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Sao Bettencourt’s MSA Coalition Travel Award Report

Sao Bettencourt’s MSA Coalition Travel Award Report

Written By Sao Bettencourt – MSA Coalition Travel Award Winner

Thanks to the support of MSA Coalition, I have attended in September (1-4th) the “Synuclein Meeting 2019: Where we are and where we need to go” in Ofir, a city in the outskirts of Porto, Portugal.

This meeting brought together over 300 participants, including leading experts in the field of Synuclein and Synucleinopathies, from both academia and industry, as well as a broad community of junior scientists. This meeting was organized in an unusual format, consisting mostly of round-table discussions, with just a few oral presentations and keynote lectures, to create more opportunities to discuss the major questions in the field. There were also two poster sessions (over 130 posters in total), during which I have presented a poster with our recent research findings on MSA (summarize below).

Attending this meeting was beneficial for me and our research group at several levels:

  1. Being able to disseminate and discuss our exciting findings on epigenetics of MSA;
  2. Having the chance to hear from leading experts, learn extensively and update my knowledge about
    ongoing research on Synuclein and Synucleinopathies (including MSA);
  3. Having the chance to meet personally and engage with both senior and junior scientists in the field,
    and discuss science as well as career development;
  4. Having the chance to network with researchers I have met/worked with before as well as with
    potentially new collaborators.

During the conference, MSA was given relevant attention in multiple occasions:

On the first day of the conference, there was a main talk by Gregor Wenning, who gave an overview about MSA, from clinical aspects to highlighting several recent studies trying to develop drugs that can then be taken into clinical trials. He mentioned that at least 25 compounds are already being or about to be tested in MSA.

MSA was also given major attention on “Roundtable 10 – Spreading of alpha-synuclein – relevant or epiphenomenon?”, chaired by Glenda Halliday and having Jiayi Li, Jeff Kordower, Donato Di Monte, Glenda Halliday, Veerle Baekelandt, and Gregor Wenning as speakers. The major discussion point was whether in Synucleinopathies the spreading of alpha-synuclein occurs in a prion-like manner. There was no overall consensus in this matter.

There were also about 15 posters mentioning MSA, some of which having MSA as the main research focus while others would use MSA as a comparison group together with other neurodegenerative diseases. From those, I would like to highlight our own poster:

PO42 – by Conceição Bettencourt et al. (United Kingdom), “DNA METHYLOME ANALYSIS IN POST-MORTEM BRAIN TISSUE OF MULTIPLE SYSTEM ATROPHY PATIENTS”. In the poster we have presented our recent findings on epigenetics of MSA. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. We explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a multi-phase case-control study, and profiled genome-wide DNA methylation (Illumina EPIC arrays) in white mater from three brain regions characterized by severe-to-mild pathology burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). We observed that DNA methylation levels in HIP1, LMAN2, MOBP, among other loci were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (MSA OPCA and SND). We also identified several molecular signatures significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the

DNA methylation signature having the strongest association with MSA included SNCA, the gene encoding α- synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, and highlight potential novel routes for diagnosis and therapeutic interventions.

I would also like to highlight several examples of excellent research done by others, including:

PO09 – by Antonio Heras-Garvin et al. (Austria), “HYPOXIA, A POSSIBLE PATHOGENIC FACTOR IN MSA AND PD”, investigating a possible role for hypoxia as a pathogenic factor in MSA and PD. The authors observed a significant accumulation of the hypoxic marker HIF2α in MSA and are pursuing this further with additional investigations.

PO17 – by Miguel Lemos et al. (Austria), “COMBINED ANTI-Α-SYNUCLEIN THERAPY FOR DISEASE MODIFICATION IN MULTIPLE SYSTEM ATROPHY” testing disease modification properties of two compounds in a transgenic mouse model overexpressing α-Synuclein in oligodendrocytes. One of these compounds consist of short immunogenic peptides (AFFITOPEs), carrying a sequence that mimics the original α- Synuclein epitope, and the other (Anle138b) is an aggregation inhibitor. The authors confirmed the efficacy of the single therapy with AFFITOPEs or Anle138b, observing motor improvement, rescue of dopaminergic neurons, reduction in α-Synuclein oligomers, decrease of GCIs density, and decreased levels of microglia activation. The combination of Anle138b+AFFITOPEs has also shown benefits but no cumulative beneficial effects were achieved by combining the two. Interesting results in this mouse model that certainly warrant further investigation.

PO35 – by Violetta Refolo et al. (Austria), “NEUROINFLAMMATORY PATHWAYS INVOLVED IN THE SELECTIVE NEURODEGENERATION OBSERVED IN A TRANSGENIC MOUSE MODEL OF MULTIPLE SYSTEM ATROPHY”, investigating the pathways involved in the neuroinflammatory region-specific events occurring, over the disease course, in a transgenic mouse model of MSA. Their findings suggest an important role of the early, alpha-synuclein-triggered neuroinflammation for the progressive neurodegeneration of the substantia nigra in this mouse model.

PO44 – by Jonas Folke et al. (Denmark), “PERIPHERAL IMMUNE CELLS CORRELATE TO DISEASE PROGRESSION IN MULTIPLE SYSTEM ATROPHY AND PARKINSON’S DISEASE”, evaluating peripheral immune cell changes in MSA and PD in a longitudinal manner, and showing changes in immune cells in both MSA and PD patients.

PO75 – by Vincenzo Donadio et al. (Italy), “INTRANEURAL SKIN NERVE Α-SYNUCLEIN DEPOSITS IN MULTIPLE SYSTEM ATROPHY”, who reports that neuritic inclusions of phosphorylated α-synuclein in somatic skin nerves can represent a sensitive biomarker for MSA.

PO116 – by Teresa Torre-Muruzabal et al. (Belgium), “CHARACTERIZATION OF TWO DISTINCT ALPHA- SYNUCLEIN STRAINS IN A MOUSE MODEL FOR MULTIPLE SYSTEM ATROPHY”, examining whether different α-synuclein strains might exert distinct pathologies in an animal model of MSA. They found distinct histopathological and behavioural phenotypes in vivo.

PO118 – by Ilaria Poggiolini et al. (United Kingdom), “DEVELOPMENT OF ALPHA-SYNUCLEIN SEEDING ASSAY AS AN EARLY, PROGRESSION AND STRATIFYING BIOMARKER FOR SYNUCLEINOPATHIES”, examining aSyn RT-QuIC assay in brain tissue from Multiple System Atrophy (MSA) in parallel to PD patients in order to see if it can stratify between the different synucleinopathies. The authors found substantially different kinetic properties on RT-QuIC in MSA vs. PD, and suggest the aSyn RT-QuIC assay has potential as an early, differential test for prodromal disease.

MSA Awareness Blues

MSA Awareness Blues

Written by Larry Kellerman

Life has a way of defining us rather than vice versa. Each and every day there are innumerable interactions, any of which could have a different outcome. The goal is to be prepared whichever directions those interactions might take, which we all know is easier said than done.

Sometimes those interactions are job-related, but often they occur in our daily lives. These interactions might be positive; meeting a new friend or finding a new place to eat. Others, not so much; seeing an accident or encountering some environmental danger.

Which of the many interactions over time cause the brain of a future MSA patient to start producing or altering the alpha-synuclein being produced, thus causing the neurodegenerative disease multiple system atrophy?

[This is written for a blog post on the Coalition’s web page but is for any and all visitors who come for the first time. Please remember when reading these bulleted points there is a reason for this post; advocacy is an on-going process and each time may help bring one, maybe ten, into the advocacy fold]

  • It’s rare – 4 in 100,000 patients will be diagnosed with MSA, 8-9 in 100,000 for those above the ages 40-45.
  • It is sporadic – To this point no known cause, genetic or environmental, has been found; to this point it is not known to be hereditary
  • No treatment – there is not one treatment that has yet made it past Phase 3 status in the clinical trials process
  • No cure – Yep, that’s right! It is a d____ s________.
  • How to solve these problems – raise awareness of the disease and monies for the premier funding entity in the MSA community, the Multiple System Atrophy Coalition, and its research grant program.

Raising awareness is a tricky proposition and many advocates have tried multiple methods to bring attention to the disease and sometimes to raise money. There are marathoners, half-marathoners, runners, bicyclists, lemonade stand entrepreneurs, and many others. All help raise awareness and oftentimes money. People wanting to beat this Beast.

Two blues aficionados and one blues artist extraordinaire, offer the BEAT MSA! Fundraiser on October 3, 2019. My wife Colleen, who brainstormed with me this entertainment approach to fundraising, thought raising awareness was best accomplished when people are enjoying themselves. This event, held on World MSA Day, will bring together some of the best in local and national blues artists, good food (included in ticket price) and silent auction items from college basketball programs and blues artists. There will be bands playing, artists soloing, wonderful blues singers singing and guitarists playing. And we can’t forget the skins or the great bassists laying down the beat.

We want it to be an enjoyable and memorable night! Come join us or email me if you have any questions or want to help.

The pictures here show Colleen’s joy at crossing Walt Disney World off her bucket list; this trip in late December 2013 was just two months before our second fundraiser – but that’s another story.

Written by Larry Kellerman, MSA Coalition Board of Directors & Support Line Volunteer

Pain

Pain

Written by Larry Kellerman

Few things a doctor does are more important than relieving pain. . . pain is soul destroying. No patient should have to endure intense pain unnecessarily. The quality of mercy is essential to the practice of medicine; here, of all places, it should not be strained” (Marcia Angell).

Yes, pain is soul destroying. I watched that with my wife, who suffered from the intense neuropathic pain that accompanies multiple system atrophy (MSA) for many patients. From the start of symptoms until her last breath chronic pain was her defining symptom. When a doctor would ask what her pain level was on the scale her response was typically “Higher than 10, more like 12 or 13.” When a body is fighting that level of pain the physical and emotional stress become overwhelming.

I bring this up because of a recent series of communications with a good friend of an MSA patient. She recently became re-acquainted with her friend after being absent for several years. During the conversations they shared her friend told her about the pain she was suffering and the lack of any medication to touch it. By the end of our first conversation I had shared with her the link to the MSA Coalition’s newly updated “MSA-What You Need to Know” booklet and a short summary of my wife Colleen’s experiences.

After the phone call my curiosity was piqued; what if any new developments in pain management for MSA patients might be found through an internet search? One of the first articles I found was a 2015 article “Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson’s disease” (Kass-Illiya et.al., 2015). The article reported the results of a small sample-size study (102 patients total) of which the aim was “to evaluate pain intensity, location, and associated symptoms in atypical parkinsonian disorders compared to PD.”

The findings were striking for the PD and MSA patients. Of the 65 PD patients 89% reported pain as did 81% of the 21 MSA patients. Even more startling – 100% (14) of the MSA-P (Parkinson’s) patients reported pain, while just 43% of the MSA-C (Cerebellar) reported the same. Location of the pain in the MSA patients was from the neck down, with the legs receiving the most reports. In other words pain is an undesirable companion on many an MSA journey.

This past Saturday evening I received an email from that friend. The MSA patient had passed away the previous day and she just wanted to say “Thanks” for sharing. The message read in part “I’m very sad because I will miss her very much. But I’m relieved that she is now out of pain.”

I started this post with a quote from Marcia Angell. Part of that quote is “…pain is soul destroying. No patient should have to endure intense pain unnecessarily.” There could well be 80% of America’s MSA patients (~20,000) who would resoundingly say “and that’s an understatement.”

 

Written by Larry Kellerman, MSA Coalition Board of Directors & Support Line Volunteer

Meeting A Mission One Support Line Call At A Time

Meeting A Mission One Support Line Call At A Time

Written by Larry Kellerman

I am the MSA Coalition support line volunteer for a coalition representing a very rare and devastating disease. I have found being that person who can share resources, advice, a shoulder to cry on and the voice of hope brings people back again and again to share their thoughts and questions. Every call helps me meet the mission my deceased wife and I developed during her last months suffering from multiple system atrophy (MSA), a rare and terminal neurodegenerative disease. “Help others who are on this da#ned journey” was her lament that led to me dedicating my life to be a support for MSA patients and caregivers.

One caller in particular is the reason for this story. I’ll call him Gary but that is not his real name. He first called the call line about 18 months ago and after our first conversation he asked if he could call back if he had any additional questions or just needed to talk. I told him it would be my pleasure to be there for him and put his contact information in my contacts list.

Over these last 18 months we’ve probably talked a dozen times. He’d call when the journey was getting difficult or when he’d see a change in his wife’s condition and needed to have some reassurance. Over those months we became comfortable talking to each other and a couple of times advice I shared helped make a positive difference in his wife’s treatment and condition. During that same period of time I heard in his voice a resolve grow that was not there at first, a resolve to be a positive part of the MSA journey.

Two weeks ago he called and told me how quickly his wife had taken a turn for the worse. She was now unable to hold herself up and leaned to one side, had difficulty eating and was very fatigued. We talked about what that might mean and I shared some advice heard at a recent support group meeting; “If there’s a change for the worse in an MSA patient it’s quite likely to be a urinary tract infection.” He was sure they were giving her antibiotics to prevent a UTI but would check. When the conversation ended I could hear in his voice that worried sound of “could this be the last time a symptom impacts her like this?”

He called four days later and when I took the call I could hear cheerful voices and laughter. He told me he wanted me to hear how crazy it was now that his wife was home and the children were there visiting. He even introduced me to his wife and we got to exchange a few words. Her voice was weak but I could understand everything she said. He got back on the line and said he just wanted to share that family time with me. Talk about feeling humbled as I hung up.

Early Friday evening the phone rang and Gary’s name appeared. I immediately answered and said “Hi.” He said to me “Larry, she passed away today, and we were all here when she did.” He shared some of the information about those last hours with the family and calling the hospice nurse to come out, only to have his MSA wife pass before the nurse arrived. I think at that point I was the more sentimental of the two of us, trying to hold back the tears of “S#*t, another MSA patient taken from us.”

Then he shared something that made my night, week and maybe even my year. We had talked a couple of times during that 18 months about his wife donating her brain. Just days before she passed he called a nearby research center that has a brain bank. Over a few hours they confirmed his wife’s approval of the harvest, contacted the funeral home and pathologist who would complete the harvest and made the process very smooth for Gary and his wife’s donation.

He told me he had asked them how many MSA brains they have in their bank and they said “less than twenty.”

I paused for a short time before words would come out of my mouth. “Gary” I said. “One of those brains is my wife’s. You have donated to the same brain bank that has my wife’s brain.”

One day in the life of a support line volunteer.

Written by Larry Kellerman, MSA Coalition Board of Directors & Support Line Volunteer

Top 10 Lesser-Known Things to Consider About Multiple System Atrophy

Top 10 Lesser-Known Things to Consider About Multiple System Atrophy

These are things not normally highlighted in traditional literature about Multiple System Atrophy. This list was compiled by the MSA Coalition from the collective experience (since 1995) of hundreds of members of the MSA online support group founded by Vanderbilt University Autonomic Dysfunction Center staff. http://groups.yahoo.com/group/shydrager

Download and print a copy:

English: https://www.multiplesystematrophy.org/wp-content/uploads/2019/07/TOP-TEN-THINGS-YOU-NEED-TO-KNOW-ABOUT-MULTIPLE-SYSTEM-ATROPHY_v1.0.pdf

Deutsch: https://www.multiplesystematrophy.org/wp-content/uploads/2019/10/German_TOP-TEN-THINGS-YOU-NEED-TO-KNOW-ABOUT-MULTIPLE-SYSTEM-ATROPHY_v1.1.pdf

Espanol: https://www.multiplesystematrophy.org/wp-content/uploads/2020/02/DIEZ-COSAS-QUE-NECESITA-SABER-SOBRE-LA-ATROFIA-MULTISISTÉMICA_v1.0_ES-1.pdf

1. WATCH FOR SLEEP AND BREATHING PROBLEMS

Sleep and breathing problems are very common in MSA patients. Sleep apnea (momentary lapses in breathing), respiratory stridor (noisy breathing), REM behavior disorder (shouting and acting out dreams) and excessive daytime sleepiness can be among the earliest symptoms of MSA. Sleep apnea is very serious and can lead to sudden death during sleep. Ask your bed partner if you snore, breathe loudly in your sleep, talk in your sleep or act out your dreams. Ask to be referred to a sleep specialist for a sleep study often this can be performed in your own home. Not getting a good night’s sleep can make other MSA symptoms seem worse both for the patient and the caregiver. Sleep and breathing .

problems can be easily treated with a CPAP or Bi-Pap – this is a mask with pressurized air worn at night

2. BE AWARE OF SITUATIONS THAT CAN AFFECT BLOOD PRESSURE

Blood pressure can DROP suddenly (hypotension) in several situations: 1. After getting up in the morning – drink a large glass (12 oz or more) of plain water before getting out of bed to raise your blood pressure and take your morning medications and wait 15-20 minutes to allow them time to work before getting up. 2. During a bowel movement – use a footstool in front of the toilet to keep your legs up and your blood pressure up. 3. After a large meal – eat 5 or 6 small meals instead of larger meals. 4. After standing in one place for a long time – sit whenever possible TIP: If someone feels faint or passes out, lay them down and elevate their legs above the level of the heart. Blood Pressure can also SPIKE UPWARD (hypertension) in several situations: 1. When lying flat (supine) during sleep – raise the head of the bed 4 to 6 inches higher than the foot of the bed at night to help prevent this. TIP: If the blood pressure is too high while laying down, sitting up or standing can bring it back down quickly. Remind your doctors that they should not overreact to a high supine blood pressure.

3. PREVENT INFECTIONS

MSA patients often register a body temperature that is a degree or more below normal. Because of this a fever may not be detected. Any sudden worsening of symptoms or confusion could be a sign of infection. An even lower temperature than the normally (MSA) low temperature can also be a sign of infection. Be vigilant about preventing and detecting all types of infections urinary tract (UTI) and lung infections (PNEUMONIA) are very common. Stay well hydrated (64 oz fluid per day) to prevent urinary tract infections. Stay dry and shift weight often to prevent skin pressure sores. Swallow carefully to avoid choking and aspiration. Puree foods when swallowing becomes difficult. Get speech and swallowing therapy to avoid aspiration pneumonia. Watch for bowel blockage from chronic constipation.

4. BE CAREFUL OF SURGERY/ANESTHESIA

If an MSA patient is to have any dental work or surgery, a local anesthetic should be the preferred choice if possible. However, some local anesthetics contain adrenaline which may adversely affect blood pressure. Ensure that the dentist or surgeon and anesthesiologist know that MSA affects the autonomic nervous system. The MSA patient must be well hydrated via IV before and during surgery to maintain a safe blood pressure. Another note on surgery: Prostate surgery should only occur if the urologist and neurologist have had a consultation with each other and agree that prostate enlargement is the cause of urinary retention (since this is a common symptom of MSA which does not improve with prostate surgery).

5. BE CAREFUL WITH OVER-THE-COUNTER COLD/FLU/ALLERGY MEDICATIONS

Many of these medications contain pseudoephedrine that can affect the heart and raise blood pressure, to dangerous levels. They also may interact with prescribed medications. Be very careful and consult your doctor before mixing any medications, including over-the-counter remedies or even vitamins.

6. PREVENT FALLS

Preventing falls is very important, if you fall and break a bone you may become bedridden and more prone to infections. When it becomes appropriate use a cane, walker or wheelchair. Install grab bars in the bathroom, use a raised toilet, use a shower chair or bench, use a Hoyer lift for transfers.

7. AVOID EXTREME HEAT OR COLD

MSA can affect the body’s ability to sweat and to maintain a proper core temperature. It’s important to stay cool during hot or humid weather and stay warm during cooler weather. Also avoid very hot baths and showers.

8. EXERCISE!

It’s important to maintain strength and flexibility for as long as possible. Do range of motion exercises and any gentle exercise that can be done when sitting. Water exercises are easy to do and very helpful. Practice speech exercises along with the other exercises to help maintain strength and clarity of voice for as long as possible. Ask for physical and occupational and speech therapy as these are all known to be beneficial to MSA patients.

9. PREPARE FOR EMERGENCY ROOM VISITS

Keep a short description of your medical history, a description of MSA, and your most recent medications list handy so you can take it with you to any new doctors’ appointments, hand it over in an emergency room, give it to caregivers, etc. If you are in any of those situations, it’s much easier to have something pre-prepared, especially if you’re talking to people who have never heard of MSA.

10. BE READY TO ADVOCATE AND TO COORDINATE A TEAM OF DOCTORS

Be ready to “advocate” with your doctors, or ask a trusted friend, family member or caregiver to play this role. MSA is a complex disorder and not every doctor will have heard of it, find a doctor you trust who is willing to learn. There is literature available and there are known MSA expert neurologists who can act as consultants. At each appointment try to focus on 1 or 2 concerns to get them addressed adequately. Have a buddy with you who will make sure you are heard! Often your general practitioner can help play the coordinator role by referring you to other experts such as a neurologist, internist, cardiologist, urologist etc. If you are participating in research studies or if you are using health supplements, let all your doctors know about this.

Also, you should spend some time thinking about your “advance directives” and make it clear to your family members, caregivers and health care providers if you have made a decision about which emergency treatments you want or don’t want (such as resuscitation, intubation or feeding tubes). Remember that you can ALWAYS change your mind and change your advance directives.

 

For more information, please see the Multiple System Atrophy Coalition website www.MultipleSystemAtrophy.org or call the toll-free support line 1-866-737-5999

 

DISCLAIMER: This information is intended to aid MSA patients and their families in their discussions with clinicians. It should not be considered medical advice or endorsements of drugs or therapies. Always consult a licensed medical practitioner for expert care.

Copyright © The Multiple System Atrophy Coalition, Inc. – Originally compiled by Pam Bower December 9, 2010, Last updated February 23, 2019