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Chronic long-term REM sleep deprivation as a cause of AD
Internal Administrator
Posted: Saturday, January 7, 2012 3:22 AM
Joined: 1/14/2015
Posts: 40463


Originally posted by: Billstrailrunning

Fellow AD Warriors,

As many if not most of you know from following my prazosin thread, I have been harping on the importance of rapid eye movement (REM) sleep for the AD patient.  To briefly summarize, AD patients have been documented repeatedly to have little or no REM sleep at night.  REM sleep is important for brain neurophysiology, for cognition, for mood, and for general health. My ADLO told me years ago she felt  she never dreamed as she simply could not ever recall having had a dream.  Curiously, I never followed up on this with a sleep study for her as I dismissed her observation as probably due to her never waking up during or shortly after REM sleep when dream recall is at its zenith. Once my girl developed AD, I obtained a  device called ZEO that can be used to monitor sleep stages at home and quickly discovered she had very little REM sleep.  On many nights no REM was detected at all and on other nights maybe 5 minutes of REM time.  Normally, most healthy adults up to around 70 years are in REM at least 2 hours per night so you see she was really deficient.  

I have always suspected her REM sleep deficiency had something to do with her disease process and early on I set about trying to stimulate her REM sleep mechanisms with virtually no success.  Eventually I discovered prazosin which appeared to not so much have the capability to enhance REM sleep as to regulate REM sleep.  It had been reported as useful in AD patient's as a means of quelling agitation,  aggression, irritability, delusions, paranoid ideation, sundowning, etc, through  its action as a nor-adrenergic blocking agent.  I found that it worked very well for my ADLO in that capacity and I was somewhat successful in pumping up her REM sleep time to almost 2 hours per night.  For the past 6 months however her REM time has been on the wane despite prazosin 2 mg at bed time as well as 1 mg doses 3x/day.  As her REM time lurched from night to night with maybe 2 hours of REM one night followed by no REM the next I noted that her mood the following day was always much better following a REM night vs. a no-REM night.  Following no-REM nights the next day she was far more delusional, aggressive, irritable, etc., than she was on days following REM nights.  The animal literature essentially confirmed my observation as rats chronically REM-deprived became aggressive by day in a dose-response curve relationship...the more REM deprivation, the worse the aggression. Both animal and human literature also confirmed the putative role of REM in memory consolidation and skill learning.

In consideration of all these things I have been thinking more and more about the role of chronic REM deprivation in the genesis of AD.  In short, I think chronic long-term REM sleep deprivation may have a lot to do with who ultimately develops AD and continued loss of REM sleep probably also plays a role in AD progression, once AD begins.  The following link seems to confirm my thinking.

Google: "The physical and psychological effects of short-term and chronic sleep deprivation" by Robin Webster

Because REM sleep or lack thereof definitely seems to be playing some sort of role in the case of my ADLO, with her progression worsening as her REM sleep has again begun to deteriorate I have been again searching for ways to stimulate her REM sleep beyond prazosin.

Two prescription medications, bupropion (Wellbutrin) and mirtazapine (Remeron) seem good potential candidates for REM sleep enhancement in AD patients, if the side-effects can be tolerated.  Interestingly, I found an herbal remedy called mugwort that stimulates dreaming, dream recall, and possibly even REM sleep.  One does not ingest mugwort, but instead simply take the dried leaves from the plant, stuff them in a sock and put the sock with mugwort inside the pillow case to create a "dream-pillow".  I tried this on my wife and Voila! Her REM time jumped from 5 minutes on Monday night to Tuesday morning, to 1 hour from Tuesday evening to Wednesday morning. On Tuesday I had to administer two prazosin rescues as she was slipping into delusions and aggressiveness.  Today, following a night that featured 1 hour of REM sleep, there have been no episodes of aggression, irritability or delusions.  We will continue to have her sleep with the mugwort and I'll keep you posted.

What might all of this mean?  From my perspective, I think REM sleep in the AD patient or lack thereof is a huge clue as to the etiology and progression of the disease.  I am beginning to feel REM sleep monitoring of the AD patient is far more than an interesting luxury.  I feel it is essential to monitor your ADLO's sleep every night and do everything you can to keep that REM sleep time as high as you can possibly make it go if your are serious about slowing AD progression and also quelling irritability, aggression, sundowning, etc. in your ADLO.  

Finally, in view of what I have observed in my LO, and what I have found so far in the literature I think it is very sad that there has been virtually no interest in the absence of REM sleep in the AD patient.  I am beginning to become convinced that REM sleep is not just another casualty of the Alzheimer's Disease process, but rather absence or nearly so of REM sleep is the CAUSE of the Alzheimer's Disease process.  Fix the REM and you fix Alzheimer's!

If you want to fight AD on its own turf, you better get a ZEO at-home sleep monitor and use it to manage your ADLO's REM sleep and I think, if it is not too late, you might, just might begin to reign in Alzheimer's in your LO.  Also, if I am correct each of you following up on this could as a group provide a huge impetus for neuroscience researchers to start thinking more about how REM sleep or the lack thereof plays a role in the development and progression of Alzheimer's Disease.

By the way...do you dream at night?

Bill
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Tom(ek)

quote:
Originally posted by Billstrailrunning:
It has been suggested elsewhere that the depression associated with AD may not be exactly the same as found in non-AD patients.


Brain is so complex that depression can be triggered by many changes...

For example, the problem with tryptophan metabolism was observed in patients with AD .

Furthermore, as we know exposure to bright light is possible approach to increasing serotonin.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077351/

If it’s true, this mechanism can be damaged in patients with AD in the same way as mechanism responsible for melatonin production.

In case of melatonin and neurodegeneration:

“the suprachiasmatic nucleus (SCN), by receiving the information from light and dark environmental stimuli through the retina, regulates the secretion of melatonin produced by the pineal gland from serotonin.”

“The main reason for the alteration in sleep-wake cycle is related to alterations in the suprachiasmatic nucleus (SCN) and melatonin secretion.”

“The functional disruption of the SCN is even observed in the early stages of AD. “

But:

“The changes in the MT1 receptor explain why large studies have failed to show improvement in sleep-wake cycle after melatonin administration in AD patients.”

And something more about REM sleep:

“The percentage of time spent in REM sleep, which remains stable with normal aging, is reduced in patients with AD. A decrease in the mean REM sleep episode duration and REM sleep percentage can be due to degeneration of the nucleus basalis of Meynert. The nucleus normally exerts an inhibitory influence on the nucleus reticularis of the thalamus, the rhythm generator responsible for NREM sleep.

REM sleep also depends on the abundance and integrity of the cholinergic system. The cholinergic disturbance in AD is accompanied by worsening of REM sleep. In addition, many subcortical structures such as the basal forebrain, distal and superior raphe nucleus, and the reticular formation of the pons and medulla seem to be involved in the initiation of sleep and oscillation between REM and non-REM states. All of these structures may potentially be damaged by the degenerative changes which are part of AD. Their deterioration may explain many of the sleep architecture and rhythm changes in AD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939436/
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Tom(ek)

Hi Bill,

this discovery about mugwort and REM is very interesting.

I started searching and found that acetylcholine (and agonists of acetylocholine) plays important role in REM sleep. As you know the main problem at the beginning of AD is low level of acetylcholine.

I read also something about positive results of REM:

"Sleep inspires insight."
http://www.ncbi.nlm.nih.gov/pubmed/14737168

"Cognitive flexibility across the sleep-wake cycle: REM-sleep enhancement of anagram problem solving."
http://www.ncbi.nlm.nih.gov/pubmed/12421655

and role of acetylcholine and norepinephrine (noradrenaline):

"REM, not incubation, improves creativity by priming associative networks"
http://www.ncbi.nlm.nih.gov/pm...2700890/?tool=pubmed

"Neuromodulation: acetylcholine and memory consolidation."
http://www.ncbi.nlm.nih.gov/pubmed/10461198

"During REM sleep high levels of acetylcholine in the hippocampus suppress feedback from hippocampus to the neocortex, and lower levels of acetylcholine and norepinephrine in the neocortex encourage the spread of associational activity within neocortical areas without control from the hippocampus."

We can observe:
1. Acetylcholine - low level in AD,
2. Norepinephrine (noradrenaline) - positive response to prazosin.

Moreover:
3. Serotonin/Melatonin - damaged control of the pineal gland (problems with day/night cycle).

I found also something else - "lucid dreaming".

One "historical" device:

http://www.freepatentsonline.com/4420001.pdf

and some new:

http://remdreamer.com/
http://www.lucidity.com/novadreamer.html

description:
http://www.freepatentsonline.com/5507716.pdf

Even here we can read about acetylcholine and dreams:
http://www.freepatentsonline.com/20040266659.pdf

but especially look at this and the list of ingredients:
http://www.freepatentsonline.com/20080107754.pdf
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: swarfmaker

Apple juice may also increased the amount of acetylcholine. It would be a simple and safe thing to try and see if a glass of apple juice in the evening helped calm things down and improve REM sleep time.

An Apple a Day for AD? Antioxidants in Apples May Help Memory and Fight Alzheimer's Disease
By Jennifer Warner
WebMD Health News
Aug. 4, 2006 -- "An apple (or two) a day may help keep Alzheimer's away -- and fight the effects of aging on the brain. A new study shows drinking apple juice may improve memory by preventing the decline of an essential neurotransmitter known as acetylcholine..."
http://www.webmd.com/alzheimer...804/alzheimers-apple

Here's a couple other articles about apple juice.

Apple Juice Can Delay Onset Of Alzheimer's Disease, Study Suggests
ScienceDaily (Jan. 24, 2009)
"In the most recent study Shea and his team demonstrated that mice receiving the human equivalent of 2 glasses of apple juice per day for 1 month produced less of a small protein fragment, called "beta-amyloid" that is responsible for forming the "senile plaques" that are commonly found in brains of individuals suffering from Alzheimer's disease..."
http://www.sciencedaily.com/re.../01/090122100826.htm


Dietary supplementation with apple juice decreases endogenous amyloid-beta levels in murine brain.
Amy Chan and Thomas B. Shea.
Journal of Alzheimer's Disease, 16:1 (January 2009)
http://www.ncbi.nlm.nih.gov/pubmed/19158432
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Billstrailrunning

Fellow AD Warriors:

You may recall from my first post on this thread that I mentioned mirtazapine (Remeron) as a likely drug candidate to management of AD symptoms such as agitation, aggression, etc.  Well, we no longer have to speculate about that.  Lookee what I just found!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626919/

Below is an abstract of the study if you rather not read the entire article:

"Agitation is one of the most devastating behavioral symptoms in demented patients but there is little evidence about effective and safe pharmacotherapy. We aimed to determine the effectiveness and safety of mirtazapine in treatment of agitated patients with Alzheimer’s disease (AD). The consecutive patients with AD who have significant agitation were assigned to a 12-week open-label, prospective study. Patients received mirtazapine 15–30 mg/day. The changes in Cohen-Mansfield Agitation Inventory-Short form (CMAI-SF) scores were primary outcome measurement. The change in Clinical Global Impression-Severity scale (CGI-S) scores and tolerability-safety profile were the secondary efficacy variables. Thirteen of 16 (81.25%) patients completed the study. There was a significant reduction in CMAI-SF and CGI-S between the pre- and post-treatment with mirtzapaine (p < 0.001). The mean baseline score was 26.54 ( ± 5.4) and mean reduction was 10.6 ( ± 7.5) in CMAI-SF. There was no significant side effect and cognitive deterioration. The results of this open-label pilot study suggest that mirtazapine may be an effective choice for treatment of agitated patients with AD."

It is no surprise to me, and should not be to you by now that mirtazapine would be a good candidate for control of agitation/aggression and the whole constellation of psychotic-like symptoms associated with AD advancement in our LOs.  Gang, I think we have another medication to control behavioral issues in AD patient's so we don't have to keep thinking antipsychotics like Seroquel, Haldol, etc. that are so damaging to our LOs and also for the most part not really very effective in AD individuals.

Interestingly, Mirtazapine and other antidepressant medications have not been found to be any better than placebo in treatment of depression in AD patients.  To my knowledge there have been no attempts to evaluate memory or other aspects of cognition while treating with mirtazapine, but I would predict that AD progression would be slowed and possibly even reversed to a small degree.  The 12 week study I provided the link to evaluated for AD progression and found none, but 12 weeks is pretty brief.  Still, that is what I would expect based on the evidence I have already summarized for you above. The link below summarizes findings on mirtazapine and depression.

http://www.bioidenticalhormone...imers-and-depression

It has been suggested elsewhere that the depression associated with AD may not be exactly the same as found in non-AD patients.  Of interest most antidepressants like the tri-cyclic antidepressants and SSRIs suppress REM sleep in normals and presumably AD patient's too although as we are now beginning to understand may be a mute point at best for the AD patient who has little or no REM sleep to begin with.  At worst, further suppression of REM can only be expected to worsen agitation/aggression tendencies if indeed there is any effect at all for the AD individual, and may even hasten AD progression.  I hasten to add my remarks here are speculative at best on my part, but I would not make these statements if I  did not think this was actually the case.

A follow-up on my ADLOs sleep last night with mugwort:  Sometime during the night, the sock I had stuffed with mugwort fell out of her pillow case onto the floor and her REM time at rise time was only 30 minutes instead of 1 hour as documented for the previous night.  Tonight, I will make sure the mugwort stuffed sock remains in place.  Her mood today has been a tad more testy, but not as bad as the day before yesterday following only 5 minutes of REM time for the night. Yesterday, following 1 hour of REM time the previous night, not a single outburst, delusion, or occurrence of irritability.  Lets here it for mugwort, or if need be mirtazapine (Remeron), and oh yes, prazosin.

Bill
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Billstrailrunning

Tom(ek)

Thx for doing such thorough home-work and filling in the details. Your effort is extremely helpful in my opinion.

My wife had only 6 minutes REM time last night despite mugwort being well-placed within her pillow. definitely a disappointment to me. I will keep using it for awhile though as like prazosin it may require many nights to pump her REM time up to a reliable level. That said, I was planning to get her going asap on mirtazapine so hopefully all our theorizing and literature review will pay off in increased REM time for her and reduced agitation/aggression. I will probably dc mugwort when I start her on mirtazapine.

I'll keep y'all posted good news or bad.

Bill
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Billstrailrunning

Tom(ek),

Notice how the pieces of the puzzle start to fit together.

I did play around with lucid dreaming with my ADLO early on but could not improve REM time at all with any of the herbal preparations. No doubt it works well for non AD folks but not so much for those already afflicted with AD.

Bill
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: Tom(ek)

It's true it fits.

In many cases herbal preparations don't have suitable dozes or proper types of different chemical constituents for AD patients and don't have such influence on norepinephrine like prazosin or on serotonin/melatonin like 5-htp but look at ingredients list which I mentioned. There is mugwort as one of the main components Smiler (and also 5-htp).

For me your observations with ZEO are very interesting because last year I wrote about aggression, agitation, confusion, apathy on some other forum (and in other language) and I began from description of REM sleep, description how different medications changes REM sleep and then I wrote about neurotransmitters and their role in REM and BPSD (behavioural and psychological symptoms of dementia). Of course it wasn't my theory but information from different medical publications. I forgot about it until I found your post about prazosin, ZEO and REM.

I wonder if REM sleep is really a cause of good behaviour or rather marker (proof) of good neurotransmitters adjustment which has also influence on behaviour or both?
Anonymous
Posted: Saturday, January 7, 2012 3:22 AM
Originally posted by: onward

Very interesting thread, Bill. Please continue to update us.
 
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