Interesting article on age and DMDs

[MermaidOP]

Aging with MS considerations

Yesterday was my 72nd birthday, so of course I needed to read this interesting thread. I have had MS for almost 50 years. Thank you all for posting.

Recently, I have been reading that as MS patients age with MS over decades, brain atrophy is frequently more of a factor in progressing disability than is inflammation. DMT's address inflammation and are evaluated for that. With brain atrophy (due to MS and even from aging itself) becoming more of a factor for us older MSers, I can see that DMTs could start to seem irrelevant. But the multiplicity of factors I know affect my own journey with MS make me question whether "seeming" is believing.

My thinking is that each of us knows our own life best. If you take DMTs and they appear to be helping, why change? If you are burned out on taking them and your neuro agrees that they aren't having much effect, why not set yourself free?

Another note, there is a recent study that suggests the drug ibudilast can slow brain atrophy in progressive MS. I read about the study in "Healthline." The Cleveland Clinic study was funded in part by the National MS Society and the National Institute of Neurological Disorders and Stroke for the NeuroNEXT Clinical Coordinating Center, part of the National Institutes of Health. Ibudilast is approved for use for asthma.

I admire how expert many of you seem to be in examining research and trials. Maybe you will want to look into this.

Again, thank you for the thread.
Mermaid Susan

[Mable]

Yesterday was my 72nd birthday

Happy birthday! I’m encouraged by the ibudilast results. It sounds like it did more than “slightly better” results too. I wonder how long it will take to find the money and time to get it through the next phase of research.

[Myoak]

Yesterday was my 72nd birthday, so of course I needed to read this interesting thread. I have had MS for almost 50 years. Thank you all for posting.

Recently, I have been reading that as MS patients age with MS over decades, brain atrophy is frequently more of a factor in progressing disability than is inflammation. DMT's address inflammation and are evaluated for that. With brain atrophy (due to MS and even from aging itself) becoming more of a factor for us older MSers, I can see that DMTs could start to seem irrelevant. But the multiplicity of factors I know affect my own journey with MS make me question whether "seeming" is believing.

My thinking is that each of us knows our own life best. If you take DMTs and they appear to be helping, why change? If you are burned out on taking them and your neuro agrees that they aren't having much effect, why not set yourself free?

Another note, there is a recent study that suggests the drug ibudilast can slow brain atrophy in progressive MS.

Enchanting Susan, remarkable lady, happy birthday and thank you so much for highlighting ibudilast for us!

In the ibudilast Phase 2 trial the annual atrophy rate was reduced by 48%. Rates of atrophy were (-.0010) or 0.1% for ibudilast and (-.0019) or about 0.2% for placebo. Those annual atrophy rates fall well below the estimated (-.0034) 0.34% annual rate of atrophy for a healthy person over age 35.

So that will require explanation. Did they measure atrophy in a different way? How strikingly unusual that the 255 SPMSers and PPMSers in this Phase 2 trial had atrophy rates well under healthy people. Placebo effect, perhaps, in those not on ibudilast?

But, let’s concentrate on the good news… ibudilast slowed atrophy significantly… and it seems possible that a treatment may become available for progressive MSers if the same holds true in a Phase 3 trial.

https://www.mdmag.com/medical-news/i...-phase-2-trial

If you are PPMS or SPMS and might consider participation in a Phase 3 trial of ibudilast then please check out the criteria as set forth in the Phase 2 trial in the link below. The Phase 2 is completed, however, you can get a good idea of trial locations and criteria in the Phase 2 info.

So, if anyone is interested you could contact the center nearest you listed in the link. In time, if/when the Phase 3 is organized the center will likely direct you to a recruiter. Be patient; it could take a good deal of time. But finding enough participants can be challenging in any trial, IMO, so these centers offer the best opportunity to be informed of a future trial, believing one will occur.

https://clinicaltrials.gov/ct2/show/...ow_locs=Y#locn

[Badaimata]

Myoak, thank you for the in depth analysis of the DMT vs age study, I certainly appreciate the time you must have spent. I suppose the purpose of studies like this one is to stimulate more specific studies along the same lines but I find it unfortunate that headline grabbing titles and incomplete or misinterpreted conclusions cause so much confusion and disinformation. As one approaching 70 years myself, I will be paying close attention to future studies although I'm afraid there is a long way yet to go. Thanks again, your efforts are truly appreciated.

[Myoak]

Myoak, thank you for the in depth analysis of the DMT vs age study, I certainly appreciate the time you must have spent. I suppose the purpose of studies like this one is to stimulate more specific studies along the same lines but I find it unfortunate that headline grabbing titles and incomplete or misinterpreted conclusions cause so much confusion and disinformation. As one approaching 70 years myself, I will be paying close attention to future studies although I'm afraid there is a long way yet to go. Thanks again, your efforts are truly appreciated.

You are welcome.

I believe it is a good sign that the FDA gave the green light to a Phase 3 trial of ibudilast in ALS. To me, it proves that MediciNova believes they can monetize the drug, which is a good sign for development. Therefore, a Phase 3 in MS is likely, IMO. They would not have funded the Phase 2 in MS if a Phase 3 was unlikely, IMO.

However, you are correct that there is a long way to go. But in the meantime, what can we do? Clearly, there are beneficial things we can do which have little to no downside.

A decent diet, exercise, lowering stress, and maintaining a positive attitude are w/o argument good for everyone. I would include 3 more things for PwMS with very little downside potential and a good deal of upside... LDN, alpha lipoic acid, and EGCG found in green tea.

As you indicate, it may involve a lengthy process getting ibudilast approved for MS. Even if it gets approved ibudilast is not nearly as free of unwanted side effects as the 7 things mentioned above.

The really mystifying one in that group of 7 is LDN. I cannot for the life of me understand why a PwMS does not try LDN. It isn't like exercise which requires effort and dedication. 3mg of naltrexone amounts to less than a dash of salt. All you have to do is swallow.

The FDA approved Dr. Jill Smith giving LDN to children for heaven's sake. I have sat and spoken with her. LDN cannot harm you. There is not a single serious adverse event regarding LDN I can find in medical literature. Compare that to MS DMTs or aspirin.

Turel at Penn State showed LDN was compatible with present MS DMTs in his study of 215 PwMS using LDN.

The reason a person with MS normally takes LDN outside the purview of their doctors is owing to the fact that LDN has yet to be monetized. It may never be available through a neurologist although they could prescribe it, virtually all decline.

There may NEVER be large trials and doctors will continue refusing to prescribe it, even if they may be aware it is harmless because the scientific evidence of benefit is lacking and always will be lacking until and unless LDN can be monetized and larger trials funded to validate effectiveness.

If you want to try LDN, you must do it on your own, or seek out an alternative medicine doctor. Most GPs and most neuros can express an opinion on LDN, however, they cannot express an opinion based on knowledge of, or experience with LDN. For opinions based on knowledge and experience you must find doctors who prescribe it and people who use it. Compared to those, the average doctor knows little about LDN. Question... Is it wise to rely on an uninformed opinion, or an informed one?

Sorry for the rant but as stated... I cannot for the life of me understand a PwMS not trying something harmless which might benefit them substantially. Such things are too rare to ignore when they come along. Life rewards the courageous!

To get back on thread's focus... alpha lipoic acid appears to help a great deal in the reduction of brain atrophy, a predictor of disability in MS.

[Jules A]

I thought this was a decent article. Sample size was more than sufficient >28,000 patients and it was based on the inclusion of 38 reputable studies with established benchmarks for measuring disability. Although different criteria of disability progression would be valuable if it isn’t established or utilized in other studies that should not be considered a flaw in this paper. The authors fairly described the limitations of this study and areas for further exploration. Overall a decent study for thoughtful consideration and an area to consider going forward in my opinion.

It seems my previous thoughts regarding the inflammatory component was a bit more complicated, naturally, and the different type of inflammation is possibly might be responsible for the lack of efficacy in advanced age MS and PPMS:
“Compartmentalization of inflammation can be defined as the establishment of a permissive environment for long-term survival and in situ activation of the non-resident immune cells, mediated by the formation of tertiary lymphoid follicles in the CNS tissue (5–7). Compartmentalization is a continuous process that starts at MS onset and evolves over time, which means that it is predominantly (but not exclusively) seen in older subjects with progressive MS (2, 5–7). Compartmentalized inflammation is inaccessible to orally or intravenously administered MS drugs with poor CNS penetrance (8, 9).”

“Alternatively, the immunomodulatory DMTs have relatively low-efficacy in progressive MS because inflammation, although present, may not be the most important driver of disability progression. Indeed, neurodegenerative mechanisms such as mitochondrial dysfunction (11), oxidative damage (12), hypoxia (13–15), endoplasmic-reticulum stress (16), and astroglial toxicity (17) have been identified predominantly (but not exclusively) in progressive MS. Even as it remains unknown which of these (if any) contribute to disability progression, it is rational to assume that these too are continuous, rather than dichotomized processes.”

Take homes for me include considering “This meta-analysis of randomized, blinded clinical trials of MS DMTs against placebo or active comparator demonstrated unequivocally that the efficacy of immunomodulatory DMTs decreases with age.” Which makes sense because most everything loses efficacy as we age and there are likely some medications that will be shown to be of more value. The authors clearly mention the “average” ms patient, if there is such a thing lol, and in my opinion this is in no way, at this point in time, means we shouldn’t be on medications simply based on age if we feel risk vs benefits indicate rather that thoughtful consideration and discussion is warranted.

Something for us all to remember: there is absolutely NO medication or supplement that can be considered 100% safe or free from consideration of possible side effects. My best recommendation, vet your source of information and discuss options with your trusted physician, you are paying for their formal knowledge and insight.

[KoKo]

Thanks, Jules, for this very engaging thread.

It definitely helps me to exercise my cognitive muscles.

Take Care

[MermaidOP]

Thank you

Thank you Myoack and Jules for your thoughtful research. (Some of which I actually understand LOL.)
Keep up the good work.
Stay lifted,
Mermaid Susan

[Badaimata]

Well thought out analysys, thank you Jules. It seems we all agree, including the conclusion of the study in question as I recall, that considerably more research on age and the efficacy of DMT's is needed. I stand by my original conclusion, "I wouldn't give up (your current DMT nor the search for a DMT) based on this particular study."

Interestingly, as I look back on the scores of studies I attempted to volunteer for while I was considered Relapsing Remitting, I was excluded from about 90% of them based on age! Seemed like I was perennially one year older than the study limits allowed for. Now that I am SP, I probably would NOT volunteer for any study in which there was a risk of not having access to an effective DMT. The reason of course is that I no longer recover from the progression to anywhere near the extent I did when I was considered RR - hence the distinction between RRMS and SPMS.

Although I whole heartedly agree that the emphasis of MS study should be on the young and newly diagnosed to preserve neural function and delay the onset of SP, as an ageing MSer, I am in no way ready to relegate my relatively active lifestyle to the progression of this disease, and in fact I find that I am increasingly more willing to incur additional risk in order to keep as much neural function as possible.

Thank you all,

[Jules A]

Although I whole heartedly agree that the emphasis of MS study should be on the young and newly diagnosed to preserve neural function and delay the onset of SP, as an ageing MSer, I am in no way ready to relegate my relatively active lifestyle to the progression of this disease, and in fact I find that I am increasingly more willing to incur additional risk in order to keep as much neural function as possible.

Well said!

I also appreciate the input and opinions. It seems like there are plenty of us old birds here, lol.

[Myoak]

I agree with the conclusion of the meta-analysis that more study is needed relative to age and efficacy. Especially, over age 55 because there is no data in the meta-analysis involving that age group.

There are severe limitations in the meta-analysis, as pointed out. Those limitations belong under a heading of "more study needed relative to age and efficacy". As stated, there is nothing in the meta-analysis regarding diminishing effectiveness in hand and arm function; nothing regarding diminishing bulbar function (swallowing, speaking) either.

So, we have no idea if these critically important values diminish at the same rate as walking ability (EDSS) or if upper limb and bulbar function diminish more slowly, doesn't diminsh at all, or perhaps may even improve on some of the DMTs as we age. Since the study does not address those values we have no data on which to make a judgement regarding them.

Tysabri preserved upper limb function in one progressive MS study so we know that preservation happens with at least one DMT. Unfortunately, the meta-analysis may lead one to assume, incorrectly, that upper limb function must deteriorate because lower limb function does. As we age DMTs may or may not preserve upper limb function and bulbar function but we don't know because the meta-analysis presents no data regarding those values.

We do pay our trusted doctors for their formal knowledge and insight, however, we do not hire them for their uninformed opinion. It is no more than counter-productive BS when physicians express a professional opinion not based on knowledge, insight, or experience.

Ask your doctor if he/she studied LDN in medical school (formal knowledge). A simple yes or no. If no, then they have no knowledge or expertise supporting their opinion. If yes, then find out if they are BSing you... ask them to recall LDN studies and explain how those results shaped their opinion. Remember, we are not paying them for BS so go to the LDN thread and read the studies which are available and become familiar the conclusions presented. That way, you can accurately assess whether your doctor can relate what is in those studies or if his opinion lacks knowledge about the subject, LDN.

As far as the generalization of no medicine or supplement being 100% free of possible side effects... Agreed! Drinking too much water can kill you. It is called hyponatremia. A 150 lb person drinking 6 liters of water at once has a 50% chance of dying from it.

If 100% free of possible side effects is going to be our standard then everything used in the treatment of MS fails spectacularly. My point about safety regarding LDN is that there is not a single serious adverse event recorded in medical literature so the reluctance for an adult with MS to try it is not based on safety but rather a lack of either knowledge, courage, or capability, IMO.

Dr. Jill Smith, with FDA approval, used LDN safely in a trial of children with Crohn's Disease and Dr. McCandless used LDN safely in autistic children for many years. Safety is not an issue with LDN.

As we have seen, drinking water is not 100% free of possible side effects. Yes, we do need to follow sensible guidelines even with the safest substances.

It is understood there are early adopters and late adopters within both patient and physician populations. It is understood you can lead a horse (or a person) to water but if they need 100% assurance of no possible side effects... well, be sure to mention hyponatremia.

If someone chooses not to drink water that is perfectly acceptable, but let's make sure unfounded personal fears are not dissuading others desperately needing water.

Fatigue is one of the biggest challenges PwMS face, as everyone knows.

In terms of fatigue, 60% reported some improvement with LDN... a drink of water they really wanted and really needed, using those terms.

Turel's 7-year study at Penn State disclosed that 60% of 215 MSers using LDN reported an improvement in fatigue. 40% didn't, of course, but the majority did.

Let's be mindful of others seeking much needed relief and purpose not to hinder them with vague generalizations but rather commit to providing specific knowledge which may help them secure a better life.

Be courageous and try LDN. LDN's safety is not an issue which depends on your doctor knowing you tried it. Yes, LDN is really that safe. Those who disagree are just plain wrong about it.

I know because I have researched LDN for hundreds and hundreds of hours. I have attended LDN conferences, and traveled the country to speak face to face with physicians using it in clinical practice and researchers using LDN in human trials. I have conversed face to face with international LDN advocates like Linda Elsegood, someone you can google as you should the several doctors I have mentioned, also. I place a great emphasis on meeting people face to face because it is the best way to discover whether they have integrity or are phony manipulators.

I don't have MS. The reason I dedicate so many hours to finding real help for MSers is because I would want someone doing that for me if I didn't have the energy or wherewithal to pursue answers with the vigor required for meaningful assistance. I'm not fishing for pats on the back; so please let's not go there. I enjoy learning. I enjoy unraveling mysteries and MS is certainly an intriguing one.

LDN is not a miracle substance but it is beneficial to many. I know that on so many levels, including my personal use of LDN for several years after careful research convinced me of its benefits.

Great thread and very helpful, IMO.

[Myoak]

It may be worthwhile to go a little further in pointing out how trials and data collection can become more useful, more usable, to PwMS. There are better methods of measuring disability than EDSS. Had the trials in the meta-analysis used GNDS (explained below) we would know a great deal more about the effectiveness of DMTs as we age. I found this post on a MS research site helpful in that regard...

PREDICTING PROGRESSION

https://multiple-sclerosis-research....g-progression/

Detecting clinically-relevant changes in progressive multiple sclerosis

https://www.ncbi.nlm.nih.gov/pubmed/25013153

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS).

METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy’s Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS.

RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW.

CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS. END.

Comment from the blog...“The Guy’s Neurological Disability Scale (GNDS) was devised as a simple and user-friendly clinical disability scale capable of embracing the whole range of disabilities which could be encountered in the course of multiple sclerosis. It has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and ‘others’...

"In the CUPID (MS) trial of THC the group did not progress as predicted…maybe the placebo effect of being in a progressive trial and whilst the whole group did not shown any difference in progression and the trial is considered a failure.

However in MSers with an EDSS less than 5.5 there was a significant neuroprotective effect.

So if the trial had been loaded with this subset of MSers it may have been a positive trial and you would have the first drug for progressive MS."