End of the Insulin Study -- Good News, Bad News

On Tuesday, we went to the VA hospital in Seattle to finish the insulin study.  This required one last round of cognitive tests and a physical.  I was anxious, because I didn't sleep well Monday night.  (I slept well before my April tests, but I bombed the February tests when I didn't get a good nights sleep before those tests.)  But during Tuesday's tests, I could sense that I was doing well.  Afterwards, the study coordinator did a qualitative "eyeball" look at the results in comparison to April, and he said it looked to him like I had done a little better this time than before.  This is consistent with my general sense that I've at least been holding steady for a long time.  This is, of course, consistent with the stability shown in my last MRI.  Did the insulin contribute to how well I did on Tuesday?  Who knows.  But these results were consistent with the trend that was in place before I started on the actual insulin.

The physical didn't go so well.  The PA who conducted the physical called in the senior Doctor and told her I had a heart murmur.  She said it was louder than a Grade 3.  The doctor listened and agreed, indicating that it was not quite grade 4, but loud nonetheless.  They said that I should get in to see a cardiologist promptly -- this week, and I should let them know if I had trouble.

After reviewing events in my life from the past couple of months, they said the murmur was likely due to a heart valve infected following a teeth cleaning.  Since then, I'd awakened at night a couple of times out of breath.  This was likely due to a defective valve causing inefficient pumping of blood.  I also had a sudden, transient event in which my eyes couldn't coordinate.  They said this was likely a TIA related to problems with the heart valve.  The best solution will be antibiotics.  Failing that, I'll need a valve replacement. 

Turned out to be hard to get into see a cardiologist.  Soonest I could get was September 24.  But I was able to get my primary care provider to order an echocardiogram for next Tuesday.  This is good.  I'm sure that my primary care provider can move my situation along as warranted by the test results without the cardiologist.

The researchers were very happy with my performance on the insulin study.  They only had three participants at their site (there were many sites across the country), and the other two had dropped out well before finishing.

When will we know the results of the study?  The team in Seattle doesn't know, but they said they'd tell me when the results are available.  I've learned that if the results aren't very promising, you hear quickly.  If they are promising, they like to wait for a big meeting where they can make a splash with the news.  It's evident to me that they are mostly interested in the results from the first year when the study was placebo-controlled.

They are very interested in engaging me in another, promising study.  I'll wait until after this heart valve business is cleared up before I look into the other one.

What I'm really worried about is the period in here where they don't want me going to the gym.  If they need to replace the valve, I'll be without exercise for a longer time.  Also, anesthesia aggravates Alzheimer's disease, so I don't want that if we can help it.  This could be a double-whammy.    

What's so bad about ApoE4?

The well-known genetic factor in AD is the presence of the ApoeE4 variant of the ApoE gene.  If a genetic testing service tells you that your DNA carries this gene variant, it doesn't mean that you will get AD.  You are, however, at higher risk.  There are other things that can trigger the onset of the disease.  I do not carry the gene, but I have developed AD.

But what does the gene variant do, and why is the ApoE4 gene a factor in development of AD?

There was an interesting article that discussed this in this week's issue of ALZForum.  The article was generally about different proteins and their genes that affect AD, and ApoE was one of them.  It discussed specifically the generation of new neurons in the hippocampus, which is where physical exercise comes in to fight AD.  (Recall from Beating the Dementia Monster that physical exercise promotes the production of "brain-derived neurotropic factor" which promotes the generation of new brain cells.  The generation of new brain cells occurs primarily in the hippocampus.)

At least with respect to the ApoE gene, research found that presence of proteins from the most common gene variant (ApoE3) supports the growth and branching of dendrites in new neurons.  The ApoE4 proteins do not do this and therefore do not support the factors that improve the hippocampus and cognitive performance. 

I thought this was very interesting.       

Party Pooper

In my July 13 post, I wrote about how the glymphatic system removes amyloids and other undesirable substances from the brain during deep sleep.  That's good, except that it appears that there are problems with complete removal of this stuff in older people -- and it aggravates disease.  This is discussed in a recent article in ALZForum that addressed some recent research with mice.

When the cerebrospinal fluid of the glymphatic system collects waste material, it delivers it to the lymph system for complete removal from the central nervous system.  The hand-off occurs with a hidden set of lymphatic vessels in the meninges, the membranes that line the skull and envelope the brain. 

The results of a recent study were discussed in an article in the July 25 issue of Nature, which found that artificially reducing the effectiveness of the hand-off apparently caused greater accumulation of amyloids in the brain and more rapid aging.  Researchers found a likely correlation between reduced effectiveness of the hand-off and reduced cognition.  Some researchers commented that “The finding has implications for normal aging and disorders such as Alzheimer’s disease.”   

Why is sleep so important?

In Beating the Dementia Monster, I emphasized the importance of getting a good night's sleep every night.  For younger people, this is a challenge, because so much is going on in their lives.  For us older folks, our physiology seems to get in the way.  Even if we allocate enough time to sleep, getting to sleep and staying asleep is increasingly difficult.

The quality of sleep is important.  REM sleep -- when you dream -- does not appear to provide the benefit of deep sleep.  (REM stand for "rapid eye movement."  Your eyes are moving around when you are in REM sleep, and you are dreaming.)  Analysis of amyloid concentrations in people who have been sleeping indicates that deep sleep does more to control amyloid than REM sleep or no sleep.

Sleep is so important!  Why?

The first question is, why do we sleep in the first place?  For a long time, it was assumed that there was some sort of repair process for the body that occurs during sleep, but no one could find any repair processes going on.  This led to speculation that it was primarily to provide an opportunity for consolidation of mental activity or to keep diurnal animals safely sleeping in hiding places during the night.  Or, for that matter, nocturnal animals would find a safe place to sleep during the day.

These ideas struggled for confirmation, so more recently a better explanation has appeared.  Researchers increasingly believe that a vital function of sleep, at least in higher order animals, is to allow the removal of toxic wastes, including amyloids, from the brain.

As recently as 2015, we discovered a cerebral-spinal fluid circulatory process in the brain which has been named the glymphatic system.  During sleep, especially during deep sleep, the cells in the brain shrink, expanding the space between the cells by as much as 60%.  Cerebral-spinal fluid enters the brain to fill the space.  Expansion and contraction of the cells promotes the movement of the fluid within the brain and its eventual exit from the brain.

As a natural part of cellular metabolism, cells expel waste products, including amyloids.  In other parts of the body, blood and the lymphatic system carry the waste away, but this is not the primary mode of waste removal in the brain.  Instead, these wastes are removed by the movement of the cerebral-spinal fluid of the glymphatic system. 

Amyloids expelled from brain cells accumulate in the space between the cells.  They are then either removed from the brain, or they congregate as plaques on the dendrites of brain cells.  The presence of amyloid plaques is a hallmark of AD, and they play some kind of role in the disease process.  It's  not entirely clear to everyone what that role is, but removing amyloids from the brain has been a focus of developing methods for stopping AD.

The bottom line:  Deep sleep promotes the removal of amyloids from the brain.  This may be a factor in resisting AD.  Failure to sleep well and often enough may be a factor in the development or aggravation of AD.

Here is a National Institute of Health article discussing what we have been learning about the glymphatic system.     

Could it be -- finally?

Will there finally be a drug to at least slow Alzheimer's disease?  This week's ALZ Forums newsletter reported on a drug study that, at the 18-month mark, was showing evidence that it could slow cognitive decline and remove amyloid plaques.  The drug is BAN2401.  It is a monoclonal antibody which selectively binds to certain amyloid cell clusters.  It appears to me that researchers had thought to abandon the trial at the 12-month mark, but persistence to 18 months is paying off.
 
This was a phase 2 trial that tested five dose regimens in people who had mild cognitive impairment due to AD or had mild AD and who had evidence of brain amyloid pathology.  Patients received infusions of a range of doses twice a month.

The trial involved 856 participants which is large for a phase 2 trial.  In fact, it's more like the size of a phase 3 trial.  Recall that, in the past, several drugs showed promise in small population phase 1 trials, but then flamed out with a larger population in phase 2.  While there may be as few as 20 subjects in a phase 1 trial, 865 participants provides much more confidence that results are meaningful!

The drug appears to be safe.  You may recall from Beating the Dementia Monster that a side effect of another monoclonal antibody, aducanumab, was causing micro hemorrhages in the brains of some subjects.  I was happy to be screened out of that one, although there is hope that it may still have a future.

BAN2401 was developed by Stockholm-based BioArctic and was then licensed to Eisai.  Biogen subsequently acquired a stake through a partnership with Eisai.  Eisai/Biogen hope to began a large phase 3 study this fiscal year.

Let us hope that continued study of BAN2401 leads to a truly effective treatment for AD!

A Typical Week with MCI

About a week ago I was contacted by someone from the University of Washington regarding my participation in a study of how people with MCI live their weeks.  The name of the study is “A Typical Week with Mild Cognitive Impairment: A Photo-Elicitation Interview."  Participants were to take five to ten photographs of their activities over a typical week and submit to a one-hour interview regarding the images.  Here's the web site for the study.

I thought this was an interesting idea, so I signed up.  (It helped that I love to take pictures.)  They said they were looking for images that showed how people with MCI learn to cope with their condition.  I thought that my best focus would be on the lifestyle changes that I've made and documented in Beating the Dementia Monster.

I took pictures and selected 10.  They are here.  I explained that the images were intended to highlight the role of physical exercise, Mediterranean diet, social connectivity, organizing daily activities, drug trial participation,  and spiritual coping in the successes that I've experienced in beating (for now, at least) this awful disease.

I was interviewed by the principal investigator this afternoon.  I emphasized the decline I was experiencing in 2015, and told her about how much better I'm doing now.  My hope is that this will be useful to others confronting MCI.

This week I was also approached by someone proposing that I speak to the Washington State Council on Aging during their September in Seatac, Washington.  The person is a member of the council and seems to be able to arrange speakers.  I don't know how serious the suggestion was, but I said that I was willing to do it.

SNAG

I'm reading a book called Anatomy of the Soul, written by a Christian psychiatrist, Curt Thompson, MD.  The book explores several areas of neuroscience, including memory formation.  He discusses a strategy to enhance growth and activation of neurons proposed by Daniel Siegel, clinical professor of psychiatry at the UCLA School of Medicine.  Siegel came up with the acronym SNAG, which stands for "stimulation of neuronal activation of growth." 

So what are the elements of SNAG?  There are three:

• Aerobic activity.  Engage in at least 45 minutes per day, five days per week.
• Focused attention exercise.  This could be some kind of meditation or prayer.
• Novel learning experience.  This is learning something that expands creativity, such as learning a new language or how to play a musical instrument.     

AD and dementia are not a focus of the book, but these three elements are certainly familiar to us.