Look into my eyes ...

So how many clinical studies am I participating in?  I'm losing track.  We're here in Seattle right now for a session that I participated in yesterday at the University of Washington, a study to evaluate methods of diagnosing Alzheimer's disease by examination of the retina of the eye.  This is to be repeated annually and indefinitely.  But I've also been taking cognitive tests at home every week for some time now so that someone can track my decline over an extended period of time.  (I am still declining, it's just that since altering my lifestyle in 2016 my decline seems to be much more in line with normal aging.)  In Beating the Dementia Monster, we wrote about our participation in the Mayo Clinic's HABIT study, and I've participated in a couple of other one-time studies of one type or another.  From time to time I'm reminded of something I'd signed up for a long time ago but forgot about.

Yesterday's test was very interesting.  Diagnosing Alzheimer's disease remains as much an art as a science, and multiple forms of evidence are required by the diagnosis protocol.  Reports are taken from family members regarding behavior, and then cogitative tests are given.  But the diagnosis still requires biomarker evidence, something tangible.  In my case, it was an MRI that showed significant atrophy of my brain.

But, as things stand today, the final diagnosis is only made in the autopsy.

More reliable methods for evaluating biomarkers are advancing.  We've discussed blood tests before, and these are very promising.  We've also discussed the possibility that evidence of Alzheimer's disease may be found by examination of the retina of the eye.  Yesterday's tests were all about my retina.  

The whole process took about three hours.  They told me that I was subject #55, and they were hoping to eventually have 150.  After a battery of cognitive tests, they gave me an eye exam, saying that I had 20/20 uncorrected in both eyes.  (This will be news to my optometrist who says I have 20/30 in one eye and 20/40 in the other.)  Then they dilated my eyes and led me through a series of retinal exams using three different machines.  Each of the machines took different kinds of images of my retina.  

I chatted with the researchers regarding what they were looking for.  I told them I knew that UW was a pioneer in finding amyloid plaques in the retina of the eye that might be a biomarker for Alzheimer's disease.  (They said other people were working on that one, not them.)  An ophthalmologist once told me that an amazing portion of all the information coming to the brain is just via the optic nerve ... eyesight.  I don't remember the number he gave me, but it was a high percentage.  And so some consider the eye to simply be an extension of the brain.  Bad things happening in the brain proper may also be occurring in the retina.  

I should have taken notes, but I didn't, and now I can't remember everything they told me.  But I recall the last machine imaged my eye for oxidative stress.  If you read Beating the Dementia Monster, you know that part of how Alzheimer's disease proceeds in the brain is via oxidation inside neurons that kills them.  One hypothesis they are testing is oxidation proceeding in the brain should be reflected in oxidative damage in the retina.

The cognitive tests they gave me were disturbing.  I take cognitive tests every Thursday, and I feel that I do reasonably well on them.  But the tests they gave me yesterday were hard, and I'm not sure I got anything right on them.  They couldn't tell me the results, but they were going to share them with my neurologist and/or my neuropsychologist.  I'll be interested in their take.

For our trouble, they gave us a $10 Amazon gift card (a typical token of appreciation for these trials) and $40 for our gas.  They said they hoped we'd be back again next year for a follow-up.  My intention is to return, since I'm always interested in supporting Alzheimer's research.

The eye -- window into the brain?

My ophthalmologist once told me that the eye has more nerve connections to the brain than any other part of the body.  He had a number for how many connections there are, but I don't remember what it was.  I read elsewhere that some neuroscientists consider the eye to simply be an extension of the brain.  Consistent with that view, it turns out that beta amyloid can be found in the retina.  Of course, we understand the generation of beta amyloid and its destructive effect on brain cells to be a central feature of Alzheimer's disease.  So, if the eye is part of the brain, whatever is going on in the brain proper would also be going on in the eye.

My friend Mike in Virginia sent me this article last week about research into biomarkers for Alzheimer's disease and Parkinson's disease "focusing" on what can be found on the retina of the eye.  The hope is that such biomarkers can provide an early diagnosis of pre-clinical disease -- before the first symptoms appear.  This can help with research, because it is believed that emerging treatments will work better the earlier in the course of the disease they are applied. 

As far back as 2018, we have discussed the value of inexpensive and easily observed biomarkers in the diagnosis of Alzheimer's disease.  Currently, doctors and researchers may use expensive MRIs and PET scans, but there is hope that blood tests will soon provide cheaper and earlier diagnosis.  So the idea is that, in the future, pretty much the same equipment your optometrist uses to check for glaucoma can be used to help diagnose Alzheimer's disease.

The article focused on the work of the leaders of two different research teams:

• Maya Koronyo-Hamaoui at Cedars-Sinai in LA who leads a team that has been developing a technique for finding amyloid plaques in the retina using a machine similar to that used in an ophthalmologist's exam.  The cost is said to be about $285 per scan.
• Ruogu Fang, an electrical engineer specializing in AI working at the University of Florida, leads a team learning to use an iPhone image to examine blood vessels in the retina. 
  

In the case of Koronyo-Hamaoui's device, the subject drinks a liquid containing curcumin, the substance that gives the spice turmeric (and hence, curry) it's flavor.  (This will resonate with those of us who love Indian food.)  The curcumin has an affinity for beta amyloid, and it can be detected by shining blue light on it.  So blue light can be used to identify amyloid plaques developing in the retina.

Fang's iPhone technique looks for changes in blood vessels associated with Parkinson's disease, but not Alzheimer's.

Early detection of Alzheimer's disease continues to be an important area of research.  The downside is what it will mean for those seeking long term care insurance.  I remember that when I applied for long term care insurance (before I had cognitive issues), they examined me very closely for memory problems.  

 

I'll speculate.  A person with a positive test for beta amyloid, but prior to cognitive symptoms, will be unable to get insurance at a reasonable price.  The insurance companies will likely insist on the tests unless curbed by legislation.  A person who tests negative my not see a justification for the cost of insurance.  This could be destructive to the industry.

 

It may not be a wise decision to skip insurance, especially since the price might go lower with Alzheimer's patients ruled out.  There are many other causes of dementia and other debilitating diseases that afflict the elderly.  

The biomarker blood tests have not rolled out as quickly as I had hoped.  We'll see what unfolds in the coming months.

Does pupil dilation during exercise predict effects on cognition?

There is a lot of interest in the eye as a window into the brain.  In a couple of weeks, we travel to Seattle for another installment in my participation on a study of the eye and Alzheimer's disease.  We said before that some scientists consider the eye to be an extension of the brain, and bad things happening in the brain might also be happening visibly in the eye.  So they are looking inside my eyes for evidence of the advance of Alzheimer's disease.

I came across another study of an association between the eye, the brain, and neurodegenerative disease.  This one found an association between pupil dilation during light exercise (yoga or walking on the treadmill) and cognitive improvement.  The researchers reported that they could associate the dilation of the eyes during light exercise with improvements in cognition.  The amount of change in pupil dilation could be associated with improved cognitive test scores.  They propose that the part of the brain controlling pupil dilation is also involved in cognition.  While this area of the brain is improving (during exercise), the pupils are dilating.

The researchers wanted to reassure people that even light exercise would improve their brain function. 

This is interesting, and it's in line with was learned by the HABIT study.  You will recall from Beating the Dementia Monster that Dr. Phatak was principal investigator for the Seattle site for the HABIT study, and she said that the only lifestyle change they measured that improved cognition was taking up yoga.  The HABIT study has since advanced from being a scientific study to being a regular program at the Mayo Clinic.

On the other hand, other research we discussed in Beating the Dementia Monster found that six or so hours a week (quite a lot for most people) was required to maximize the effect of exercise among patients with young onset Alzheimer's disease.  The study did not say how light or hard the exercise was.  And I've seen varying opinions on how hard exercise must be to produce results.  

In my case, I go kind of hard, but I'm really happy with my results.  Would my results be just as good if I went 2.5 mph on the treadmill with zero degree incline, rather than the 3.5 mph at the 15 degree incline that I do now?  There's only one way to find out, but I'm not willing to pursue it.

Why do we sleep? And does it matter for AD?

I recall that in the 1970s science was drawing a complete blank on why we sleep. The traditional explanation was that it was an opportunity for the body to repair itself, but no one could find any repairs in progress. The best explanation seemed to be that diurnal animals should be rolled up somewhere safe at night, and nocturnal animals should be doing the same during the day. An imperative for sleep would force this behavior. So it all seemed to hinge on the geometry of the eye. Eyes were designed for either diurnal or nocturnal animals, and there was no design to accommodate both.

But researchers are now going back to the repair concept, and it seems to have implications for our understanding of AD.  In Beating the Dementia Monster, I cited research correlating interrupted and inadequate sleep with increases in beta amyloids in cerebral-spinal fluids.  This strongly suggests a connection between sleep problems and AD.

A recent understanding is that deep sleep (as opposed to “raid eye movement” (REM) sleep) facilitates the removal of waste products from between brain cells. (REM sleep is lighter sleep, and it’s when you dream.) As cells function, they create wastes that are expelled from the cells through their membranes and into the space between them. During deep sleep, the space between the cells expands and allows a fluid system to flush the wastes out of the brain. Here is one study analyzing this. There is a hypothesis that when the wastes build up between the cells and are not flushed out, the presence of the wastes promotes AD.

Another thing to understand about sleep relates to what’s called “plasticity.” Neurons are constantly disconnecting and reconnecting to other neurons as a part of the memory retention process. This process occurs primarily during sleep (including REM sleep), and is important to memory. In AD, sleep patterns are disrupted, complicating the brain’s challenges with respect to memory consolidation and retention.

I Saw my Neurologist Again...

This past weekend we traveled to Seattle, and I saw my neurologist yesterday.  I was specifically concerned that my balance has gotten very bad, and I've begun to shuffle like men I know that are 10 years and more older than I am.  It's keeping me from some things I enjoy that require physical agility, such as going places for photography.  I haven't fallen yet, but it seems like a matter of time.  But something very unexpected (to me) came out of the visit. 

In the past year I have flown twice to the East Coast, once with my wife, and once (in August) by myself.  On this past trip I was shocked by the number of people offering me their seats or helping me with my bags on buses, on the airplane, in the airports, etc.  It didn't happen on our trip in the spring.  I guess I have begun to look really, really old and frail to people, although I feel plenty strong at the gym, working out on the treadmill and with weights.  The problem is that my balance issues cause me to shuffle and appear a lot more feeble than I am.  And I look increasingly awkward getting up and down stairs.

If you read Beating the Dementia Monster, you know that the very first sign of trouble for me back in 2013 was problems with balance.  They sent me for physical therapy, where I learned very effective habituation exercises that gave me great relief.  Following 10 minutes of exercises, the relief would last three or four days.  But that stopped working just about a year ago.  I have been able to systematically evaluate my meds, and I know they aren't the problem.  Or rather, I've been able to stop taking the ones that have clearly contributed.

During my visit I met a new colleague of my neurologist who specializes in movement problems, such as with Parkinson's disease.  She did most of the examination, and then the two neurologists collaborated on trying to find a resolution. 

One very good outcome is that I will get another MRI.  My last one was in 2018, and I am personally interested in physiological changes in my brain that research shows may have come as a consequence of my lifestyle changes.  I'm specifically hopeful that my hippocampus may have grown.

However, they are interested in a possible connection between my balance problem, a chronic cough that I'm trying to resolve, and visual migraines (more properly called "scintillating scotoma") that I experience daily.  I had always called these "ocular migraines" (more properly called "retinal migraines"), but they are not the same.  Ocular migraines originate in the eye, while visual migraines occur in the occipital lobe of the brain; in the back, where the optic nerves plug in.  Ocular migraines affect only one eye, while visual migraines affect both eyes simultaneously.  

I will look into this further, but I'm thinking there may be a connection between visual migraines and Alzheimer's disease.  A quick Google search suggests there are.  As we noted in Beating the Dementia Monster, one of my early challenges was being unable to drive, likely due to Benson's Syndrome, also called posterior cortical atrophy.  My occipital lobe was under attack, and my brain was having trouble forming images in my mind using information from my eyes.   

Both of these phenomena are associated with migraine headaches, but I'm very fortunate to be in the minority that does not get the headache part of the experience.  So it ends up being kind of like what I imagine an LSD trip might be like, with brightly colored shimmering shapes all through my field of view.  Here are some artists' reasonably accurate renditions of what we see when we're having one.  (Some of these incorrectly confuse visual migraines with retinal migraines, calling them ocular migraines.)  Most of my episodes last about 20 minutes.

Yesterday I had one while we were on the freeway returning from Seattle.  (Speed limit 70 mph.)  A rest area came up quickly, so I pulled into it until the episode has passed. 

But I've also been trying to resolve a chronic cough.  The cough comes as a result of excess mucous production in the nasal cavity.  The first ENT specialist I saw about it a few years ago said that the solution was some significant surgery, but that it hadn't helped some of his previous patients.  So he wouldn't do it.  Later, I was told that the surgery involved removing a nerve connecting the nasal cavity to the brain.  My new ENT suspects a neurological component to the problem, and he is pursuing that angle.  The neurologists are also picking up on this theme.  It's why they think a new MRI is called for.

The neurologists are both of the opinion that my intermittent fasting routine may be contributing to the problem, at least to the visual migraines.  I don't know if the fasting didn't have a significant influence on my improved test scores last July, so I'm reluctant to back off on that.

So now I'm trying to get a new MRI, but they also want me to see two more specialists at Harborview.  Hopefully, these can be done online.  And hopefully they can find me some new answers, especially that might help with my balance. 

Guinea pig ... again

So I have been wanting to write on a couple of subjects, but we're on the move.  Right now, we're in Seattle, and I'm due for a three-hour battery of tests this afternoon.  They want to compare the results of these tests when I took them over Zoom several months ago to what I do today.  Is testing over Zoom just as valid as in person?  If so, it'll save us a lot of travel over the mountains!  Bad in winter.  They're expecting 4 to 8 inches of snow in the pass today and another 4 to 8 inches tonight.  They do a good job of clearing it, so I hope for a smooth trip home tomorrow.

Because it's a research study, they won't tell me the results.  But I've had enough of this testing to know when I've done well or poorly.  And, I'm due for my regular diagnostic cognitive tests this summer. 

One variable is sleep, and I didn't sleep that great last night.  So we'll see how it goes.

Normally, we have the Alzheimer's Association annual Facts and Figures Report by the first week in March.  And it's always fascinating.   But, so far, nothing.  Is that because there just hasn't been that much going on in the world of Alzheimer's research?  Who knows.

There is a new study I want to write about concerning our ability to detect Alzheimer's disease well before the first symptoms appear by examining the retina of the eye.  I've been involved in just such a study, and there's news coming out in this area.  Some consider the retina of the eye to be an extension of the brain, and so, if there are amyloid plaques in the brain there should be some in the retina.  I'll write on this as soon as I can.

Seeing and Believing

On July 28 of this year, we posted regarding the four syndromes of Alzheimer's disease; the memory, language, visual, and frontal syndromes.  These point to different ways that Alzheimer's disease and dementia first asserts itself, and they vary based on which part of the brain is being attacked first.  Most common and most familiar is the memory syndrome, but mine may actually have been the visual syndrome.  It is known as posterior cortical atrophy or Benson's syndrome.  Benson's syndrome is referred to as "an atypical variant" of Alzheimer's disease.  In my case, I had to stop driving because I sometimes failed to see a car in the lane I wanted to move into, or I didn't see a pedestrian in a crosswalk.  (This problem has not recurred since 2016.)

Today, Firefox offered me an interesting article on how the brain processes vision that discussed how vision changes in the elderly ("Your Brain Chooses What to Let You See").  It discussed how changes in the brain affect the way the brain processes information delivered by the eye to assess the environment for threats or access to food.  First and foremost, it must screen out distractions, so that you focus on what's important.

The principal idea was that something moving is more important than something stationary, so your brain will be interested in that first.  Also, something small that's moving may be more important than something big that's moving.  They give as an example that a raptor must distinguish a moving mouse from the windblown grass and tree branches.

One of the research findings they discussed was that elderly people have a harder time separating smaller moving objects from larger moving objects.  This is consistent with Benson's syndrome, in that evidence of Benson's syndrome includes difficulty in distinguishing the relative sizes of objects.

I will speculate that we will see something here that is similar to distinguishing memory issues in normal aging from Alzheimer's disease and other dementias.  In normal aging, the brain is atrophying.  If you're a Baby Boomer you know this, regardless of your Alzheimer's disease status.  In normal aging, the word you want to use is still in your memory, you just have trouble pulling it up for use.  It will come back to you later, but too late to have been used in the conversation.  In Alzheimer's disease, it has been erased from your memory.  You may be able to re-learn it, but it's gone.  I have met several people recently who's own names have been erased from their memories.

The authors of the article discuss limitations of seniors on their brains' ability to distinguish relative sizes of objects in motion.  I speculate that the article is referring to the consequences of normal aging.  In Benson's syndrome of Alzheimer's disease, the damage to the areas of the brain responsible for interpreting the information from the eye are much more seriously damaged, and the visual function of the brain is more seriously degraded.  

     

Aducanumab DOA -- Probably

It's all over the news.  The FDA's Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee voted against recommending that the FDA approve Aducanumab.  The FDA is not bound by the committee's conclusion, but I would be surprised if the FDA disregarded their recommendation and went ahead with approval.

It's not surprising that Biogen's presentation painted the monoclonal antibody in a positive light.  But it surprised me that the PCNS criticized the FDA for speaking positively about aducanumab when they tasked the committee with their evaluation.

There were 10 voting members of the committee, but only one member supported pursuing approval.

The sponsors, led by Biogen, conducted multiple trials of the drug, but only one trial yielded positive results.  That was the one where the full dose was administered throughout the trial, and Biogen's case was efficacy was proven in that trial.  One of the committee members said that was like shooting an arrow at the side of a barn and then painting a target around it with the arrow in the bull's eye.

You will recall from Beating the Dementia Monster that I auditioned for the third phase trial of aducanumab but was rejected.  I wasn't disappointed in this because I doubted that the drug would be successful.  The treatment had shown promising results in the first phase (probably 12 statistically problematic test subjects), but had not shown promise in phase 2 with a larger cohort of test subjects.  I wondered how they justified proceeding with the third phase.  My conclusion was that there were so few other prospects for an effective pharmacological treatment that grasping at aducanumab seemed to be the only promising near-term option.  This explains the great wailing and gnashing of teeth that followed Biogen's initial conclusion that the treatment was ineffective. 

All of this underscores that the multi-domain lifestyle interventions we describe in Beating the Dementia Monster are, for the moment, what we have for holding back the advance of Alzheimer's disease.

More News from the World of Research

I continue to keep an eye out for interesting developments in the world of Alzheimer’s research.  A few have recently popped up for me. So here are some of them: 

1. SHIELD – A new acronym. You may be familiar with the mnemonic for recognizing stroke: FAST – face, arm, speech, time. So now there’s a new one for Alzheimer’s: SHIELD – sleep, head injury prevention, exercise, learning, and diet. Paying attention to these will reduce your risk of developing Alzheimer’s and at least slow it down if you do develop it. This mnemonic was developed by neuroscientist Rudolph Tanzi, co-director of the McCance Center for Brain Health at Harvard-affiliated Massachusetts General Hospital. You can read more here. 

2. Your brain needs sleep. And speaking of sleep, we’ve had a lot to say about it and its relationship to Alzheimer’s disease. Now, there’s new evidence regarding how sleep works to protect the brain. It’s known that human growth hormone, or somatotropin, is released in the body while we sleep. It stimulates growth, cell reproduction, and cell regeneration, notably in the brain. Researchers at the University of California, Berkeley concluded that sleep and growth hormone form a tightly balanced system with feedback loops. Neuroscientist Daniel Silverman is quoted as saying, "Sleep drives growth hormone release, and growth hormone feeds back to regulate wakefulness, and this balance is essential for growth, repair, and metabolic health." You can read more here. 

3. More on sleep and your brain. And still speaking of sleep, a study at the Mayo clinic found that chronic insomnia may be just as influential on the development of dementia as being a carrier of the APOE4 gene. This was found by following 2,750 people over the age of 70 for five and a half years. The study participants took annual cognitive tests and had brain scans. Researchers tracked the development of amyloid plaques and “white-matter hyperintensities.” The white-matter hyperintensities were damage to parts of the brain involved in communication within the brain. One thought is that these two factors might magnify each other. Here’s a link to the published research. You can read a more easily understood article here. 

4. Cocoa and multivitamin supplements may – or may not – delay cognitive decline. New research provides evidence that cocoa and multivitamin supplement consumption may reduce the progression of cognitive decline and help protect against cardiovascular disease. For brain health, the results were more compelling for multivitamins than the cocoa supplements. Called the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), it was conducted at Brigham and Women’s Hospital – an affiliate of Harvard Medical School in Boston – and the Fred Hutchinson Cancer Research Center in Seattle (where my wife was treated for cancer a number of years ago). Wake Forest University also participated. The study involved 12,666 women aged 65 or older and 8,776 men aged 60 or older. They were followed for an average of 3.6 years through the end of 2020. At least with regard to the multivitamins, daily multivitamin slowed cognitive aging by approximately 60%, or the equivalent of 1.8 years over the 3 years of the study.  It was harder to find a positive effect from the cocoa for brain health.  However, the study suggested a 27% reduction in cardiovascular death and greater cardiovascular benefits among those taking the cocoa supplements regularly. Here’s a link to the research. Here’s a link to an article on the study. 

5. Are all ultra-processed foods (UPFs) bad? Perhaps not. While ultra-processed foods (e.g., frozen dinners, chips, soft drinks, and packaged snacks) are clearly inferior nutritionally to fresh fruits and vegetables, applying the same negative label to them all may be a mistake. According to some researchers from the UK, the label UPF is a blunt instrument that excludes some foods that may actually be good for you.  Since UPFS taste good and encourage eating (or overeating), they may be beneficial to older people who tend to lose weight, sometimes dangerously. And whole grain breakfast cereals would qualify as UPFs while being quite nutritious. Here’s an article on this. Here’s a link to the research. (This is all well and good, but I’m sticking with the MIND diet.)

A new concept for pre-clinical detection of Alzheimer's disease

We wrote in Beating the Dementia Monster about the search for a reliable test that would detect the development of Alzheimer's disease well before the appearance of the first symptoms.  We reported on several promising blood tests, although none of them have yet found FDA approval.

Why should we want a test for Alzheimer's disease?  Most people say they don't want to know that they have it.  They've been told that there's no cure, so why go through the painful process of consciously confronting a monster you can't beat?  This is an understandable attitude.  (Although they should read Beating the Dementia Monster.)

But there are reasons we want to know.  Alzheimer's is a disease with a very long incubation stage.  It's perhaps 15 years before the first symptoms become evident and another five years before the advent of dementia.  But if there will be a more effective treatment and, dare we say it, a cure, it will likely be most effective if applied during that pre-clinical (or "prodromal") 15-year stage.  But that's before anyone knows anything is wrong.  

Also, for testing new drugs and treatments, we want certainty that the test subjects actually have Alzheimer's disease and with as few comorbidities as possible.  So we want them as young as possible to minimize the number of late-appearing comorbidities because these can confound test results.

While current research on a reliable test for Alzheimer's disease has focused on looking for beta amyloid in blood samples and plaques in the retina of the eye, there's a new idea building steam.

Spectral phenotyping using Fourier Transform Infrared spectromicroscopy.  What's that about?

The idea is that, during both Huntington's and Alzheimer's diseases, there are changes in cells throughout the body that can be detected by analyzing the absorption of different frequencies of infrared radiation.  These changes seem to follow a set pattern in both Huntington's disease and Alzheimer's disease.  So (I guess) shine a heat lamp (broad spectrum of infrared radiation) on a skin cell and see which frequencies are absorbed.  

The nerds among us will understand that the absorption will depend on the specific bonds between different atoms and molecules, so that the presence of certain proteins and lipds with characteristic bonds will have their own signatures.  So just apply some artificial intelligence (AI).  Show a bunch of easily accessible skin cells from people known to have Alzheimer's disease to the system, and have its AI compare them to cells from subjects who do not.  Then let the AI figure out how to predict Alzheimer's disease from skin with unknown status.  You don't have to know what elements and molecules are absorbing the radiation, just look for consistent patterns.  The claim by scientists at the Lawrence Berkeley National Laboratory is that this method predicts Alzheimer's disease very reliably. 

On reading their report, I'd say it's very promising, but they're at a relatively early stage of developing their testing method.  They've had good success, but with a small number of test subjects.  Also, most of the research on humans is with Huntington's disease and less with Alzheimer's disease.  Huntington's disease is far more a product of genetics than Alzheimer's disease, and so, in Huntington's disease, you should find a very consistent pattern of proteins in the cells that are a consequence of the Huntington's gene.  Of course, the rare young onset form of Alzheimer's disease is also a product of genetics, and so I would expect their method to work well there.  But I'm having trouble seeing from what I read in their reporting how this is supposed to work with the much more common old onset form of Alzheimer's disease. 

And I can't get past the damage a test will do to the cost/availability of long-term care insurance.  Once a pre-clinical person is known to have Alzheimer's disease, how will that affect the willingness of an insurance company to take them on -- and at what price?  (Of course, our systems of funding healthcare are in flux, so people may not see this as a problem in a few years.)

People who had cataract surgery have a lower incidence of dementia

I just got my regular newsletter from the University of Washington's Alzheimer's Disease Research Center with a surprising research finding.  People who had cataract surgery had a 30% lower risk of developing dementia.  Obvious question: why would that be?

The findings come from the Adult Changes in Thought Study that's been going on since 1994.  The study tracks thousands of older people known not to have dementia and follows them until they do develop dementia.  Obviously many never will, but they'd like to know about the lifestyle differences between those who do and don't develop dementia.

So why would people have a lower incidence of dementia if they had cataract surgery?  An article in Science Daily provided some speculation.  The article noted that the research report did not provide any answers, but some people have proposed some.

One idea is that, after cataract surgery, people get higher quality sensory input, and that's somehow good for brain health.  

Another idea is that after cataract surgery people are getting more blue light.  Cataracts cause the light getting to the retina to be more yellow, filtering out blue light.  Blue light may stimulate some cells in the eye associated with cognition.  The new, bluer light might stimulate those cells somehow.  This affects the sleep cycle that depends on blue light to tell the body that it's day.  So it might promote better regulation of the circadian rhythm and better sleep.  If you read Beating the Dementia Monster, you know that sleep is extremely important in how Alzheimer's disease does or does not develop.  

So get outside during the day when there's lots of blue in the sky and blue in the light.  You're teaching your brain what time of the day is daylight.  But don't expose yourself to light containing a lot of blue in the evening, such as cool fluorescent and LED light.  This goes double for light from computer and phone screens.  It's been super-juiced with blue.  (I've calibrated the colors on my computer screens to be warmer -- more yellow, less blue.)

I'll add my own speculation which I think is consistent with these ideas.  We have associated hearing loss with dementia, likely because hearing loss interferes with communication with other people.  As we said in Beating the Dementia Monster, social connection is very important to brain health.  Impairing social connection, such as through hearing loss, raises the risk of Alzheimer's disease.  Maybe the same thing applies here -- untreated cataracts interfere with social connection.

Another thing we noted in Beating the Dementia Monster is a correlation between glaucoma and dementia.  People are often diagnosed with glaucoma very near the time they are diagnosed with cognitive impairment.  In my case, only a few months separated my two diagnoses.  I don't know what the connection would be, but an ophthalmologist once pointed out to me that the biggest sensory input to the brain is from they eyes, and we've said before that some consider the eyes to be an extension of the brain.

On "misremembering"

My classmate Mike in Virginia sent me this article from the Washington Post, "Why some misremembering might show your memory is functioning properly."  It's not about Alzheimer's disease or dementia, but it's still a very fascinating review of some things we're learning about how the brain works, written by a researcher in neuroscience.  

What initially caught my attention in the article was that it began with the work of  Daniel Kahneman and Amos Tversky.  Their partnership was the subject of the book The Undoing Project by one of my favorite authors, Michael Lewis.  My son got me this book for Christmas a couple of years ago, and I loved it.  It followed the careers of the two pioneering psychologists through their research years, through the breakup of their partnership, and to the death of Tversky from cancer.  Both would have received the Nobel Prize, except the recipient must be living.  So Kahneman accepted it for them both.  If you follow this stuff, you'll know that they came up with the concept of "heuristics" which now governs many statistical processes that we engage in.  This includes methods to detect viruses in your email.

If you're interested in the topic of the WaPo article, you should read it.  The upshot of it is that your brain is constantly assessing the meaning of inputs of varying quality from a myriad of sources.  For example, your ability to quickly assess the speed of a moving object that may not be in the center of your vision.  How clearly is your eye, working with your brain, able to discern it?  Is it in focus?  Then the registers in the parts of your brain containing your working memory can get filled up and make cognitive activities difficult.  This is easier to understand if you know how dependent your computer's processing ability is on its own memory.

The assumption in the 1960s, when Kahneman and Tversky were working together, was that there are a lot of deficiencies in how the brain works.  That's why people make mistakes.  One thing they studied was why military pilots made errors and crashed airplanes.  Some of their techniques improved pilot performance.  And they had other amazing insights regarding how people assess situations and make decisions.

However, the author of the article (who is working in this field) refers to newer research showing that the brain does an incredible job with the resources it has.  For example, it won't use up valuable space in working memory with unnecessary details about a topic, when that space could be used for more important information. 

ALZForum comes out tomorrow morning.  I'll see if there's anything interesting there.

First Day of the "Collaborating for a Demenitia-Friendly Washington" Conference

Today was the first day of the conference, and it did not disappoint.  We have been working hard on planning this for nearly a year, and our efforts are paying off.  Tomorrow is the second and last day.  Thanks to covid, we are again this year entirely on Zoom.

The keynote speaker, LueRachelle Brim-Atkins, told a moving story about her mother's decline.  There wasn't a dry eye in the house.  

Lue-Rachelle's presentation was followed by a panel discussion, that included a participant whom I had recruited from our local parks and rec department.  She spoke about how, as the city Recreation Manager for Parks and Public Facilities, she ensured that people working at the rec center desk would know how to recognize and respond to someone showing evidence of dementia.

I then attended a breakout session led by a woman from Prince George's County, MD who spoke on programs they have implemented in churches to care for those among them with dementia.  This included "purple services," periodic shortened worship services structured for people with dementia.  Prince George's County is near where I grew up.

After this was a talk by someone from the American Library Association in the mid-West (a Seattle ex-pat) who spoke about programs that libraries implement to serve those in the community with dementia.

If you read Beating the Dementia Monster, you know that the ability to read is one of the very late casualties of Alzheimer's disease.  People preserve their ability to read until very late in the progress of the disease.  As a result, libraries are in a unique position to serve victims of Alzheimer's disease throughout much of it's course.  

And it's the same thing with music.  In even the later stages of dementia, people respond very positively to music that they recall from their youth.  Back in 2019 we posted about a documentary called Alive Inside.  It attracted attention at the 2014 Sundance Film Festival and was all about the impact of music on people with dementia.

I expect that tomorrow will be just as interesting.

A Covid-Related Death?

In September 2019, we posted regarding two friends living in elder care facilities.  For reasons of privacy, I called them "Bill" and "Mike."  In January 2020, I wrote that Bill had died.  He was a WWII veteran who was usually quite lucid but occasionally hallucinated.  He was almost 100.

Mike, on the other hand, was in a memory care facility where he lived largely in isolation.  I visited him daily in the afternoon, and he was always happy to see me.  But I know he didn't get out of his room much, and I believe he thought I was a different person each visit.  His wife also visited him often, usually late in the morning.  When I spoke with him, he could always tell me his first name but often could not recall his last name.

In January of this year we posted some observations (well, speculation) about people with neurodegenerative diseases living there in isolation.  In the time that I had been visiting Mike he had not seemed to decline, although others around him did -- at least to my eye.  I wondered if this wasn't a result of frequent visits and social interactions with his wife and me.  In Beating the Dementia Monster we discussed the role of social interactions in slowing the progress of Alzheimer's disease.

Then came the Covid-19 lockdown, and I have not seen him since.  On April 26, we posted about my concerns with respect to the impact of the lockdown's loneliness and isolation on people with Alzheimer's disease.  I didn't say as much, but I worried that the lockdown might accelerate Mike's disease.  I don't know if it did or not, but he died a few days ago.

My Annual with my Neurologist

This past week, we traveled to Seattle for my annual review with my neurologist there.  Or a couple of neurology people.  We also went for an annual inspection of the retinas of my eyes, which we wrote about before.

The eye research seemed to go as planned, but my data gets anonymized, and no one gets to look at it in the context of a single person.  I don't even get to see my own data.  Instead, maybe someday they'll produce some interesting results and publish them where I can read them.  But this is a multi-year study, and they're tracking a number of us over time.  The way I've seen these things go, I don't know if I'll ever see what came of it.

The meeting with my neurologist may have been pivotal.  While I meet with my neurologist at the University of Washington Brain Wellness Center at Harborview every year, they have not tested me since 2021.  The tests take at least 3 hours, and they are both grueling and expensive.  They have begun to skip years, because my results have been consistently pretty good.

This year, when they called to schedule, I said I didn't see why we needed to test again.  In fact, I said I didn't see why we even needed to meet again.  What are they going to find that would cause a change in my treatment?  The only thing they could add is treatment with Aduhelm or Leqembi, but I wouldn't be interested in either of those.

My neurology meeting began with a resident I'd never met before.  She was very nice and asked good questions.  Of course, I gave her a copy of Beating the Dementia Monster.  Then my regular neurologist came in, and we talked about my future with them.  They clearly wanted me to stick around, but we decided we should move from annual reviews to meeting every second year.  We'll only test if I become concerned that there has been a change.

I told them that I have a number of things I watch to monitor where I'm at.  Most importantly, I look for problems with my driving.  Like close calls with pedestrians.  That caused me to stop driving once before, but for the past several years, I've had no problems.

I also watch to see if I remember to lock my car door when I go into a store.  This was a big problem for me in 2019, but not now.  Also, if I park in a big parking garage or parking lot (like the garage at Harborview!), can I find my car again easily?  (Yes I can.)

Also, for more than 2 years, I've been participating in their Clinical Core Study.  Essentially, I take short memory tests every week.  I don't get a score, but it's easy for me to see how well or poorly I'm doing.

And then, there's using the Spanish language.  If you read Beating the Dementia Monster, you know that I began learning Spanish when I was 59.  (I'm now 74.).  I read from the Bible every day in Spanish, and I speak with friends in Ecuador and Mexico over the Internet a couple of times a week for practice.  The parts of the brain that deal with language are attacked directly by Alzheimer's disease, and I watch for any changes in my ability to converse in a foreign language.

So I have things to watch, and they tell me a lot.  Maybe not as much as their tests, but as much as I think I need to know.

They observed my gait, which has really gone down hill.  I mentioned before that a neurosurgeon diagnosed me with cerebellar dysfunction ataxia, and this is a separate disease from Alzheimer's disease.  He said I should expect my gait to continue to deteriorate, and they have no cure for the problem.  The neurologist also observed that, in my speech, my diction has deteriorated.  I said I had noticed that myself, although it has seemed to come and go as a problem all the way back to 2015.  (We wrote about this in Beating the Dementia Monster.)

So for now, things are really pretty good, at least with respect to my cognitive impairment.  They have pretty smart people there at the University of Washington Brain Wellness Center, and I know I can turn to them if things start to go bad again.

Another Study on Diet and Alzheimer's Disease

A doctor friend of mine shared with me a study that correlated larger hippocampal volume with good dietary habits.  You will see from my earlier post of December 17 that I discussed a Finnish study of diet, and this new study referenced the Finnish study.  The new study is Effect of Diet on Hippocampal Volume in a Population at Risk for Alzheimer's Disease.  It found a strong correlation between scores on the Alternative Healthy Eating Index 2010 (AEHI) and hippocampal volume.

The "alternative" AEHI is an alternative to the earlier Healthy Eating Index.  The AEHI emphasizes low carb eating over low fat eating.  A Mediterranean diet gets you pretty close to the top of the AEHI, but maybe not so much with the earlier index.

This study caught my attention because hippocampal volume is an important biomarker for Alzheimer's disease.  My care team at Harborview in Seattle used it to diagnose my own Alzheimer's disease.  You will recall from Beating the Dementia Monster that an MRI in 2015 measured my hippocampal volume in the 36 percentile of the general population, but two 2017 MRIs found it at the one percentile.  The radiologist in the 2017 MRIs said that the decrease might be due to differences in technique, but, taken together with the changes in the size of my ventricles, even the 2015 reading was sufficient biomarker evidence for the diagnosis.  (Biomarker evidence must be taken together with cognitive testing evidence to produce a diagnosis of Alzheimer's disease.)

The researchers in the new study studied a cohort 459 British civil servants with an average age of 60 years.  Nineteen percent were female.  Subjects were evaluated every five years over an 11 year period.  They were followed with respect to diet and other possible confounding factors, such as physical activity.  (They didn't say "exercise."  Not sure what that means.)  Hippocampus volumes were measured by MRI once near the end of the study.  Volumes were compared between study subjects. 

The study drew from an earlier cohort of about 10,000 subjects that was selected in the 1985-1988 time frame.  The earlier cohort was used by the same researchers to study long-term outcomes with respect to cardiovascular disease.  The study explained little about the earlier study, but I speculate that the large cohort formed a rich population of subjects with similar characteristics who were already known to the researchers.  

The results were remarkable.  Each 8.7-point increase in the AEHI score (one standard deviation for you statistics nerds) correlated with an eye-popping 92.5 cc increase in hippocampal volume.  I want that kind of increase in my hippocampal volume.  Do I need to wait 11 years to get it? 

In the News

I haven’t posted much lately, especially with summer travel to the East Coast and North Cascades mountains.  But I have been watching the news on Alzheimer’s disease research.  Here are some things that caught my eye:

1. A study found that having a purpose in life was linked to lower dementia risk.  The study of “over 13,000 adults found that having a strong sense of purpose in life is linked to a reduced risk of dementia. People with a greater purpose were 28% less likely to develop cognitive impairment, even when accounting for genetic risk and other factors.  This was consistent across racial and ethnic groups and modestly delayed the onset of decline by more than a month over eight years. The findings suggest that building purpose through relationships, goals, or meaningful activities may help keep the brain resilient with age.”  Click here.

2. A study found that two supplements can affect levels of gamma-glutamyl transferase (usually referred to as GTP), which is a protein where low levels are seen in Alzheimer’s disease.  (I didn’t know this.)  Some study findings which were published in the journal GeroScience, described how two compounds, nicotinamide (a form of vitamin B3) and epigallocatechin gallate (an antioxidant found in green tea), helped restore guanosine triphosphate, a key molecule that fuels energy production in brain cells. In laboratory experiments on neurons, this treatment not only reversed age-related cellular decline but also enhanced the cells’ ability to clear away amyloid protein clusters, a defining feature of Alzheimer’s.  But these findings seem to have a long way to go before we get to a protocol.  I already take nicotinamide myself, although I don’t drink green tea as often as I should.  Click here.  And here.

3.  We already knew this, but Wendy Suzuki continues to bring attention to the importance of aerobic exercise for brain health.  Click here.

4.  Researchers at St. Jude’s found that a protein, called midkine, blocks amyloid beta from forming harmful clumps linked to Alzheimer’s.  If this checks out, it could lead to breakthrough treatments.  Click here.

5.  Researchers at Harvard found a connection between lithium deficiency in the brain and Alzheimer’s disease.  “The team discovered that loss of lithium in the human brain is among the earliest alterations linked to Alzheimer’s, while in mice, reduced lithium sped up both brain damage and memory decline.”  Click here.

6.  Deficiencies in omega-3 fatty acids may promote Alzheimer’s in women but not in men.  Is this why women are more likely to develop Alzheimer’s than men?  Click here.

7.  Researchers at Rush University (home of the MIND diet) believe they have found out why the MIND diet is effective.  Click here.

8.  In Beating the Dementia Monster, we said that there was a sweet spot for exercise to improve brain health.  But too much is detrimental.  Here’s new research on how it is that too much can be detrimental.  Click here.  Of course, we’re talking a lot of exercise to get over the peak for benefit to get to a downside.

9.  Can AI develop an even better diet for dementia prevention?  The Chinese say they have it.  Click here.  (China is second only to the US government in Alzheimer's research.) 

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.

A big day tomorrow...

As we wrote earlier, it's suddenly unclear if my neurological issue is Alzheimer's disease or normal pressure hydrocephalus (NPH) - or both.  NPH is often misdiagnosed as Alzheimer's disease, but also, the two disease often occur together.  Thirty percent of NPH patients also have Alzheimer's disease.

Tomorrow morning, I have an appointment for a consult with a neurosurgeon in Walla Walla.  Walla Walla is about an hour's drive from here. The purpose of the visit is to lean on his experience with cognitive and balance-impaired patients to see if it's appropriate for me to receive a shunt.  The high volume spinal tap I had in December suggests that it would be, but my neurologist cautions that there are many potential surprises here.  She wanted me to see an experienced neurosurgeon to find out what his experience says about my scenario.

One thing I want to discuss with him is the changes in my computed hippocampus volumes.  The evidence is that the normalized values for men my age went down from 2015 to 2017, stayed steady to 2018, but then improved remarkably into 2021.  My ventricle volumes remained unnaturally enlarged throughout this time.  NPH would explain my ventricle volumes, but not the changes in hippocampus volumes.  Alzheimer's disease could be responsible for hippocampus changes from 2015 to 2017, and lifestyle changes could explain the hippocampus changes from 2017 to 2021.  Or that's how it looks to my uneducated eye. 

I'll know more tomorrow.  I hope.

Is my brain growing?

If you read Beating the Dementia Monster, or if you've heard me speak, you know that I had five MRIs of my brain between 2012 and 2018.  The MRIs of 2017 and 2018 found that my brain had atrophied to the point that, among 100 men my age, I would have had the most tissue loss.  Under normal circumstances, all brains atrophy, but brains with neurodegenerative diseases atrophy much faster.  And mine was going pretty fast.  (My first MRI was in April 2012, and it explicitly found no atrophy.)

You will also know from my book that some researchers have found an increase in brain volume among elderly people who began to get more exercise.  This could include just exercise from working in the garden -- which can be hard work.  This appears to occur when the body generates the brain-derived neurotrophic factor which prompts stem cells to form new brain cells.

What about me?  I've gotten a lot of new exercise since my last MRI.  Has my brain volume increased?

It would take another MRI to compare to the past, and that's not likely to happen.  The insurance company wouldn't pay for it because it wouldn't alter my course of treatment -- it would be for the sake of curiosity.  It would be a different story if I were to begin taking Aduhelm, because brain swelling and micro-hemorrhaging are a problem with it, and you get an MRI monthly during the course of treatment.  But I'm not doing that.  So, unless I'm involved in another drug trial that uses MRIs to assess what's happening in the brain, I won't be getting one.

Unless, of course, an unanticipated medical condition emerges that demands one.

About two weeks ago, I was sitting at the computer when I felt as if a fist or something hit me in the back of my head, kind of hard.  I was alone, so it wasn't a fist but rather some event inside my head.  It was quite jarring.  For the next minute or so, I couldn't coordinate my eyes; they just looked in whatever direction each eye wanted to look.  It passed, and things seemed to return to normal.  I had a minor headache the next day.

This actually happened once a few years before, and my neurologist and primary care provider scolded me for not going to the ER.  So I went this time.  The ER people wanted an image of my brain to look for abnormalities, so they gave me a CT scan.  The results surprised me.

First, they found no new abnormalities, and they have no explanation for either of the two events.  So now, life just seems to be going on as before.  A few days later, I had almost four hours of cognitive testing for my annual evaluation, and, as I reported before, I think I may have done better than last year.  (I'll find out for sure on Tuesday, July 20.)  So, whatever it was that happened, it doesn't seem to have had a lasting effect.

A CT scan is not an MRI, and when I discussed this with the neuropsychologist before my tests, she pointed out that the CT scan has less resolution.  Nevertheless, as with all of my MRIs from 2015 and later, the analysis of the CT scan image noted there has been tissue loss.  However, on the standard rubric of "mild," "moderate," and "severe," the report classified my tissue loss as "mild."  My previous MRIs from 2015 and later noted "moderate diffuse cerebral and cerebellar volume loss."  So I've gone from moderate to mild ... maybe. 

A question that comes to mind is, if my brain had atrophied enough to put me in that < 1 percentile category, why isn't my volume loss "severe?"  I don't know.  I'd just guess that, for men my age, the number of men with severe volume loss may be considerably less than 1% of the population of interest -- men my age.  There would then be room for men with moderate volume loss who were still in the <1 %.

That this CT scan shows that my brain volume might be increasing is pure conjecture on my part.  And my neurologist warns that changes in brain volume don't always correlate with changes in cognition.  But it has me wondering what another MRI would show.