Coming Out of Lockdown -- What Will that Mean for Elder Care?

Unless you live in Wyoming, Utah, Oklahoma, or a few other states, you have been living in quarantine for what seems like forever.  But sooner or later a mix of improving infection statistics, economic necessity, and public frustration will lead to a relaxation of the shutdown orders.  What will that mean for people living in memory care, retirement, nursing, and other elder care facilities?  This is where the most vulnerable members of our communities live, and mortality rates are the highest.

In our city, there is one nursing home with fully 100 infections.  I've visited that facility many times, and I didn't believe there were 100 people there.  So it must be that about everyone there is infected. 

It's pretty clear that your state will not lift all restrictions simultaneously.  Restrictions will be lifted systematically to favor less hazardous activities as well as activities with economic imperatives.  Elder care facilities have the most hazard for their residents, and there is no economic imperative for opening them.  So they will likely be the last to get to wherever it is we're going with a re-opened society.

Before our shutdown order came, I was visiting elder care facilities pretty much every day, seven days per week.  I had seen one period of time when there was a scare about the flu or something, and all residents were confined to their rooms for a week or so.  What struck me about this was the terrible sense of loneliness that would pervade the living areas.  (I was told I could enter at my own risk, and I decided to risk it.)  Some of the residents receive periodic visits from family and friends, but many have no visitors at all.  They do have an opportunity to see others at meals or while traveling the halls and community areas.  But in quarantine, the only human contact residents have is when someone brings them their food, or someone comes in to bathe them or help them go to the bathroom. 

For prisons, some have tried to make the case that solitary confinement is cruel and unusual punishment.  This doesn't seem to be much different from what many elder care facility residents experience during quarantine.

Recall that human contact -- or rather, lack of it -- is a risk factor for Alzheimer's disease, and increased human contact is recommended for people who have AD.

I saw quarantines lasting a week or so, and marveled at what the residents suffered through.  And so I can't imagine what these people are going through now.  When restrictions are relaxed for the rest of us, how soon will it be safe for elder care residents to return to the level of human contact they had before?  How long will their suffering last? 

Another Possible Vaccine for Alzheimer's Disease?

As we discussed in Beating the Dementia Monster, Alzheimer's disease continues to be a black box.  There are so many hypotheses surrounding beta amyloid, tau protein, P. gingivalis, herpes, and others.  When we can finally go to press with the second edition, we will note that cancer research began in earnest in 1913, but Alzheimer's research only got going in the 1980's.  So it's not surprising that we still struggle to get a handle on the basic disease mechanisms. This has implications for progress in both disease prevention and treatment.

In two earlier posts (this one and this one) we considered the possibility of a vaccine for Alzheimer's disease.  The first article considered the possible role of P. gingivalis in the genesis of the disease, and the idea that a vaccine against this pathogen might work.  The second article concerned trials for a vaccine that might work against beta amyloid, training the body to treat it as a foreign intruder.

But what about a vaccine against tau protein?  During the perhaps 15 years of the pre-clinical stage of the disease, abnormal tau is being generated within brain cells.  But at the beginning of the MCI stage, tau is expelled from the cells and spreads throughout the brain.  This produces the tangles that are observed during autopsies.  The spreading tau appears to play a role in the advance of the disease.

This invites another idea for a vaccine.  How about a vaccine that attacks the abnormal tau protein?

At the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually from April 2 to 5, work on such a vaccine got attention.  (We discussed some other interesting takeaways from the conference on April 12 and 13.)

Presenters addressed several initiatives to develop tau vaccines.  In one case clinical trials had not gone well, and others were still trying to get off the drawing board.  But one showed promise in clinical trials. 

The most promising candidate is called "Axon peptide 108 conjugated to KLH" or AADvac1.  Basically the vaccine prompts the generation of antibodies that target one of several abnormal tau proteins.  AADvac1 has completed its phase 2 clinical trial and should -- hopefully -- go into phase 3.  The first two phases of a drug trial look for efficacy of a new drug, but they are first intended to demonstrate safety.  Phase 1 trials are fairly small, and phase 2 will involve more subjects.

In the case of AADvac1, the test subjects had "mild Alzheimer's disease."  (I don't know if that meant they had MCI or were in the mild (first) stage of Alzheimer's dementia.)  After some people dropped out, the phase 2 trial for AADvac1 had 100 subjects on the study drug and 63 on the placebo.  The trial ran for two years.

There were no problems with safety, but does the vaccine work?

Unfortunately, in the two trials there was no evident effect on cognition.  (A subset of younger test subjects may have shown some improved cognition.  "Younger" means ~65-67 years.)  On the other hand, there was pretty good evidence that the process of neurodegeneration was actually slowed.  This was evaluated through changes in blood that are associated with neurodegeneration.

The biotech company Axon Neuroscience plans to move ahead with a phase 3 clinical trial, but they believe they first need to find an international partner.

So what do we make of the fact that the drug slows neurodegeneration but does not appear to improve cognition?  We've found that we can remove amyloid plaques from Alzheimer's brains without improving cognition.  But it appears that cognition will improve somewhat if people stay on a drug long enough after removal of the amyloid to allow healing of the brain.  Will the same apply when removing the abnormal tau protein? 

Can Exercise Fight Alzheimer's Disease and Covid-19?

We know that aerobic exercise fights a lot of ailments including Alzheimer's disease.  But does it fight covid-19 infection?  Some think it does.

Dr. Zhen Yan at the University of Virginia Medical School says "Regular exercise has far more health benefits than we know. The protection against this severe respiratory disease condition is just one of the many examples."  This quote comes from an article in studyfinds.org.  His research on exercise and infection was published in the journal Redox Biology.

Dr. Yan's statement centers on "acute respiratory stress syndrome" which is the manifestation of respiratory infection that most concerns us.  He believes that during aerobic exercise, the body produces the antioxidant extracellular superoxide dismutase (EcSOD) which could have a lot to do with keeping the majority of coronavirus cases mild.  This occurs because the antioxidant neutralizes free-radicals which initiate damaging chemical reactions in the body.  In so doing, EcSOD protects various body tissues from disease.

An article in the NY Times from March discusses other research on exercise and immunity.  It emphasizes evidence dismissing the idea that the exercise might temporarily suppress the immune system.  In fact, exercise appears to strengthen the immune system, even in the window shortly after the exercise.  At least, that seems to be what happens with mice.

In Beating the Dementia Monster, we emphasize the importance of aerobic exercise in fighting Alzheimer's disease.  But it has a lot of other benefits as well.

More on my MRIs

After yesterday's post, I got an email from my Mom about the last paragraph.  She correctly perceived that I had some pretty ugly MRI results, but I may have been confused about how much I've said about this in the past.  The MRIs in question came about after publication of the first edition of Beating the Dementia Monster, but I will be giving them a thorough treatment in the second edition.  I'm still working on the second edition, so I may sometimes get confused between what I've shared here and what I've written into the new edition.  If I have given my MRIs adequate discussion here, it was a while ago.  So I should probably recap.

I had five MRIs of my brain from 2012 to 2018.  The first one was to look for the brain tumor I had thought might be causing my initial issues, but it found nothing of concern.  However, they were not looking for neurodegenerative disease, and they did not measure volumes.

Regarding volumes, there are two key volumes when diagnosing Alzheimer's disease.  One is the volume of the hippocampus and others are the volumes of the ventricles.  When mine were measured in 2015, 2017, and 2018, they were normalized with respect to other men of my age.  Results were expressed as to what percentile of men my age my volumes would fit.

The hippocampus translates short term memory into long term memory.  It also keeps you oriented in time and space, so that you know where you are, what day it is, etc.  The ventricles are void spaces in the brain that are filled with cerebrospinal fluid.  They expand to compensate for the loss of brain mass, and an increase in their volume is therefore a proxy for general brain atrophy.

If February 2017, I had two MRIs in the same week in the same facility at the U of Washington.  One was for the insulin study, and the other was for a database and library of MRIs they were creating of people with Alzheimer's disease.  I asked why they couldn't use the same image for both, but they weren't able to explain it.  Nevertheless, I lay in the very narrow tunnel of the machine for 40 minutes, twice in one week.  I was able to obtain the radiologist report for the insulin study MRI, but I don't think I got one for the other one.  Or maybe I did, and I lost it.  The 2018 MRI was to complete the insulin study, and the radiologist report simply said that my brain had been stable between 2017 and 2018.

The baseline MRI is the one I received in 2015 for my initial diagnosis at Harborview.  It found that the volume of my lateral ventricles placed me in the > 99 percentile for men my age, and the volume of my hippocampus placed me in the 36 percentile for men my age. 

However, the 2017 insulin study MRI found that the lateral ventricle volume could still fit > 99 percentile for men my age, but my hippocampus volume now fit < 1 percentile.  In other words, in a room of 100 men my age, I would have the smallest hippocampus and the most loss of brain volume.

There was a note in the radiologist report indicating that the difference in hippocampus volumes might reflect a "difference in technique."  If that's the case, which was correct -- 2015 or 2017?  (This might not be a meaningful question, since different techniques might reflect finding different kinds of information.)  I would say from this that it's likely that my hippocampus volume was already at the < 1 percentile in 2015 because the lateral ventricles were already > 99 percentile.

So how could I have such good cognition after so much damage to my brain?  The nun study found that some (a few) women retained good cognition despite considerable damage to their brains.  Perhaps these nuns were doing all of the things we discuss in Beating the Dementia Monster.

More Insight from the AAT-AD/PD Online Conference

Yesterday we posted some news on blood tests for Alzheimer's disease from the AAT-AD/PD online conference.  (The conference was held online due to the coronavirus pandemic.  Otherwise it would have been in Vienna, Austria.)  But there's more.

On February 16, we wrote about the failure of a couple of proposed drug interventions to improve cognition during Alzheimer's disease, including two candidate drugs named ganternerumab and solanezumab.  The news from the conference was that ganternerumab had been extraordinarily effective at removing beta amyloid (the type of amyloid associated with Alzheimer's disease) from the brain, and that it also removed pathologic tau protein.  There was an implication that, even though cognition didn't improve during the trials, it might improve given more time. 

The idea was that, after the amyloid plaques and tau are removed from the brain, it may be that the brain just needs time to heal afterwards.  Therefore, further testing is in order.

This was all discussed in an article in this week's ALZForum.

These conclusions may explain the results we discussed regarding the candidate drug BAN2401 back in July 2018.  BAN2401 needed further testing, but it appeared to improve cognition in Alzheimer's subjects if they remained on the drug for six months after the amyloid plaques had cleared.  With ganternerumab at least, and maybe with solanezumab, we have the bonus of clearing both the tau and the amyloid.

But there was a bonus in the ALZForum article.  About half-way down in the article was a graph that mapped the various dynamics of the disease progress.  The x-axis was a timeline beginning more than 20 years before the onset of symptoms (the beginning of MCI) and proceeding 10 years beyond.  "0" marked the onset of symptoms.  While it is very variable, five years in MCI and five years of Alzheimer's dementia ending in death is a possible scenario for an Alzheimer's patient.  We have noted before that the disease likely begins 20 years before any noticeable symptoms appear.

The graph displayed the rise of amyloid concentration in the cerebrospinal fluid, peaking at the 0 mark, and then declining gradually.  As we discussed previously, the later decline probably results from the amyloids beginning to agglomerate on the brain cells.  At the same time, the tau protein takes off right at the 0 mark -- when symptoms first appear.

The graph displays the decline of hippocampus volume, consistent with what my own MRIs have shown.  It also describes the decay in the ability of the brain to metabolize glucose.  It did not have an element describing the decline in brain volume, but that can be inferred from from the decline in hippocampus volume.  In my case, a hippocampus volume of <1 percentile for men my age corresponded with an increase in lateral ventricle volume to >99 percentile for men my age.  Those findings were from my MRIs in 2017 and 2018.  (The ventricles are void spaces in the brain that expand with the loss of brain volume, so it is an inverse proxy for loss of brain volume.)

I hope everyone stays safe during the pandemic! 

Progress on blood tests for Alzheimer's disease

Back in January, we discussed some promising advances in Alzheimer's disease research, noting that we could soon get some very good news on several blood tests for early detection of the disease.  Most of our hopes had been riding on tests to detect beta amyloid in the blood, but there was also some hope for a test for blood serum tau protein.

Recall that both the malformed protein beta amyloid and a certain variety of tau protein in the brain are recognized biomarkers for Alzheimer's disease.  These can be detected using a PET scan, but this is usually done after symptoms have developed.  Since the disease starts a decade or two before the first symptoms appear, the hope is that very sensitive tests could detect the buildup of these factors early.  And we have been hoping that some apparently ineffective drug interventions might actually work if we could start people before they showed symptoms.

The 2019 Alzheimer's Association Facts and Figures Report described our understanding of how the disease progresses in the brain.  It noted that Amyloid accumulates in the cerbrospinal fluid until the first cognitive symptoms appear.  At that point, the pathologic tau suddenly bursts out of the cells and spreads throughout the brain, although some had likely been getting out all along.  The expulsion of the tau protein coincides with the appearance of the "tangles" that Alois Alzheimer noted in a brain autopsy in 1906.

The focus of the search for a blood test had focused on finding trace amounts of amyloid, but that can be tricky.  At first the amyloid builds up in the brain and blood, but then it begins to agglomerate on the brain cells.  So at that point, the concentration of amyloid in blood and cerebrospinal fluid begins to go down instead of up.  That makes interpreting the results a little harder.

So there is also attention on the protein p-Tau181.  The hope is that this will be a more reliable biomarker, and a couple of recent studies support this hope.  At the recent Advances in Alzheimer's and Parkinson's Therapies meeting, participants discussed some recent research showing that very small concentrations of tau protein could be detected in the blood, and the concentrations could be specifically correlated with the advent of Alzheimer's disease.  This was very promising.

The meeting is normally held in Vienna, Austria, but it was conducted online this year due to the pandemic.

Why do we want to know if someone has Alzheimer's disease before it manifests itself in cognitive symptoms?  Most Baby Boomers don't want to know.  They likely saw a parent or other loved one live through it, maybe die from it, and they believe that there's nothing that can be done about it.  So what good would it be to know?  (They should read Beating the Dementia Monster.)

Certainly, the long-term care insurance companies would like to know.  They will want to screen out applicants that will likely develop Alzheimer's dementia in the coming years.

The real benefit is to the researchers, at least for now.  It's believed that acting early, well before symptoms of cognitive decline appear, will be much more powerful than waiting until someone has already developed MCI or dementia.  So it's important to find preclinical research subjects.  In the past, researchers have used preclinical test subjects with the younger-onset variety of the disease, because they can be confidently identified through genetic testing.  But a reliable blood test for preclinical test subjects with the older onset variety will break down some of the biggest hindrances to the effectiveness of Alzheimer's research. 
  

Dreaming Our Way Through the Pandemic

I have been focused on doing everything I can to improve my sleep, especially since my neurologist expressed concern about my sleep.  We were concerned with some erosion of my cognition that was occurring during the spring and summer of last year, and sleep problems were likely the culprit.  Part of trying to improve my sleep has been reading and studying what we know about sleep, including the thoughts that Freud and Jung had about dreams.

So I had been paying attention to my dreaming, noticing that I recently had been dreaming more -- or at least remembering more about my dreams when I awoke.  I very rarely have nightmares, perhaps less than one a year that I will remember.  But I recently had two relatively mild ones in the same week.  This caught my attention.

Those of us who use the Firefox web browser are treated to new, interesting stories every day when we first open it.  Yesterday one story popped up about an upswing in remembered dreams all over the world -- and an upswing in nightmares.  So I didn't seem to be alone in my experience.

Firefox brought the story over from InStyle, an online magazine that generally focuses on fashion and popular culture.  But this topic is probably of interest to all of us.  The article was "Why You're Suddenly Remembering Your Dreams in the Morning."  Of course, the cause of the change in our dreaming behavior seems to be the anxiety being produced by the covid-19 pandemic.

The article associates our recent behavioral changes with reactive activity in the hippocampus and the amygdala structures of the brain.  Both are members of the limbic system and so are associated with both memory and emotion.  They are generally subservient to the structures associated with reason.  The article suggests that reactions of "dread and rage" in the limbic system are responsible for changes in our dreaming behavior.  Dreams are a way in which we process intense experiences.   Therefore, unusual stresses and uncertainty lead to reactions of dread and rage which prompt increased dreaming activity.

As an aside, I recently experienced some confusion when talking with a friend in Spanish.  It turns out that the word "amygdala" means the same thing in both Spanish and English in reference to the brain, but it can also be translated from Spanish as "tonsil."  So when we used "amygdala" in our conversation, we were talking about two different things.  The conversation got very strange very quickly. 

Journal of the Plague Year for Alzheimer's Disease

(With apologies to Daniel Defoe... )

Covid-19 isn't the Black Death, but it's pretty deadly.  No one reading this is unaffected, and some may be losing friends or loved ones.  I have one friend in a senior living facility who has been diagnosed with covid-19 and has been given a respirator.  He lost his wife to other causes only a few weeks ago.  The virus is active in several senior living facilities here locally with a number of deaths.

It has been, of course, disruptive to care for persons with dementia, whether in a memory care facility or at home.  There are reports that non-family caregivers are cutting back on the time they spend caring for elderly people, both for the sake of the caregiver and the sake of vulnerable older people.  The memory care facilities cut back and then stopped allowing visitors some time ago, so I have stopped making visits.

The Alzheimer's Association has advice for ways to support caregivers.

Social services have also been disrupted, especially volunteer based services.  Most volunteers are more vulnerable older people.  The food bank where I volunteer has shut down but will now be staffed by members of the National Guard.

Alzheimer's disease research has also been impacted, notably drug trials.  This certainly affects medical trials in general, because test subjects aren't able come in for testing.  Research around the world has been shut down due to the need for social distancing among researchers.

Let us all hope for rapid advances in medical science to quickly end this plague.  But let's also hope that the challenges strengthen the bonds of love between us and others, social distancing not withstanding.

Stay safe.