Important new Science

Crushed

An important new study from the Karolinska Institute in Sweden shows demonstrated clear (albeit small) favorable long term effects from three common Alzheimer's medications galantamine, donepezil and rivastigmine. It is published online in Neurology, the top Journal in the world for this type of research

Neurology Publish Ahead of PrintDOI: 10.1212/WNL.0000000000011832

 Long Term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

   https://n.neurology.org/content/neurology/early/2021/03/19/WNL.0000000000011832.full.pdf  

Easier to read Story about the research also from Karolinska

  https://news.ki.se/common-alzheimers-treatment-linked-to-slower-cognitive-decline

Short Article from the AAAS on the study  

https://www.eurekalert.org/pub_releases/2021-03/ki-cat032521.php

Jo C.

 Thank you to Crushed for this information.   I do however, have a caveat:

 NOTE:  It is absolutely imperative that before prescribing medications, that an accurate diagnosis for type of dementia be made by a medical professional who specializes in dementia.  

Many persons with dementia are misdiagnosed for actual "type" of dementia and that can make a huge and sometimes negative outcome when meds are prescribed.

 From the Association for FrontoTemporal Degeneration:

 "Although cholinesterase inhibitors help with behavioral symptoms (including apathy) in Alzheimer’s, FTD patients may have adverse responses, including worsening impulsivity and disinhibition, so care should be taken in using these agents in FTD patients with prominent behavior problems. Many doctors prescribe these medications as a trial, especially when the etiology of disease is not definitive."

From the NIH:

"Frontotemporal dementia (FTD) is a common and devastating disease. Once thought to be rare, FTD is now recognized as being at least as common as Alzheimer’s disease (AD) among middle-aged adults. Despite this wide prevalence, and the exacting toll of the disease on patients and their families, there is no US FDA-approved therapy for FTD.

To fill this void, off-label medication use in FTD is common. Among the most frequently prescribed medications in FTD are the drugs FDA-approved for the treatment of AD, despite fundamental pathophysiological differences between the two diseases.

In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms."

 

In our situation in personal experience,  my LO was diagnosed with Alzheimer's Disease by her Board Certified Geriatrician.   She was started on meds for AD; cholinesterase inhibitors. In a day or two, symptoms of dementia became much worse with extremely dreadful behavioral changes to the very negative side of the ledger.  It was dramatic.  Initially I thought it to be fast evolving demenita, (I was new at  this).

But observing more closely I soon realized something was way off.  In short, I got an urgent appointment with a good Neurologist who sees dementia patients as  a routine part of his practice.  After a full exam and a SPECT Scan, (MRIs showed nothing); there it was, as clear as could be, FTD; not AD.  Meds were adjusted with the offending ones being discontinued and it made a huge difference to both the quality of life for my LO as well as for family.

So . . . . be sure to get an accurate diagnosis right from the beginning.

J.

jfkoc

and please make certain the diagnosis followed the correct protocol....example the MMSE does not count as a proper diagnosis

I question that different forms of dementia were lumped together. I have been told that Parkinson's and LBD are under a separate "umbrella".

I wonder why galantamine is under used. It seems like Aricept is the go to drug. 

Galanamine is also labeled Razayne and is manufactured by Johnson & Johnson. Good time to check that stock price...lol

ADDED; My husband was prescribed galantamine by a psychiatrist some years before a neurologist was seen who then changed him to Aricept.

Michael Ellenbogen

This is great as I have fought for this for so many years and now there is finally a study that confirms what I have been saying all along. So many had it wrong including AA. And the pharma companies could never claim this.  

Lane Simonian

This unfortunately is not a particularly useful study.  For one thing, there are significant differences in the status of those taking cholinesterase inhibitors versus those not taking these inhibitors, only some of which appear to have been factored into the results:

Matching removed many of the significant imbalances especially in age (standardized difference decreased from 67% to 1%), baseline MMSE (46% to 0%), hypertension (29% to 0%), congestive heart failure (28% to 2%), history of atrial fibrillation (28% to 0%), and prescription of β-blocker (26 % to 1%).  

Secondly it looks like the researchers are speaking about improvements over non-users rather than over baseline (and these improvements are not likely to be clinically significant).

"At baseline, the mean MMSE scores were 22.0 points in ChEI-users and 21.9 points in non-users. ChEI-users presented with better MMSE scores at any visit compared to non-users (0.13 MMSE points change-slope; 95 CI [0.06, 0.20] for real cohort)." [.18 point difference for those taking galantamine].

What cholinesterase inhibitors due for many patients is to improve cognition for a relatively short period of time (around eix months) in early Alzheimer's disease; for  these drugs inhibit the breakdown of acetylcholine which is needed for the retrieval of short- term memory.  Some speculate that as neurons die these drugs begin to lose their effectiveness.  But more likely, as Alzheimer's disease progresses, the main problem becomes the lack of producation and release of acetylcholine as a result of the oxidation and nitration of choline transport systems, choline actetyltransferse, and muscarinic acetylcholine receptors (at therapeutic doses acetylcholinesterases are not particulary good antioxidants).  You can either try to inibit the factors and processes that lead to this damage or you can try to reverse the damage itself.  The former (including anti-amyloid drugs and acetylcholinesterase inhibitors) only slightly slow down the progression of the disease.  The latter largely stabilize mild Alzheimer's disease and substantially slow down the progression of moderate Alzheimer's disease.  For the difference see the chart in the linked study comparing the rates of decline in those taking only conventional Alzheimer's medications with those taking these medications in conjunction with Chinese herbs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/

Crushed

Scientific comments are made directly on the Journal page

This is what makes it real science .  It is the most widely read neurology journal in the world

Not a single person has mentioned your concerns , so I am sure they will welcome your comments  about the lack of utility of the study 

  https://n.neurology.org/content/early/2021/03/19/WNL.0000000000011832

The Karolinska is routinely ranked as one of the top pharmaceutical research institutes  in the world.  

Lane Simonian

It is really more about the interpretation of the numbers than anything else.  If one does not look at the numbers, one might assume acetylcholinesterase inhibitors provide a real benefit in terms of cogntion over a long period of time, but it is doubtful that a .13 to .18 less decline in MMSE scores per year over up to a five year time period is even statistically significant let alone clinically significant.  I would make exactly the same argument against Biogen's aducanumab.  

Crushed

Send it to the journal

the statistical significance is in the publication.  If the MMSE is not precise enough to be used at the level indicated that should be noted. 

The effect is modest but from a scientific point of view if it exists at all it is important

Michael Ellenbogen

When your brain is running on empty every little bit help. As person who does not have dementia you can not understand that but to me its a lifesaver of not falling over the cliff.

Lane Simonian

I have submitted my comment to the journal.  Some drugs may slow down cognitive decline as measured by tests, but produce no clinically significanct change in the person taking them.  If there had been a one or two point slowing of decline in MMSE scores that would have been something.  But a .13 to .18 change is very close to nothing.

jfkoc

I believe it to be true that while a MMSE score can indicate "dementia" it can not tell you the cause of the dementia which can be as simple as a thyroid problem or a vitamin dificiency.

It was not an easy read so perhaps this was discussed and I missed it.

Jo C.

jfkoc makes a very good point re testing.  The MMSE is worthless in diagnosing FTD as in that particular dementia, much of memory is often retained until far later in the disease process.  Diagnosis for this dementia needs detailed input by the family; so be prepared to provide information re cognition, function, and especially behaviors and changes over time.

In the behavioral variant of FTD, when memory is pretty much maintained and the behaviors go over the moon - much mischief can occur; some of it very serious.   Ours decided to go after bank accounts, etc.  Also capable of buying items from catalogs and by phone.  One day I was fortunate the lady who ran errands overheard my LO buying a $10,000 golf cart by phone.  She used a credit card. 

EEEK!!  I had to do some fancy footwork and gain cooperation of the company to undo the sale.  She had never golfed a day in her life nor could she operate such a cart.  Puff, puff, pant, pant.  At that point the credit cards went into lockdown and I removed their contact numbers from my LOs phone book.  All three credit reporting agencies were contacted for information . . .. to my utter surpriise, she had no less thn 16 open credit accounts at department stores, catalogs, etc.   All had to be closed.

Accurate diagnosis really is key to all else and especially treatment protocols.

J.

KatieKat1

I have to agree with Jo C. My husband has FTD and both of the commonly prescribed medications such as Donepezil etc., Did nothing for him. He was on both medications for a while...9 months and the Donepezil caused more agitation and other issues. The Mematine did absolutely nothing. The neurologist took him off both medications and replaced them with Seroquel and Citalopram. Cholinesterase inhibitors do work well for many who have dementia/Alzheimer but did not for DH with FTD.

Crushed

the study is limited to Alzheimer's , It has noting to do with FTD or other dementia uless the person also has Alzheimer's.

Iris L.

I've been on Exelon patch (rivastigmine) and memantine xr since 2009.  They keep me living independently.  I'm wary of losing them!  I don't have Alzheimer's Disease.  

Iris

Michael Ellenbogen

First of all, everyone focus on MMSE or other similar test. Those test are useless to measure these issues we have. If you do not have a form of dementia you would have no idea on what they do or how they help. New ways are needed to measure success and theta is what needs to change. In fact a meeting I was in yesterday is starting to do just that. This disease is so complicated that it will take input from those living with the dises to help the scientist and medical people define new ways. I see things slowly changing but it will take many more years till we get there.

 

Without these dugs I would be a zombie. When people spoke to me I was glassed I looking at them with tunnel vision and could not understand most of what they said after a few minutes of conversation. My wife knew I was gone. This has changed my life to be able to continue a much better life. So keep in mind all of your negative will hurt 50 person of the population that benefits from these drugs. While they may not be great sometimes it takes very little to keep you from falling of the cliff and I was that that point. It also gave me the time I needed to find other drugs I now take that are slowly helping me delay it even more.  I am living proof of the success of my custom formula that I created for myself after doing lots of research. And yes it is proven medications that most are clueless to use and had real success. In fact the more we learn about the disease the more they make sense of why I have been taking them and I have declined so slowly.  

Michael Ellenbogen

Just FYI these are some of the folks that had helped to push for such a report.

 

 

From: Woodcock, Janet
Sent: Thursday, April 8, 2021 12:25 PM
To: Michael Ellenbogen <>
Subject: RE: [EXTERNAL] FW: Cholinesterase Inhibitors

Thank you. Fascinating work.  Janet Woodcock

From: Michael Ellenbogen <>
Sent: Thursday, April 8, 2021 11:47 AM
To: Woodcock, Janet

Subject: [EXTERNAL] FW: Cholinesterase Inhibitors

CAUTION: This email originated from outside of the organization. Do not click links or open attachments unless you recognize the sender and know the content is safe.

Hi Janet,

 

I hope all is well. Not sure if you remember but you tried to help me with this many years ago. Someone finally created a report. Hope you help me get the word out.

 

Thanks

Michael

 

From: Marc Wortmann
Sent: Thursday, April 8, 2021 10:15 AM
To: Michael Ellenbogen <>
Cc: George Vradenburg
Subject: Re: Cholinesterase Inhibitors

Dear Michael,

Thanks for sharing. I always thought this, but nobody wanted to confirm (only Rachel Doody who now works at Roche, but not officially).

Sweden has this wonderful registry long before anyone talked about Big Data.

Best wishes, Marc

 

On 2021-04-07 14:12, Michael Ellenbogen wrote:

This is great as I have fought for this for so many years and now there is finally a study that confirms what I have been saying all along. So many had it wrong including AA. And the pharma companies could never claim this.  And Marc was the one who help me get the word out.

   https://n.neurology.org/content/neurology/early/2021/03/19/WNL.0000000000011832.full.pdf