Jean-Pierre Le Rouzic
Forum Replies Created
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but it looks to identify the specific genetic source of each “type.”
Actually most (95%) of ALS cases have no genetic origin, as they are proteopathies, mainly due to TDP-43, which is also shared with several kind of dementias (FTD, 1/3 of Alzheimer, some Parkinson).
Even for the familial cases were there is an obvious genetic origin, scientists did find proteopathies.
But one can ask what creates the proteopathies in the first place, it can be a lot of things, including DNA or RNA damage as most proteins involved in ALS are related to DNA or RNA damage. Probably what we subsume under the umbrella term “aging”.
But really there is no scientific consensus about ALS, scientists do not even agree on very broad hypothesis such “dying forward” or “dying backward”. In one case the disease starts in the Pons or the medulla oblongata, in the other case it starts at the neuromuscular junction or even with muscle waste. There are strong evidence for both cases.
On a related topic, there is a recent tendency in clinical trial to divide the patients in subgroups. But those subgroups are not based on genetics, they are based on various biomarkers. Maybe that would help to better stratify ALS.
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There are many subtypes of ALS but it is very artificial as there is no biomarker for ALS.
As long as there is no biomarker, we do not really know what is exactly the disease, except that its clinical signs in the “classical” form involve both upper and lower failing motoneurons.
For example here is ALS type 23:
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Many thanks Dagmar!
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Hi all,
I wrote a book about the state of ALS research. It includes sections about the main achievements, the main drugs that are studied, a possible genetic therapy with current state of art and glimpses on future therapies:
https://www.amazon.com/dp/1698147899
My intention is to keep its content up to date as research progresses.
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Both are tiny studies, one with 37 people (the first in your post), and the other with 114 people.
The first study could easily have a big uncertainty, and it shows little information (only one figure and one table). One thing bizarre is that there is much less death with vitamin D, than without!But the ages of the two groups were very different, as were very different their vitamin D levels at the start of the study. It is a botched study!
The second study is better designed, but somehow the table III completely contradicts their conclusion: The group treated with vitamin D has much better results than the untreated group!
So I guess all this proves that scientists like all of us, have lot of prejudice and they first want to prove what they suspect (or what their boss tells them to find), and they are not interested in discovering new facts.
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That’s wise Tim, no one should follow some random advice on Internet, without informing their doctor and without having measurements (lab works) showing a deficiency.
As for this study, one should be aware of the following:
* It is a very small study, the total cohort is 48, one tenth of what is considered the minimum in clinical trials. From an ethical point of view, no such news should be reported, because they have wide deviations that have no biological meaning.
* As it is a small cohort, it cannot study the influence at different stages of the disease, and in different kind of patients, and there are many variants in ALS! What is in common between a pALS having a C9orf72 pathology and one having a WT TDP-43 pathology, apart that they have similar symptoms?
* They report about vitamin D3 in serum, which they acknowledge is useless, because bioavailability is poor and could tell a very different story if measured in the CNS.
* It actually shows to have a beneficial effect on the respiratory parameter at high doses.
* What is studied is calciferol, one of the three types of vitamin D3, vitamin D is an umbrella term that encompass vitamin D1 to D5.
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Amanda Sifford:
You asked me: Did you read the article posted on ALS News today?
As I can’t answer directly to your notification (you have a strange forum software), and as it is not a private issue, I answer here.
I assume that you mean the article about BMI that was posted the 28 of June?Yes I did, it is another article on this subject that confirms that having a high BMI means a lower risk of having ALS.
Nakken and al did several nice studies, including on multiple sclerosis risk for women in Norway.Several words of caution about ALS and BMI:
1. My understanding is that for people who have ALS, it is dangerous to get a low body mass index (<22), particularly for women. For ALS women it seems that a BMI of 27 is perfect.
2. For me (ask a scientist) it does not mean that for a healthy person, being lean creates a risk of having ALS. What I read in the scientific articles is that people with ALS have a high metabolism, so they are naturally lean and active. This is why I pointed to articles about insulin resistance in ALS.
3. I do not think either that for a person diagnosed with ALS, getting overweight protects against ALS. pALS have to have a diet fitted for people with a high metabolism. ALS centers have a role here.
4. All those articles that make statistics on large populations, may only apply to sporadic ALS cases, not to familial cases. -
The article where one can find those pictures was published in:
Neurology. 2013 Feb 26; 80(9): 829–838.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598455/It was cited 32 times!
What I am telling is not some outlandish view of someone in Internet. On contrary it is the standard view on dieting and ALS since four decades:
1. Lipids are as much important as proteins.
2. Survival in ALS is best for people who have a BMI a bit higher (see figures) than what is usually recommended.But I am not a doctor, so I may be wrong, but I would like to read research that tells a different story.
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I read this article which has this nice picture:
At left is the relation between ALS risk and BMI for men, and at right for women.
While the relation for men seems to be what I wrote (medicine books are written by and for men), for women the story is much more complicated: A BMI of 27 seems to give the best outcome.
The study was to investigate the association between body fat and risk of amyotrophic lateral sclerosis (ALS), it included 518,108 individuals recruited from the general population across 10 Western European countries.
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Dagmar, first I completely agree with you that reducing mental stress is extremely important.
The sentence that you quote about “beneficial’ cardiovascular profile” can be found in the reference [5] in the fourth paragraph of the background section. I would say that it is a rather common view.
In second I am not a native speaker, and finding the right words is not so easy for me. In addition there are some limitation in vocabulary, “fat” means many different things depending on the context. It can means being overweight or refer to one chemical which is a building block of life. When I see fat, I understand lipid, but not being overweight.
I do not want to push the idea that becoming unfit is a good thing to pALS, that would be stupid and having a BMI > 30 is proved to worsen the prognostic. Rather I think that when doctors tell patients that they need to not loose weight, it is very important. And lipids are very important for pALS, the brain and nerves are bathed in lipids. There would be no life without lipids.
You say also “The unfit ALS patient …; thus they atrophy quicker“. It seems to me that scientists found the contrary to be true. But you are right, scientists agree with the need of exercise in ALS to maintain the neuro-muscular junction. For example in this article. Targeted and slow exercises are needed and you are probably one of the best experts on this subject.
Finally I would argue that having a criteria to measure something is intellectually a satisfying perspective, but the reality is probably very complex and it may be very unproductive for a pALS to focus on their body fat. And I have no alternative to offer.
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About body fat and ALS, I did a little research through the literature on this topic:
Many times, those diagnosed with ALS have led healthy and active lifestyles. In fact, it has been repeatedly shown that ALS patients have lower rates of antecedent disease than that of the general public [4] .
Scientists known that a conventionally ‘risky’ cardiovascular profile, such as a high body mass index (BMI), or diabetes mellitus type 2, might protect individuals from ALS by delaying the onset of symptoms and/or slowing clinical progression. Hypertension, hyperlipidemia, arthritis, COPD, thyroid disease, and non-ALS neurological disease are found to be significant factors associated with a delay in ALS age of onset. These conditions have also been found to be less prevalent in the ALS population.
On contrary, and equally surprising, a ‘beneficial’ cardiovascular profile, with a low body mass index, an athletic lifestyle, and low blood cholesterol levels, may increase the risk or worsen the prognosis [5][6] .
In 1978 scientists[2] were surprised to see that insulin was strongly increased in ALS patients which suggested insulin insensibility. This leads to a flurry of drug trials with variations of IGF-1, Insulin growth factor until 2000. In 1997 a study shown that IGF-1 slowed ALS progression by 26% [3] , which is very similar to current ALS drugs such as Masitinib and much better than Riluzol.
One study in 2010 seems to recapitulate the 1978 study as it finds that patients with ALS show abnormal glucose tolerance that could be associated with increased free fatty acids levels, a key determinant of insulin resistance [1]. However no suggestion was made to explain the association between ALS and insulin resistance.So my own conclusion is: there is no clear indication that fat is good or bad for ALS, but insulin resistance is probably a problem in pALS. However take it with a grain of salt 😉
[1] https://www.ncbi.nlm.nih.gov/pubmed/20184518
[2] https://www.ncbi.nlm.nih.gov/pubmed/661736
[3] https://n.neurology.org/content/49/6/1621
[4] https://www.ncbi.nlm.nih.gov/pubmed/25720304/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278047
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810157/
(An uncommon large study)So my own conclusion is: there is no clear indication that fat is good or bad for ALS, but insulin resistance is probably a problem in pALS. However take it with a grain of salt 😉
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There are many drugs that were granted the status of orphan drugs for ALS by FDA. But for most it was retracted later.
And this clinical trial EH30 is quite controversial. Please look at the comments in:
https://www.alzforum.org/news/research-news/small-trial-eh301-appears-halt-progression-alsThree of the authors of this study received stock options from Elysium Health, the company that owns EH301.
My own remark would be about several of the authors who did not published previously on neurodegenerative diseases but rather on some strange topics such as:
Bone quality in young adults with intellectual disability involved in adapted competitive football.
or
[EFFECTS OF VOLUNTARY INTAKE OF FLUIDS (WATER AND SPORTS DRINK) IN AMATEUR MOUNTAIN RUNNERS].
or even
That looks like very impressive qualifications for participating in a breakthrough research on ALS!
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I understand now: You are on one of the most difficult task in today’s human communities: Changing the medical perception of ALS.
I had colleagues (I am retired) and I know a few univ professors that wanted to offer help to MDs. They had to let go, MDs are a very conservative group, look for instance at the stethoscope. Not only it is completely obsolete but most doctors claim they master it, yet most studies shown they do not.
Another example is the use of checklist in hospitals, it is simple, life saving, yet nobody wants them.
Providing advice is complicated, it depends on the context, there are not textbook or quick answer. And to complicate the matter (and to explain why MDs behave this way) patients ask for quick answers. A lot of patients do not care about life style, they just want to swallow another pill and forget the disease. Current medical practice fills this need.
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Many thanks Dagmar,
Out of curiosity, you are interested in a “Lean muscle/body fat” measurement, some retail scales give that information, but how would you use this information? What do you expect to learn from it?
I ask because I have access to the PRO-ACT database and there is no such high level information in it. They seems to be interested in muscle degradation and recorded it in more than 10,000 pALS: Creatine Kinase, Triglycerides, Total Cholesterol, Lactate dehydrogenase and 44 other measurements.
If you (or another person) are interested in the mean value of those parameters, or something else not too hard to compute, it would be a pleasure for me to provide it.
This list of measurements is easily available in the PRO-ACT database:
[0] = “Absolute Eosinophil Count”;
[1] = “Albumin”;
[2] = “Albumin/globulin ratio”;
[3] = “Alkaline Phosphatase”;
[4] = “ALPHA1-GLOBULIN”;
[5] = “ALT(SGPT)”;
[6] = “AST(SGOT)”;
[7] = “Basophils”;
[8] = “BETA-GLOBULIN”;
[9] = “Bicarbonate”;
[10] = “Bilirubin (Direct)”;
[11] = “Bilirubin (Total)”;
[12] = “Blood Urea Nitrogen (BUN)”;
[13] = “C-Reactive Protein”;
[14] = “Calcium”;
[15] = “Chloride”;
[16] = “CK”;
[17] = “Creatinine”;
[18] = “Fibrinogen”;
[19] = “Free T4”;
[20] = “GAMMA-GLOBULIN”;
[21] = “Glucose”;
[22] = “Hematocrit”;
[23] = “Hemoglobin”;
[24] = “IMMUNOGLOBULIN A”;
[25] = “Lactate Dehydrogenase”;
[26] = “Lymphocytes”;
[27] = “Mean Corpuscular Hemoglobin”;
[28] = “Mean Corpuscular Hemoglobin Concentration”;
[29] = “Mean Corpuscular Volume”;
[30] = “Monocytes”;
[31] = “Partial Thromboplastin Time”;
[32] = “Phosphorus”;
[33] = “Platelets”;
[34] = “Potassium”;
[35] = “Protein”;
[36] = “Prothrombin Time (clotting)”;
[37] = “Red Blood Cells (RBC)”;
[38] = “Segmented Neutrophils”;
[39] = “Sodium”;
[40] = “Uric Acid”;
[41] = “Urine Appearance”;
[42] = “Urine Bacteria”;
[43] = “Urine Color”;
[44] = “Urine Mucus”;
[45] = “Urine Specific Gravity”;
[46] = “Urine Squamous Epithelial Cells”;
[47] = “Urine Uric Acid Crystals”;
[48] = “White Blood Cell (WBC)”; -
I think this lab is about Advanced Light Sources. Which looks very interesting but is about the electromagnetic spectrum. It is true that this includes advanced topics about biology such as imaging molecules in the cell’s membrane, but I doubt they are actively involved in solving the ALS disease.
The only pages related to “our” ALS, are about getting information on misfolded proteins with a technology called “small-angle x-ray scattering (SAXS)“. A very interesting topic, but these pages are years old.
If you have publications or simply scientists names I can look further in that topic.
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>> I am looking for more objective measurements.
So are scientists as well 🙂
There are many proposals for biomarkers for ALS, for example neurofilaments. The easiest to test by yourself is your body weight: Eat proteins and lipids!
A successful biomarker is something that is sensitive but highly specific: It must be able to detect small changes in the progression course, while not be sensible to markers that are common to several diseases.
If you have access to cheap labs tests, then you can ask for periodic tests indicating muscle waste and liver dysfonction: Creatine kinase, Gamma Glutamyl Transferase, Bilirubin…
The idea is that if ALS progresses there will be more muscle waste, which had to be recycled by liver and kidneys and they suffer from overload. So it shows in blood works.I am not a doctor, nor a scientist so ask to your doctor what makes sense for her/him.
I wrote a small Web page on ALS biomarkers with the common value (beware when it comes to medicine, nobody is average)
https://padiracinnovation.org/en/ALS/-
Sorry for the people who tried to access my Web site: The server was down for the last 24 hours, everything is OK now.
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Hi Galina,
I am not a doctor but what was prescribed by the doctor of your mum, seems to me quite sensible.
In France, my uncle who died nearly a year ago, had only Riluzole, vitamins and anxiolytics. His nephew who died 10 years ago was in a similar situation.
As people often say, some key points are important to survive:
* Plan ahead of the disease progression, get whatever will be needed in three months.
* Help breathing, there are several means depending on the severity of the case.
* Help feeding, pALS have difficulties to use their hands and often they do not swallow their saliva, so feeding is difficult, people can die simply because some food goes in the trachea. Again, there are several means depending on the severity of the case.
* Helping to communicate. There are phone applications that helps. The speech therapist of my uncle was stupid enough to ask him to practice until the end. What means practicing when it is hard to breathe air as lung’s muscles became very weak? There are some better means to communicate. My wife made a sheet with the common words (and situations like “I want to rest alone” or “I want to pee” and it was OK.
* Keep in mind that once someone is in wheelchair, everything is much more complicated. And it is very boring. My uncle read a book every two days on his kindle and watched TV, even if he had problems with his eyes. Some pALS had wrote books, others have invented stuff.
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The outcome of the Ice Bucket in terms of research is minuscule. Prize4Life which had a sensible approach, stopped funding research last year, they understood the problem is not that more money is needed, the problem is that ALS research is not focused, on contrary it is fragmented.
The last breakthrough in ALS was the finding of the C9orf72 gene. What has been done since which is not marginal? And it was found in 2011 so the IBC has nothing to do with its finding.
I am not a US citizen, but I think that a minimum of planning like what DARPA is doing, is necessary. If there was a principal project manager like those that the DARPA recruits, someone like Virginia Lee or Brian Kaspar then all the weird things that ALS scientists did and are still doing, would never have happened. ALSA could have done that, it did not.
Just a reminder of things that still stall the ALS research:
* Scientists spent many years (from 1993 to 2008) on ALS animal models based on SOD1, before switching to TDP-43. SOD1, not only is a gene when 95% of cases are sporadic, but it is a quite rare gene in ALS (2% of all cases). TDP-43 aggregations was shown, as early a 2009, to be a consequence of stressed cells [1], not a cause of ALS. So why are scientists spending decades making animal models after artificial diseases they invented, which we know are NOT ALS?
* Astonishingly scientists were and still are using mice to model ALS. There are around 50 ALS mice models today. But <i>the prefrontal cortex (PFC), is much less developed in rodents than in primates</i>. Rodents lack the direct cortico–motor neuron projections[2] that support fine control of forelimb movements. Many of the drugs used to treat CNS disorders exert their effects via neurotransmitter and neuromodulatory systems, and many of these systems differ between primates and rodents.
* Why are scientists spending times on old topics, after spending 15 years on the stupid concept that SOD1 was an explanaotry model for sporadic ALS (they are still wildly interested in SOD1, in 2018 they published 561 papers!), they are since 2006 obsessed by TDP-43 but less so, too modern perhaps, in 2018 they published 317 papers on it? On the more recent (2011) topic of C9orf72 they have only produced 210 papers in 2018! Why are people still funding SOD1 research?
Why don’t scientists move to engineered adult neurogenesis through glia-to-neuron conversion as a few scientists had already done? At their pace they will need centuries…
[1] Eran Perlson and Erika Holzbaur, 2009
[2] Lemon, R.N. Descending pathways in motor control. Annu. Rev. Neurosci. 195–218 (2008).
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I think that the problem stems from a weak definition of what ALS is. There is no strict medical definition of ALS, there are many mimics and probably 10% of ALS cases are misdiagnosed. There are no known pathogen agent, no biomarkers (lab works), so the diagnostic is differential, which means that when doctors have proven it is not another well known disease, and if it is obviously a motor neuron disease, then it is labeled “ALS”.
ALSFRS and the other scales are just the reflection of the fact that it is a motor neuron disease and they are very practical, easy to understand and compare from patient to patient.
However the scoring method which aggregates its components has been criticized, for example if the patient’s symptoms did not changed but if she/he received a treatment for excessive salivation, then the overall score increases. -
It’s a great post Bill!
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Thanks Dagmar,
But do not expect too much from me I am not a doctor or a scientist, only a retired R&D engineer with a strong interest in biology. I will try to do my best to answer those questions. Another caveat: ALS diagnostic is achieved through an exclusion process, and if your neurologist is in hurry, the diagnostic might not be so accurate. My advice to people having a familial form is to take a genetic test for the 10 most common “ALS genes”.
> How this will impact ALS patients?
It will impact only the fraction (8% of all cases) of patients that have a familiar form of ALS. The familial form is said to represent 10% of all cases. In the familiar form (as far I understand it) there are two main sub families:
- SOD1. The first discovered gene that is implicated in familiar ALS. This accounts for roughly 2% of all ALS cases. pALS with SOD1 have lowered resistance to the oxidative stress (which is a part of metabolism). This study is not about SOD1.
- C9orf72. The study is about the 8% of all pALS, that have a mutation in this gene. A gene produces one or several proteins, it’s a quite convoluted process. When there is a mutation in a gene, proteins are altered and diseases happen. In C9orf72 ALS mutations proteins are produced which are toxic for the neuron. Just for the reference they are called dipeptide repeat proteins (DPRs). Poly(GR) is an instance of DPR which is particularly damaging specially to vesicles in cells that are called mitochondria and that are essential to the cell metabolism. The scientists show that reducing the amount of Poly(GR) (also written Poly-GR). A doctor, Ludo Van Den Bosch, said: “It strongly indicates that therapeutic strategies lowering the expression of toxic dipeptide-repeat proteins can reverse disease phenotypes, even after disease onset”. Reversing disease phenotype means that cells that were slowly dying from the toxic proteins have recovered.
- For the pALS that do not have a familial form (90% or more) the cause of ALS is quite clear since a couple of year, it is misfolded proteins. So they are not interested in this study. Misfolded proteins result of a different mechanism than in SOD1 or C9orf72 cases.
– SOD1 mechanism is a reduced expression of a gene.
– C9orf72 is a gene that produces toxic proteins.
– non familial ALS is about mismanagement of proteins after they are produced by the cell’s nucleus. Normally proteins are processed in a complex organ in cell that is named ER, which role is to fold the long filament that was produced by the gene (and RNA and ribosome). Folding a protein is very important because it confers additional functions to the protein. In non familial forms of ALS, misfolded proteins such as TDP-43 or FUS are not processed and aggregate in granules in the cell cytoplasm, which in turn slowly disrupt the cell, and indeed the proteins are missing elsewhere, for example TDP-43 is useful against some viruses.
> Will this open the door to a new understanding of cause?
For C9orf72 related ALS, the cause is clear at least since 2013: Toxic DPRs are produced by the mutated genes.
What is new knowledge is that cells can recover. Indeed when a pALS is diagnosed she/he had lost a significant number of cells that will not recover. But that is an area for treatments like Nurown and its successors.
> How long will it take to go from discovery to actual human trials and a successful treatment?
That is more a question about politics and business that science. And it will need at least 10 years before this research translates in drugs on the market.
When an university scientist finds something that have a business potential they patent it. Healthcare is one of the largest market in many countries, so I am quite sure they will patent their findings.
Then someone has to take an interest to develop the research, sometimes it is the scientist that found something but usually it is not. Often their management do not agree to develop the treatment because in academy is interested only by academic matters and clinical trials are a costly, uncertain and complex project which needs much more resources that any university lab can mobilize. Discovering is the easy part of the job, creating a safe drug and making doctors prescribe it is much more difficult.
So a biotech pays the patent, sizes the research and invents a safe drug (a hard task), and tries to do a clinical trial. To do so it had to convince investors which is a bit tricky, investors will fund the research only if there is business potential. Then it has to convince authorities that it is serious enough, that they won’t kill patients.
If after 5 years the biotech succeed in the three phases of clinical trials, often their research is bought by a major company such as Novartis, the investors get their money and more, and the major firm has the not so obvious task to “educate” medical doctors about the new treatment, before they accept to prescribe it. Sometimes they need several years to do so. Medical doctors are extremely conservative, they do not want to take risks with a new drug. So major companies have to write articles in professionals journals, make presentations at conferences, organize workshops, discuss with doctors and patients organizations. It costs them billions Dollars. -
The case for “ALS reversals” made in 2015 by dr Bedlack and his team and specially about Curcumin is a bit strange.
* They report that there were nine cases who regained normal strength. One pALS without an ALSFRS-R score came off a ventilator after 17 years of dependency and another began walking after a year of quadriplegia! They are the only scientists to claim that one can heal from ALS.
* They mixed confirmed ALS cases with non confirmed case as well with patients with PMA, why?
* They are supposed to have found ALS reversal in literature then confirmed “reversals” by EMG. How can they confirm anything if there was no EMG done in non confirmed cases?
* They include one case who, at nadir, was unable to stand and after her improvement was able to walk several miles but did not have a formally documented strength exam. So why including it in the study?
* They wrote (and it is their main point) that odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were higher for their cases than for controls. As the control is the PRO-ACT database, and there are NO MENTION OF ANY OF THOSE PRODUCTS IN THE PRO-ACT database, they could not reach any conclusion.
No one has shown a true case of ALS reversal up to now (May 2019). You can see here that, as of today 4 years later after the first article about “ALS reversals”, that dr Bedlack does not claim that Curcumin “cure” ALS.
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Hi Marlon,
Just nitpicking if you pardon me:
You tell that Vanessa has SOD1 thr114lr
On the RCH-4 web site, Vanessa tells she has SOD1 Lie114tr
If I do not make any mistake, there is no amino acid named tr, there is however trp (tryptophan), there is as well no amino acid named Lie, but there are Ile (Isoleucine) and Leu (Leucine).
However I would bet that Vanessa has SOD1, isoform P00441 and point mutation Ile114Thr, which means that on the SOD1 gene, in the P00441 isoform, the Isoleucine at position 144 has been replaced by Threonine.
More information here and here.
(edit: I just saw that the correct value is on the chart on your other post)