Why me? -- Part 2

After posting a few days ago about my youthful indiscretions with respect to lifestyle, I thought of another likely factor in my development of Alzheimer's disease.  From when I was 21 until my early 30s I worked at a job that was very tough on sleep schedule.  I was an engineer in a shipyard, and it involved shift work.  But my schedule was very uncertain.  I might come in to the office in the morning expecting 10 hours of office work (we usually worked 10 hours/day for five days and 8 hours on Saturday) but be told to go home and come back for graveyard shift.  Assignment to that shift might last only two or three days, and then I had to cycle my metabolism and sleep schedule back to day shift in the office.

So how does that work for sleeping well?  I had just gotten up after a full night's sleep, so when would my next sleep period be?  Maybe a nap in the evening, but no one can ever get good sleep under these conditions.  By 4 a.m. I would be really dragging.  And when I was assigned graveyard shift over a longer period of time I could never sleep well.  I could never learn to sleep well during the day.

When I moved up in management, it got worse.  I was responsible for whatever happened 24/7 in my domain.  So the phone would often ring after midnight, and I might need to go in to work to investigate an emerging problem.

From what I've learned about the role of sleep in the development of Alzheimer's disease, I would not be surprised to learn that my sleep deficiencies during those years played a significant role in why and how I developed the disease.

Why me?

Why did I get Alzheimer's disease?  It's not something that sticks out in the family tree, although it's possible my mother's father had it.  They looked for it in my Dad's autopsy and couldn't find it.  My mom is still doing quite well, although she complains about forgetting words and names.  Who older than 60 doesn't?  I'm the oldest of nine, and no one else has been diagnosed with it, at least so far.  23andMe says I do not carry the APOE4 gene which most often correlates with the "sporadic" form of the disease that I have.   

The APOE4 gene is not the only gene associated with Alzheimer's disease.  There are probably more than 30.  But none of these genes, including the APOE4 variant, directly causes the disease.  They simply set up conditions that favor the disease, most notably by making the brain more subject to inflammation.  So things you do that fight inflammation (like staying away from refined sugar and refined flour) help prevent the disease from starting.  Diet and exercise when you're young can make a difference.  And research presented at the Alzheimer's Association 2020 Conference found that lifestyle choices in your teens and twenties are shown to strongly affect your vulnerability to the disease. 

One of those lifestyle choices is how well you care for your teeth.  As we wrote in Beating the Dementia Monster and in posts on this blog there are some who believe all Alzheimer's disease can be traced to gum disease.

Therefore, there are a couple of things in my past lifestyle that may have contributed to my disease, starting from my teen years.

After I got my first job and had some money to spend, I spent a lot of it at McDonald's.  There was little about my diet to discourage inflammation (or that other problem, oxidation) until I was in my 60s.

What about my teeth?  After I left home at 18, I didn't see a dentist until I was in my late 20s.  And I didn't take flossing seriously until I was probably in my 50s.  Bleeding gums are evidence of gum disease, and I've had plenty of that.

Alzheimer's disease is increasingly considered a preventable disease.  How preventable depends on who you ask, but the prevention needs to begin when you're young. 

I remember when I was in the 8th grade and we had an assembly in school to talk about cigarette smoking.  As was common at the time, my father had been advised by his doctor to start smoking to help raise his low blood pressure.  But the correlation between smoking and cancer was becoming very clear, and a presenter had come to the school to warn us about the health risks from smoking.  When he started talking about the bad things that could happen to you in your 50s and 60s, I remember saying to myself something like, "who cares?"  That was so far off.  (But I never started smoking anyway.)  So would warning teenagers that poor lifestyle decisions may cause Alzheimer's disease in 50 years going to make a difference?  Probably not.

Of course, the things I've done since 2015 to fight inflammation, to fight oxidation, to fight gum disease, and to strengthen my cardiovascular system have had spectacular benefit.  But it would have been good to start earlier ... a lot earlier! 

Aduhelm is still looking for some respect

Two basic issues with Aduhelm are still in debate:

• Does it have to cost so much?
• How well does it really work?

In early November, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave Aduhelm a no-confidence vote on both counts, when Biogen applied for a license to advertise their product.  CHMP may revisit the question later, but this was nevertheless a strong rebuke.  It shouldn't surprise us that sales are less than what Biogen had predicted ... and hoped for.

There is, however, some promising new evidence about its effectiveness, at least in meeting secondary objectives.  If you read Beating the Dementia Monster, you know that both the presence of amyloid plaques and tau protein tangles are markers for development of the disease.  The rationale for Aduhelm was that it would remove amyloid plaques, but researchers were also keeping an eye on the presence of "bad" tau in the cerebrospinal fluid and in blood.  So, while the primary objective is to at least slow the progress of memory loss, two secondary objectives are to reduce the amyloid plaques and tau proteins.  The trials showed that the amyloids can be removed, but what about the tau?

There's some new evidence that Aduhelm does lower tau.  During the trials for aducanumab (the generic name for Aduhelm), blood samples were taken from many test participants, and the samples were retained.  As it happens, the technology for measuring tau has been improving steadily, and the concentration of the specific "bad" tau proteins was more recently measured.  The new measurements found that the tau rose about 9% in those who were on the placebo (620 participants), signaling that the disease was continuing to progress.  But it fell by as much as 15% among those who were receiving aducanumab infusions (571 and 624 participants receiving different doses).  

Unfortunately, it has been very challenging to correlate changes in beta amyloid and tau with the meaningful changes in cognition that we really want.

So how do we sort all of this out going forward?  Biogen is making one contribution by creating a registry to track outcomes of all Alzheimer's disease-modifying treatments.  How many treatments are there?  So far, just one -- Aduhelm.  But we anticipate that 2022 will bring a few more.  Lecanemab, (or BAN2401) and donanemab appear to be on the FDA's fast track and could be out there soon.  So fresh data should accumulate.

Let's fix the thalamic reticular nucleus and get better sleep

Dr. Matthew Walker, in his book Why We Sleep, explained to us that our sleep is controlled by a center in the pre-frontal cortex right above your nose.  This center atrophies as we age even faster than the rest of the brain, which causes insomnia in us older adults.  And so we have more and more trouble with insomnia.  In Alzheimer's disease, this atrophy is even worse, and people with Alzheimer's have even bigger problems with insomnia.  Ask anyone who works in memory care.  

And as we explained in Beating the Dementia Monster, deep sleep is incredibly important in preventing and controlling Alzheimer's disease.  A record of poor and interrupted sleep is strongly associated with the development of Alzheimer's disease.  Our sleep repeats a 90-minute cycle throughout the night, and the most important part of that cycle for Alzheimer's disease is deep sleep.

But there's a lot more to sleep than what the prefrontal cortex does.  Another actor in the brain is the thalamus.  According to Dr. Walker, the thalamus acts as a gate to keep distracting thoughts out of your brain and let you get to sleep.  And that gate is more than a metaphor.  Certain proteins can punch physical holes in the gate, and disruptive thoughts can then enter and contribute to insomnia.  

Within the thalamus is a structure called the thalamic reticular nucleus (TRN).  While there is debate about what the TRN does and how it does it, scientists believe that it plays a role specifically in the regulation of deep sleep.  In fact, mice experience insomnia when activity of the TRN is low.

So what if we could stimulate the TRN in a way that would promote deep sleep?  Recent research suggests that we can.  Dr. Jeannie Chin at the Baylor College of Medicine found they can stimulate the TRN leading to restored sleep maintenance and reduced amyloid plaque load in both the cortex and the hippocampus -- of mice. 

These were mice that had had their genes edited to produce the human amyloid precursor protein that we discuss in Beating the Dementia Monster.  Enzymes cutting the protein produce the amyloids that accumulate in plaques on neurons in Alzheimer's disease.  So we can associate sleep problems with the generation of beta amyloid and their plaques in these mice.

Of course, we've talked before about how great an idea seems to be when working with mice, but it falls apart when we try to apply what we learned to humans.  Sometimes it's helpful, but research with mice can lead to disappointment.

So what did Dr. Chin and her team do?  They injected the mice with a virus that would carry a special receptor to the TRN.  They then injected a chemical that would be received by the receptors and stimulate the TRN to do a better job controlling deep sleep.  And that seemed to work. 

Are they ready to try this out on people?  Well, hold on.  People are not mice, and what worked with mice isn't necessarily expected to work with people.  So they're mapping the TRN to figure out a receptor system that could do something similar.  But this whole idea is in early stages.  It'll be a while, but we'll watch for news.

Meanwhile, I still have a heck of a time getting a good night's sleep. 

More on my hippocamups volume

Since my last post about my MRI, I've had a chance to talk to my new neurologist about the results and to get the actual volumes the radiologist saw.  I don't know if they're transitioning me to the new neurologist, or if she's just working with me on my increasingly serious balance problems.  However, she said that the two neurologists had reviewed the results together, and they were quite pleased.  (So was I.)

Unfortunately, the MRI gave no clues about my balance, which was the reason they had it done.  Or maybe that's a good thing, because a problem showing up in the MRI might be more serious.  Like the balance problems my grandfather had from a brain tumor.  In any event, they want me back in Seattle in January for a follow up.  (We're supposed to have extra snow this year, so the mountain pass getting to Seattle could be dicey.)

But the neurologist also gave me something I'd been hoping to see -- the actual volumes of my hippocampus and ventricles.  We saw that my standing by percentile has improved, but I was wondering about actual volumes.  It appears that I've improved when compared to other men my age, but they are also losing ground at the same time, even due to normal aging.  So has my hippocampus actually grown, or has it simply shriveled up more slowly than everyone else?  Here are the numbers from 2015, 2017, and 2021.  (If you read Beating the Dementia Monster, you know that the volume of the ventricles is a proxy for overall brain tissue loss.  So bigger is bad.)

Year   Hippocampus volume/percentile         Lateral Ventricles volume/percentile

2015           8.88 cc^3 / 36%                                         90.86 cc^3 / >99%

2017           8.18 cc^3 / <1%                                         100.76 cc^3 / >99%

2021           7.42 cc^3 / 52%                                         126.88 cc^3 / >99%

A couple of things stand out.

• My hippocampus is not growing.
• The ventricles have grown a lot. 
  
• I don't know how to norm these, but the rate of change of hippocampus volume does seem to have slowed.  Hippocampus volume lost 8% between 2015 and 2017 (4%/year), and it lost 7.3% between 2017 and 2021 (1.8%/year).  That's a pretty substantial difference, but I don't know how fair my simplistic mathematical approach is to the meaningfulness of the numbers.

The neurologist said that, while they are very pleased with these results, the radiologists may have changed how they norm the scores to get percentiles since 2017.  

 

So, who knows?  I'll just say that I feel as well about my memory and cognition as I did in 2017.  My main intuitive measure is how well I speak Spanish with Carlos in Ecuador over Skype.  We talk in Spanish twice a week, and my fluency fluctuates, apparently as my brain fights the disease.  Lately it's been quite good.  My big problem is my deteriorating balance.

Can cab drivers in London teach us something about Alzheimer's disease? Maybe.

My Aunt Peggy recently shared this interesting story with me about researchers studying London cab drivers to learn about how their brain's work.  They're looking for clues about how Alzheimer's disease starts and unfolds.   You'd think at this point we'd already understand the disease well enough to not need seemingly esoteric studies, but we don't.  Alzheimer's is an incredibly complex disease.  It seems that whenever we think we have something figured out, we're soon back at the drawing board.  So novel ways of investigating the disease are still welcome.

It's a lot harder to get a permit to work as a cabbie in London than it is here in our town.  It's been that way for a long time, since 1865.  (Maybe it was easier back then when cabbies drove horse and buggy?)  License applicants must demonstrate a knowledge of 400 possible routes within six miles of Charing Cross -- the center of London.

If you read Beating the Dementia Monster, you know that the hippocampus is the structure in the brain that keeps track of where you are in time and space.  It encodes a map of the floor plan of a new hotel where you're staying or the streets of your town.  (It's also important to memory.)  So, to pass their license exam, London cabbies must memorize the layout of the city streets and be able to mentally construct routes between any given points.  Without a GPS.  And there are somehow 26,000 streets to consider.  A London cabbie's hippocampus is a pretty busy place. 

If you've followed my experience, you know that the hippocampus shrivels up in people with Alzheimer's disease.  (Unless you apply the tools of the Dementia Toolkit in Beating the Dementia Monster.)  But it's also known that the hippocampi of London cab drivers actually grow.  Apparently, the more the hippocampus is used the more new neurons will blossom from stem cells located there.

Is that true?  And if so, does a growing hippocampus correspond to better memory and cognition?  This makes sense, but it turns out that the relationship is not at all clear in research.  So can we learn more from the cabbies?

In a project from University College London called "Taxi Brains," they're putting about 30 taxi drivers in MRI machines and then having them construct taxi routes throughout London.  I'm guessing these are "functional MRIs" that show levels of activity in different parts of the brain as the subject solves mental problems.  

So what do they hope to accomplish with this investigation?  According to the article, they're looking for new ways to detect the onset of Alzheimer's disease.  This makes sense, since, more often than not, the first symptoms of disease are in those cerebral functions driven by the hippocampus.  Most notable is memory, since it's the hippocampus that translates short term memories into long term memories.

Are we seeing any interesting results yet?  According to this story from the BBC, the rear quadrants of both the left and right hippocampi of London cabbies was larger than those of control subjects, but the frontal quadrants were actually smaller.

This research has gotten some recent attention, but the researchers have been at it for a while.  According to this Scientific American article from 2011, how the cabbies' hippocampus changes has been known for a while.  What has also been known is that, as the cabbies increase their spatial memory, they do less well on a memory test called the Rey-Osterrieth Complex Figure Test.  (I've been given this test annually since 2015.)  A thought is that as one part of the hippocampus grows another part atrophies -- taking with it some cognitive ability.

I couldn't find any information on whey they'll publish the results of the latest tests.  I'll be on the lookout for some news.  

This just in -- new MRI results!

We returned from Seattle this evening, having gone over for a brain MRI, an appointment with an ENT specialist, and to go trick-or-treating with our 5-year old granddaughter.

The trick-or-treating was great.  Josie's Mommy, Daddy, and10-month old baby sister all came along.  Unlike our neighborhood, their neighborhood was just packed with little children in all manner of costumes.  We came home with a substantial haul of candy.

Sunday afternoon, I went for my first MRI since 2018 and my sixth since 2013.  I was again lying in a tiny tube for 45 minutes or so listening to all manner of strange, very loud banging sounds.  When we arrived home, an email told me that the results were now available.

As I mentioned before, I have been very anxious to see what the results would be because I'm looking for evidence that my brain has actually been recovering some brain cells.  As we said in Beating the Dementia Monster, some research has shown actual increase in brain volume from physical exercise.  The idea is that the brain-derived neurotrophic factor (BDNF), generated during aerobic exercise, prompts stem cells in the hippocampus to form new neurons.  And the brain grows.  So has this been happening with me?

Maybe so.  I have the radiologist's report (that was quick), but I haven't discussed it with my neurologist.  I can just get a preliminary sense of it by applying my uneducated intuition.  But it looks pretty positive to me.

They can find all kinds of stuff in a brain MRI, but for neurodegenerative diseases like Alzheimer's disease, two areas of interest for the radiologists and neurologists are the volumes of the hippocampus and the ventricles.  The hippocampus is a key structure in the formation of long-term memory, and the ventricles are a proxy for overall volume loss in the brain.  So measuring the ventricles measures overall brain atrophy.  

The ventricles are void spaces that expand to compensate for tissue loss.  The volume values are normalized for age and then represented as a percentile with respect to other men my age.  In my 2015 MRI, they measured my hippocampus volume to be < 33 percentile, and my lateral ventricles were > 99 percentile.  In my 2017 and 2018 MRIs, they said that my hippocampus volume was < 1 percentile for men my age, and the ventricles were > 99 percentile for men my age.  So in a room of 100 men my age, I would have the smallest hippocampus and the largest ventricles.  That's not good.

So what did they find on Sunday?  They said my ventricles were > 99 percentile -- similar to 2018.  But my hippocampus volume was now "within normal limits for age."  They have it at the 52 percentile!  Smack dab in the middle of normal!

Again, I'll need to discuss with my neurologist, but it looks to me like BDNF generated on the treadmill at the gym every day has lived up to its promise and generated new brain tissue.  It also explains why my cognition remains as well as it has.