August Q & A

A

Happy Yorkshire Day (1 August)

If you have a comment unrelated to a post. This is the place for You.

About the author

MouseDoctor

80 comments

Leave a Reply to Sarah Cancel reply

  • Regarding targeting plasma cells. In the SIZOMUS trial you have a doseing intervall of weekly dosing for the duration of the trial. Why wasnt it possible to have a doseing schedual like with mavenclad? Couldnt clearing the plasma cells work with a induction like approach.

  • Is the hypothesis that microglia become “hot” due to activation by inflammatory cytokines and continue tissue damage within the brain in the absence of other more obvious inflammation?

    If so, would a reset of the microglia population help to stop this inflammation via CSF-1R targeted depletion? There are compounds which are already in testing for various cancers including PLX3397/Plexxikon, along with more specific inhibitors like PLX5622 or BLZ945.

    Could a post explain the thinking behind the hesitancy for using this as an add on to the current immunotherapies?

    Han, et al from 2019 GLIA https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.23529

    • The problem is you need macrophages for.life, insects don’t have lymphocytes they do have macrophages. Therefore expect side effects

      • You are thinking about it as a permanent deletion while a reset is what I am thinking of. Microglia turn over slowly (28% per year, with some lasting over 10 years according to cell; 2% at any one time are Ki67+). If you reset them or stimulate a few cycles of turnover are you flushing the hot cells out? That paper even goes over repopulating with fresh microglia.

        Also you have safety data from cancer studies where they have tested continuous dosing of 1000(!) mg/day of PLX3397 for many days in patients pre and post surgery which resulted in minor side effects ranging from fatigue to hair coloration to elevated ALT and AST levels. They didn’t see much effect of the PLX3397 as a group, only paired tests showed some reduction in IBA1 microglia. PLX5622 also targets CSFR1 within macrophages and is being tested for RA in Phase I trials to reduce inflammation.

        Don’t be so dogmatic or dismissive about additional possible ways to inhibit the cells most likely chewing everything up, especially with drugs that penetrate the brain and are already in clinical trials with favorable safety data.

  • When will we stop treating with mono therapy? For example for those on Ocrelizumab to prevent new relapses, when will we also be able to add on something else to repair or also treat the underlying “smouldering” disease? How or when will this be studied?

    • We’ve been banging on about this for at least a decade. However once you try to do trials with more than one therapy (and probably from different companies) it gets complicated very quickly. Very, very, frustrating but Prof G is trying to move the boulder.

  • *****If nobody knows what causes MS, how are they ever going to cure it?

    *****If it takes years if not decades for trials/new stuff to even begin to get put through (as per Gavin Giovanonni’s posts), how many more generations are going to be given the reality that there isn’t really any hope?

    This MS for me feels like it’s only one step away from Motor Neurone (ALS) of which my grandma died of 24 years ago when I was 22
    Motor Neurone = just about guaranteed life sentence
    MS = a prolonged life sentence with a morale-crushing reality that you have no idea how bad it’s going to get.
    Or is that just me thinking negatively?

      • What about the extra £350 million that Brexit will free up for the NHS? Surely, Boris and co. weren’t making stuff up???

        At least your Cricket team has come good 😁

        • We are now looking at a situation that nobody was proposing during the campaign and which will be disastrous for the UK. 🙁
          As for the cricket team, it was looking good at 120 odd for eight……………..

          • So, a hard Brexit equals no free trade agreements equals a possible increase in DMT costs? At least until new trade agreements are secured??

            Brexit, Boris, and Trump continue to dominate the news ‘Down Under’. We’ve all but given up on the idiots that run our country.

          • “You must think we have undergone a bout of mass insanity”…..

            The global rise of popularist politics is somewhat worrying. The problem with these movements is they propose simple solutions to complex problems. From what I understand, the Brexit movement, initially at least, was very much a popularist movement based on anti-immigration sentiment. Unfortunately, the UK is now on uncharted waters with Beaker from the Muppets at the wheel.

            Mind you, it could be worse. You could live in a politically apathetic country like Australia where Nick Kyrgios is big news.

  • MS and delaying menopause – I wondered if news this weekend that scientists have come with a new procedure to delay the menopause by 20 years – could be used to help women with MS? From what I understand, there could be a link between women with MS getting the disease worse after menopause (possibly due to falling oestrogen levels). Could this be a chance to delay this – if they can delay menopause?

    • Richard Anderson, the deputy director of the Centre for Reproductive Health at Edinburgh University, has performed ovarian tissue freezing for young girls and women for 25 years. He said it was “old news” that the transplants could restore hormone levels, but added: “What is less clear is whether this is a safe and effective way of doing so.”

  • If permitted, please can I ask your readers if they can recommend an affordable and lightweight, foldable electric wheelchair (to transport easily in boot of car) for use outdoors and capable of handling grass, gravel and hills etc? Thankyou.

    • Yes excellent. History being re written, is this the death of the Treg. I have a name for the post life on Mars.

  • Hello
    I follow your great blog since 2016 (37 Lesions, 1 Relapse, 56 years, EDSS < 1) am on Tecfidera. Last scan (2017) showed no additional Lesions. But still wondering because of smouldering progression. You mentioned that in Prague (https://multiple-sclerosis-research.org/2014/09/clinicspeak-ms-phenotypes-by-mri/) MRI does measuring BVL, Atrohpy etc. Do you have a list of possible centers. Is there an alternative like: PLACE/COMPANY WEBSITE REMOVED. Think to switch to counteract possible progression.
    Thank you for your answer
    Juan

  • Given ECTRIMS 2019 is just around the corner. Any exciting piece of research news or trial results to look forward too? Or the same old stagnant plug pharma old drugs with new purpose stuff?

  • ‘Mice without the protein calnexin were resistant to MS’.
    2018 study shows.
    People with MS have higher amounts of calnexin.
    What are your thoughts on this MD? Thanks

  • From animal models to mechanisms that control multiple sclerosis
    David Baker
    (Queen Mary University of London, London –UK)

    Great …What are the mechanisms?

  • This is GOLD 🙂

    “Previously published results from our own laboratory have shown that inflammatory Tcells
    can stimulate oligodendrogenesis in adult mice”

    T02-020A
    Proteomic profiling shows changes in proteins involved in oligodendrocyte differentiation in
    ceruloplasmin knockout mice
    B. Villadsen1,2, C. Thygesen1,2,3, M. Grebing1,2, S.J. Kempf3, H.H. Nielsen2,4, M. Thomassen4, T.A. Kruse4, M.R.
    Larsen5, B. Finsen1,2
    1Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense C, DK
    2Department of Clinical Research/ BRIDGE – Brain Research – Inter-Disciplinary Guided Excellence, University
    of Southern Denmark, Odense C, DK
    3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, DK
    4Department of Neurology, Odense University Hospital, Odense C, DK
    5Department of Clinical Genetics, Odense University Hospital, Odense C, DK

    Glia 2019

  • I read that pwMS might have weak knee joints and weak thigh muscles due to MS causing balance issues.

    I wonder if some deterioration of physical movement in MS, in some cases might be due to osteoarthritis and not the MS?

    Osteoarthritis is common in the general population and a family member has become quite disabled with it, quite quickly, they don’t have MS.

    There’s no blood test for osteoarthritis apparently, diagnosis is through xrays. And of course there is possibility of having MS and osteoarthritis together.

  • Fasting Fasting Fasting

    When some neuro doc tell you that dietary intervention are not good for your disease shown him or her this study

    Of course your neuro could have some pharma conflict and he/she may rather give a drug

    Mount Sinai Researchers Discover That Fasting Reduces Inflammation and Improves Chronic Inflammatory Diseases

    Fasting regimens have gained public and scientific interest in recent years, but fasting shouldn’t be dismissed as a fad. In a study published in Cell, Mount Sinai researchers found that fasting reduces inflammation and improves chronic inflammatory diseases without affecting the immune system’s response to acute infections

    “Caloric restriction is known to improve inflammatory and autoimmune diseases, but the mechanisms by which reduced caloric intake controls inflammation have been poorly understood,” said senior author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai.

    Working with human and mouse immune cells, Dr. Merad and colleagues showed that intermittent fasting reduced the release of pro-inflammatory cells called “monocytes” in blood circulation. Further investigations revealed that during periods of fasting, these cells go into “sleep mode” and are less inflammatory than monocytes found in those who were fed.

    “Monocytes are highly inflammatory immune cells that can cause serious tissue damage, and the population has seen an increasing amount in their blood circulation as a result of eating habits that humans have acquired in recent centuries,” said Dr. Merad”

    https://www.mountsinai.org/about/newsroom/2019/mount-sinai-researchers-discover-that-fasting-reduces-inflammation-and-improves-chronic-inflammatory-diseases

    Highlights


    Fasting reduces the numbers of circulating monocytes in healthy humans and mice

    Fasting also reduces monocyte metabolic and inflammatory activity

    Hepatic energy-sensing regulates homeostatic monocyte numbers via CCL2 production

    Fasting improves inflammatory diseases without compromising antimicrobial immunity

    https://www.cell.com/cell/fulltext/S0092-8674(19)30850-5

    Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5′-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.

    • yes this will be a hot topic the issue of fasting and oligodenroctye maturaration has been doing the rounds and how this manipulated pharmacologically

      • Boa 🙂

        You know i would be digging

        Autophagy Promotes Oligodendrocyte Survival and Function following Dysmyelination in a Long-Lived Myelin Mutant

        The Long–Evans shaker (les) rat has a mutation in myelin basic protein that results in severe CNS dysmyelination and subsequent demyelination during development. During this time, les oligodendrocytes accumulate cytoplasmic vesicles, including lysosomes and membrane-bound organelles. However, the mechanism and functional relevance behind these oligodendrocyte abnormalities in les have not been investigated. Using high-magnification electron microscopy, we identified the accumulations in les oligodendrocytes as early and late autophagosomes. Additionally, immunohistochemistry and Western blots showed an increase in autophagy markers in les. However, autophagy did not precede the death of les oligodendrocytes. Instead, upregulating autophagy promoted membrane extensions in les oligodendrocytes in vitro. Furthermore, upregulating autophagy in les rats via intermittent fasting increased the proportion of myelinated axons as well as myelin sheath thickness in les and control rats. Overall, this study provides insight into the abnormalities described in les as well as identifying a novel mechanism that promotes the survival and function of oligodendrocytes

        • So what is the best fasting method
          – Fasting a week twice a year
          – Fasting for 52 ours a week
          – Fasting for 14 hours a day
          and then how to keep your weight.

        • Here, we have shown that intermittent fasting can upregulate autophagy in oligodendrocytes and increase myelination in les as well as control CNS. Interestingly, disruptions in oligodendrocyte protein homeostasis have been described in several CNS myelin disorders, including vanishing white matter disease (van der Voorn et al., 2005; van Kollenburg et al., 2006), multiple sclerosis (Getts et al., 2008), and Pelizeaus-Merzbacher disease (Dhaunchak and Nave, 2007). Moreover, autophagy can be easily enhanced through diet or pharmacologically with drugs, such as rapamycin (Menzies and Rubinsztein, 2010). Therefore, further investigation of this pathway may lead to novel therapies that aid in the survival and function of myelinating cells in certain myelin diseases.

  • Fasting Improves Chronic Inflammatory Diseases
    Without Compromising Monocyte Emergency
    Mobilization During Acute Inflammation
    Dietary interventions such as hypocaloric diets and fasting regimens
    improve chronic inflammatory and autoimmune disorders
    including multiple sclerosis and rheumatoid arthritis (Choi et al.,
    2017; Piccio et al., 2008). Intriguingly, gene modules associatedwith ‘‘inflammation of joint’’ and ‘‘rheumatoid arthritis’’ were
    reduced in monocytes isolated from fasting mice (Figures S6A
    and S6B). Further analysis revealed strong gene regulation
    related to pro-inflammatory activity in monocytes upon fasting
    (Figure S6C). These results prompted us to examine whether
    fasting-induced changes in monocyte molecular program could
    improve chronic inflammatory disease outcome.
    We focused our analysis on mice induced to develop experimental
    autoimmune encephalomyelitis (EAE), the main preclinical
    model for multiple sclerosis. EAE progression strongly
    depends on the recruitment of monocytes to the central nervous
    system (Ajami et al., 2011; King et al., 2009). Ccr2-deficient mice,
    in which monocytes are unable to exit the BM (Serbina and
    Pamer, 2006), were resistant to disease induction (Figure S6D),
    as was previously shown (Mildner et al., 2009). Similarly, mice
    that were subjected to intermittent fasting had reduced pro-inflammatory
    monocyte numbers in the blood during disease
    development, while neutrophil and T cell numbers were unaffected
    (Figures S6E, S6F and S6G). Intriguingly, we observed
    that intermittent fasting led to a strong reduction of monocyte
    accumulation in the spinal cord of mice with EAE (Figure 6A),
    accompanied with a significant improvement of EAE clinical
    course (Figure 6B), as previously shown (Cignarella et al.,
    2018). We also profiled infiltrating monocytes from the spinalcord of mice that were fed ad libitum or subjected to intermittent
    fasting during EAE (Figures 6C and 6D). Strikingly, purified spinal
    cord-infiltrating monocytes from fasted mice most significantly
    downregulated pro-inflammatory genes such as TNFa, IL-1b,
    CXCL2 and CXCL10, and gene modules associated with monocyte
    pro-inflammatory activity, inflammation and inflammatory
    disease compared to monocytes from fed mice (Figures 6D
    and 6E and S6H). These data suggest that intermittent fasting
    leads to reduced myeloid cell accumulation in lesional sites as
    well as reduced monocyte inflammatory activity and is associated
    with improved disease outcome in EAE

  • We
    found that fasting not only reduced the size of the circulating
    monocyte pool but also modified metabolic activity and gene
    expression patterns predicting improvement of chronic inflammatory
    and autoimmune disorders, such as rheumatoid arthritis
    and multiple sclerosis, diseases that were shown to be responsive
    to fasting in clinical trials (Choi et al., 2017; Darlington
    et al., 1986; Kjeldsen-Kragh et al., 1991; Sko¨ ldstam et al.,
    1979). Accordingly, caloric restriction and intermittent fasting
    strongly reduced the accumulation of pathogenic monocytes in
    the central nervous system, reduced monocyte pro-inflammatory
    activity, and ameliorated disease outcome in a preclinical model
    of multiple sclerosis (Cignarella et al., 2018; Piccio et al., 2008).

  • Could this be applied to ms? (see the video)

    High-intensity step training boosts stroke survivors’ walking skills

    “Rehabilitation that allows walking practice without challenging the nervous system doesn’t do enough to make a statistical or clinically significant difference in a patient’s recovery after a stroke,” Hornby said. “We found that when stroke patients are pushed harder, they see greater changes in less time, which translates into more efficient rehabilitation services and improved mobility.”

    https://medicalxpress.com/news/2019-08-high-intensity-boosts-survivors-skills.html

  • Hi there

    A (not-so) hypothetical question. If you are a person who is just 50 and has just been diagnosed with MS, you have been doing lots of research regarding DMTs, but have also been made aware that your MS has most likely been hanging around for a long time, what do you do about the hit-hard-and-early DMT approach? To add to the mix, your hypothetical person is very prone to side-effects from medication and is the bread-winner at a very mentally demanding job that doesn’t mix well with lots of hospital visits and time off sick from DMT side-effects.

    Your hypothetical person is aware that they are not young, are not trying to build a career, are not going to necessarily benefit from all the things that DMTs will bring younger pwMS. Also, there is a nagging doubt that actually, SPMS is more of a correct diagnosis.

    Are there general rules for how to approach DMTs when potentially starting them so late down the track? This normally intelligent and astute hypothetical person is completely confused.

    • Snap…. although I was just 51 when I was diagnosed, and I think that I had had ms for at least 15 years when I was diagnosed, and yes I also wonder if it might actually be SPMS. Not sure if it helps, but after doing lots of research (I have a biomedical/pharmaceutical background), including this blog (which I love), I decided on oral cladribine. Basically I looked at efficacy vs side-effects and took in to account things like convenience, and to my analysis oral cladribine came out top… also left at least one more effective treatment (but more serious potential side-effect and less convenience) in reserve.

      • Thank you! I’ve found it hard (yes I am that hypothetical person!) to get my head around this, since I feel like I am an older then normal first-timer.

        I don’t want to not take anything, but I do have take other things into account, as noted.

        Thanks for to taking the time to reply and to give me the sense of not feeling quite so alone.

        • Even my said he was really surprised when he saw my MRI scan…. he didn’t expect to see MS (since confirmed by LP) given my weird symptoms and age. By that time I was pretty relieved because I had had so many tests that said I was the healthiest person alive, and if it wasn’t MS it was either going to be a brain tumour or ME (at least that’s what I had convinced myself), so although it was a lot to get my head around, at lest I knew that I wasn’t imagining things and there was treatments available.
          I definitely did take that time is brain in to account, coupled with the fact that I had probably already had MS for quite a long time.
          And no, you are definitely not alone… I have read quite a few accounts of people in their 50s and even 60s getting diagnosed with MS.

          • Yes, I had that experience as well – so many tests, so many conditions ruled out, so many things wrong but no reason for it…

            Thanks again – Fox for thought!

        • Hi I was also diagnosed at 51yrs and figure I had had MS for around 15yrs. I didn’t have the question of SPMS as I’d lesions popping up constantly. I’m not the breadwinner and our son was 20 andantes uni when I was given the diagnosis.
          Using this site, Aaron Boster vids, and papers provided online by likes of NIH, I figured that I wanted to go for the hit it hard, f not early, approach with the aim of retaining what neurological reserve I have left. Consequently I plumped for Alemtuzumab. One and half years from receiving I’m NEDA and physically stable – according to the neuro physio I see. I had shingles post round two infusions. Otherwise, I’ve had no infections etc. I still experience full on fatigue and pain – take strong ibruprofen and Gabapentin.
          What we all know is we are all different with our ms – ‘snowflake disease’ as Americans call it + demands on you are very different to mine. I took attitude that I’d take a monster to try and subdue a bigger monster and in these Earl days it’s working for me. Hope whichever DMT you go for that you obtain the max benefit.

    • Incidence of late and very late onset of MS, and analysis of clinical
      features that may to help predict disability progression
      R. Roy (Ottawa, CA)

      Ectrims 2019

  • Hi

    I have simple question. I walk at 6 km/hr. For half kilometre. And can walk 5.5 km non stop. When I do the 25 ft walk test is 4.5-4.75secs. But norm is less than. 4 secs. That can’t be right? R u allowed to jog in the test? Also why isn’t there clarity and standardisation? On the barts edss scale I have edss of 1-2. At charring Cross my EDDSS is 0. I told them but barts have a different value. They humoured me and said don’t worry dear all clinics use this scale. Can you establish some clarity on what is precieved normal in speed, distance so ms patients can self monitor themselves accurately?

    • Is the 25 ft walk test measured from standing still at start or does the counter begin when mid stride?

      I wonder if starting mid stride, then you would be warmed up, and possibly quicker.

      • Thanks. Your absolutely right. Starting from 0 acceleration contributes to time. Now my time is 4.01 secs. I’ll taje that as normal. Don’t care what the doctors say. I’m 111kg guy that is fast even for normal people.

  • Fasing fasting fasting … part 2 🙂

    Clinical trial shows alternate-day fasting a safe alternative to caloric restriction

    The investigators found several biological effects in the ADF group:

    The participants had fluctuating downregulation of amino acids, in particular the amino acid methionine. Amino acid restriction has been shown to cause lifespan extension in rodents.

    They had continuous upregulation of ketone bodies, even on nonfasting days. This has been shown to promote health in various contexts.

    They had reduced levels of sICAM-1, a marker linked to age-associated disease and inflammation.

    They had lowered levels of triiodothyronine without impaired thyroid gland function. Previously, lowered levels of this hormone have been linked to longevity in humans.

    They had lowered levels of cholesterol.

    They had a reduction of lipotoxic android trunk fat mass—commonly known as belly fat.

    “Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet,” says Thomas Pieber, head of endocrinology at the Medical University of Graz. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day.”

    “The reason might be due to evolutionary biology,” Madeo explains. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

    “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo says.

  • Ladies and gentlemen the moment we all been wayting for

    Hsct vs Alemtuzumab

    result
    Hsct 1 Alemtuzumab 0

    Efficacy of aHSCT and Alemtuzumab: A Case-Control Study in Hamburg MS-patients

    http://www.professionalabstracts.com/ectrims2019/iplanner/#/presentation/1377

    We observed significantly more patients fulfilling NEDA in the aHSCT group (0.48/0.35, p = 0.048) compared to the alemtuzumab treated patients

    Conclusion: This case-control study suggests that aHSCT suppresses inflammatory activity in MS more effectively than alemtuzumab. Despite longer disease duration and lower pre-treatment relapse activity in the alemtuzumab group, which hypothetically should be associated with less inflammatory activity, more MRI activity and relapses were observed in this group in comparison to aHSCT treated patients
    Ectrims 2019

    Ps: After all Hsct does stand “some” chance aganist Alemtuzumab

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives