  My urologist tells me that no one likes him very much after it's all done. 

I have one reservation.  The kidney stone procedure requires general anesthesia, and this is known to aggravate Alzheimer's disease.  What will this mean for my memory and cognition?  And then, the doctor tells me that some fragments of the stone may still be too large to pass, and I may need to return in a couple of weeks to try again with another course of general anesthesia.  This will put more stress on my brain.  On the other hand, the stone could kill my kidney if it's not removed.

Is it about the Christmas colors? Green tea and red wine continue to attract attention of research.

If you read Beating the Dementia Monster, you know that red wine is considered part of the MIND diet, a diet that appears to be effective in supporting brain health.  As I mentioned in the book, I don't drink, and so I don't turn to red wine as part of my own diet.  (I make an exception for celebration of the Eucharist.)  Red wine contains resveratrol, the chemical component thought to be helping the brain.  Unfortunately, research has not found that extracting the resveratrol and taking it as a supplement will help with brain health.  At least not until recently.

Green tea has also attracted interest for brain health, and I have taken it at times.  However, it has caffeine, and the caffeine and acids in the tea get to be a problem with my insomnia and nocturia.

Recently, my friend Teale sent me this article in Neuroscience News about some research at Tufts University on green tea and resveratrol.  The researchers claim to have found green tea catechins and resveratrol may reduce the formation of amyloid plaques in neural cells.  

What did the resveratrol and the catechins do?  The researchers believe that they acted as antiviral agents against the herpes virus.  As we discussed in Beating the Dementia Monster, the herpes virus is high on the list of suspects for causes of Alzheimer's disease.  Researchers at Tufts have done other work tying herpes to Alzheimer's disease.

But don't get your hopes up too high.  This was not research done in humans or even in brains.  It was done in the laboratory with cells on a sponge simulating a brain.  And lot of work has been done already simply seeing what happens when people consume more resveratrol and green tea.  The benefits have been marginal.  The real value of the research seems to be to support the hypothesis that the herpes virus--the variety that causes cold sores and chickenpox--also causes Alzheimer's disease. 

My new Fitbit

So, for Black Friday, Amy encouraged me to get a Fitbit.  My mother wears a Fitbit every day, counting her steps.  And one or more of my siblings have theirs to track their exercise and other health parameters.  My friend Carlos, in Ecuador, recently got himself a Fitbit.  

I actually bought one a year or two ago, but I balked at activating it when I saw how much personal information they were collecting about me.  And it's not much use if it's not connected.  So I returned it.  This time, there were profuse claims in the literature about how they protect and won't share my information.  (Alphabet (Google) owns Fitbit.  So who's left to want to get your information?)

I'm already satisfied with my exercise plan and other things I do with respect to my lifestyle, but I want to know more about my sleep.  The Fitbit appears to do a good job of monitoring and grading your sleep.  

I wrote recently about my use of sleep meds.  They have helped a lot, but I don't use them every night.  Many nights I sleep very poorly, even when I take a pill.

If you read Beating the Dementia Monster, you know how important sleep is to brain health, especially the deep sleep phase.  You cycle through the phases of light sleep, REM sleep, and deep sleep throughout the night.  It's during deep sleep that changes in the flow of cerebrospinal fluid will sweep Alzheimer's-related trash out of your brain and into your lymphatic system for removal.  So insufficient deep sleep promotes Alzheimer's disease.  As a treatable factor in Alzheimer's, it's #2 behind exercise for resisting the disease.  The best research points to seven hours of good sleep as optimal for brain health, with perhaps 18 to 30% of that being deep sleep.

I've been using the Fitbit for a few days now.  What have I found?

First off, I've confirmed that I don't sleep well.  Each night I get a numeric score on my sleep, with it classified as poor or fair.  I presume people who sleep better than I do can score "good" and maybe "excellent," but I haven't gotten high enough numbers to find out.

In fact, the first night I used it, I couldn't sleep long enough for it to even score me.  Subsequently, I've had one night graded as poor, and three nights graded as fair.

For deep sleep, the first night I got 10 minutes.  Over the following nights, I got 39 minutes, 47 minutes, 47 minutes, and 54 minutes.  This is all less than optimal, since I should be getting at least 18 % of seven hours.  That's 76 minutes.  At least, that's how I understand these things.

The Fitbit is just taking a measurement.  At this time, I have no reason to expect my sleep to improve no matter how much I wear it.  However, my memory and cognition seem to be doing OK for now, and I feel well during the day.  I occasionally doze off for a couple of minutes, but I'm otherwise alert throughout the day.  At night, when I'm done sleeping, I'm done sleeping.  I'm only rarely able to get back to sleep and get to that seven hours, and then only with a pill.

I have been very curious about my sleep for some time.  The Fitbit seems to be answering my questions.

You heard it here first!

In both editions of Beating the Dementia Monster, we wrote about two prospective monoclonal antibody treatments for Alzheimer's disease.  These were aducanumab (now known commercially as Aduhelm) and BAN2401, code name for lecanemab.  After my experience auditioning as a trial subject for aducanumab, I was less than fully enthusiastic about it, but I had great hopes for BAN2401.

Well, as events have played out, much of the Alzheimer's world is disappointed in Aduhelm, and lecanemab may struggle as well.  On November 29, the New England Journal of Medicine published the peer reviewed results of the clinical trials for the treatment with results that disappointed some.  For one thing, two deaths due to brain swelling occurred with patients during the trial that were initially associated with the treatment.  Recall that all of the amyloid-eating "mabs" cause brain swelling and micro-hemorrhaging.  Biogen's partner, Esai, subsequently released a media statement claiming that the deaths can't be blamed on lecanemab.  You can make up your own mind about accepting their claim. 

As with Aduhelm, the Alzheimer's Association is all in on lecanemab, and is pressing for prompt approval by the FDA.  They made this statement, encouraging the FDA to move ahead.  The Alzheimer's Association has perhaps an outsized political presence, and their viewpoint carries a lot of weight.

The researchers who conducted the trial were a bit more circumspect and less optimistic.  They concluded, "Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events.  Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease."

Is this the setup for another drama like the one we had when the FDA approved Aduhelm?