Category Archives: MSA

Big news- MSA seems transmissable, LBD does not, etc.

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Though this email is of most interest to the MSA folks in our support group, I’m sending this to everyone as it may be that similar findings will be made with PSP and CBD.  I’ve added a note near the bottom of this email; it seems that these findings don’t apply to LBD.  …  Also, I want to note upfront that this ground-breaking research is made possible through generous people donating their brains.

My email inbox exploded this afternoon — first Candy, then Jen, then Denise, and then several others.  There was big news today (Monday, 8-31-15) about MSA research.

Prions are “infectious proteins” that spread in the brain like a virus or bacteria.  The Nobel Prize-winning discoverer of prions is Stanley Prusiner at UCSF.  The most well-known human prion disease is Creutzfeldt-Jakob Disease (CJD), a very rare disorder involving PrP prions.  The most well-known animal prion disease is made cow disease.  Suggestions have been made over the last several years that perhaps Alzheimer’s or Parkinson’s is caused by prions.

Two weeks ago and today (in two separate papers), Dr. Prusiner and a team of researchers reported that “multiple system atrophy (MSA) is caused by a…human prion composed of the alpha-synuclein protein.”  This is all over the news today.

Here’s a link to NPR’s All Things Considered’s discussion of this research today:

Scientists Discover New Disease Caused By Prion Protein
www.npr.org/2015/08/31/436377464/scientists-discover-new-disease-caused-by-prion-protein

The 3.5-minute radio segment notes that MSA may be transmissible from person to person!  (There’s no transcript posted yet of this radio story.)

Here’s a related part of the UCSF press release on the public health aspect of this research:

“The discovery that alpha-synuclein prions can transmit MSA raises a public health concern about treatments and research that involve contact with brain tissue from neurodegeneration patients, because standard disinfection techniques that kill microbes do not eliminate the PrP prions that cause CJD. Whether the same challenges hold for alpha-synuclein prions in MSA remains to be determined. … The authors write that clinicians and researchers should adopt much more stringent safety protocols when dealing with tissue from patients with MSA and other neurodegenerative diseases, many of which they believe may also be caused by prions. For instance, MSA is frequently initially diagnosed as Parkinson’s disease, which is often treated with deep-brain stimulation. The disease could potentially be transmitted to other patients if deep-brain stimulation equipment is reused. … [The] researchers stress that there is no apparent risk of infection by MSA prions outside of specialized medical or research settings.”

This makes me wonder if some people who had PD and got deep brain stimulation (DBS) surgery, actually acquired MSA from the surgical instruments used during DBS.  That’s alarming to consider.

This excerpt from the UCSF press release explains how the discovery was made:

“The new work has its origins in experiments conducted in Prusiner’s lab in 2013, showing that samples of brain tissue from two human MSA patients were able to transmit the disease to a mouse model for Parkinson’s disease, expressing a mutant human alpha-synuclein gene. To confirm this finding, Prusiner and colleagues expanded this experiment to include tissue samples from a dozen more MSA victims from tissue banks on three continents…  The results were the same: When exposed to human MSA tissue, the mice developed neurodegeneration. In addition, the team found that the brains of infected mice contained abnormally high levels of insoluble human alpha-synuclein, and that infected mouse brain tissue could itself spread the disease to other mice.”

Note that this research was made possible only through the generosity of those who donated their brains!

You can read the full UCSF press release here:

www.ucsf.edu/news/2015/08/131416/new-type-prion-may-cause-transmit-neurodegeneration

And you can read the abstract for the Prusiner article here:

www.pnas.org/content/early/2015/08/27/1514475112.abstract

What does this mean for LBD?  Both Lewy Body Dementia and Parkinson’s Disease are also disorders of alpha-synuclein protein.  If I’m understanding the full Prusiner paper accurately, researchers also tried to get human Parkinson’s Disease  tissue from six brain donors to transmit PD to transgenic mice.  None of the mice developed Parkinson’s Disease.  It would seem that the “strain” (or variant) of alpha-synuclein that causes PD is different from the transmissable strain that causes MSA.

(Actually, four patients were diagnosed with “Lewy body disease” or Parkinson’s Disease.  And two patients were diagnosed with “diffuse Lewy bodies,” which is Lewy body dementia.)

Not sure where we go from here!  Fortunately we are right at the center of prion disease research with UCSF.  I think lots of MSA researchers are going to be changing their strategies as a result.  And probably PSP and CBD researchers will want to investigate if these disorders are transmissable as well.

Robin

Spinal fluid biomarker research – PSP v. MSA v. PD, and which PDers will develop LBD?

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There was an interesting – but hard to understand (at least for me!) – paper published a couple of weeks ago in JAMA Neurology, an important journal.  A lot of the worldwide research community is focused on biomarkers.  If we could give someone a blood test (or a spinal tap, in the case of this paper) to determine if the person had PD, PSP, or MSA, that would be groundbreaking.  And it might be helpful to know which of those who have PD will eventually develop dementia (or Lewy Body Dementia in particular).

In this paper, Swedish researchers looked at cerebrospinal fluid (CSF) of 128 people with Parkinson’s Disease (PD), Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA) over a 5-9 year period.  None of the 128 had dementia.  CSF of 30 older healthy controls was also examined.

Here’s an (understandable) excerpt from a useful summary of the paper on Alzforum, posted last Friday:

“Scientists…report a combination of useful candidates in the cerebrospinal fluid (CSF) that may help [differentiate these diseases and predict who will decline cognitively]. One biomarker in particular, neurofilament light chain (NFL), a neuronal cytoskeleton protein, best distinguished PSP from PD. In helping predict which patients with PD would become demented, NFL joined two other proteins: Aβ42 and heart fatty acid–binding protein (HFABP), which helps carry fatty acids to the mitochondria for oxidization. All in all, the results propose useful diagnostic biomarkers for these diseases and may offer clues to their pathophysiology. … No single biomarker or combination separated MSA from PD.”

In the study, 35 percent of the PD patients developed dementia over the five to nine years of participation.  This seemed to be a high conversion rate to dementia for John Growdon, a neurologist at Mass General in Boston.  He said:

“‘To be able to predict with some certainty who’s on the path to dementia and who’s not is a very important finding,’ he told Alzforum. If these results can be reproduced, it could mean that Aβ-lowering therapeutics for Alzheimer’s disease (AD) will be applicable to the PDD group. It would be useful to compare these biomarkers in other disorders that might also cause diagnostic confusion, such as AD and dementia with Lewy bodies, he said.”

For what it’s worth, Dr. Growdon described this as a “very important study.”

Here’s a link to the Alzforum post, if you’d like to read more:

www.alzforum.org/news/research-news/biomarkers-differentiate-parkinsonian-diseases-and-forecast-decline

I’ve copied the abstract below.

Robin

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Abstract

JAMA Neurology. 2015 Aug 10.

Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease.
Bäckström DC, Eriksson Domellöf M, Linder J, Olsson B, Öhrfelt A, Trupp M, Zetterberg H, Blennow K, Forsgren L.

Importance:
Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies.

Objective:
To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders.

Design, Setting, and Participants:
Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by a movement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison.

Main Outcomes and Measures:
Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria.

Results:
Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders.

Conclusions and Relevance:
The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

PubMed ID#:  26258692

Falls and Dysphagia (new publication co-authored by BSN)

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This post will be of interest to those dealing with falls and/or dysphagia (swallowing difficulty).

Local support group member Phil Myers and I co-authored a case study on falls and dysphagia in the latest issue of the Association of Frontotemporal Degeneration (AFTD) newsletter.  The case study is about “Jackie Riddle” — a composite of my father’s PSP symptoms (confirmed through brain donation) and Phil’s wife Jackie’s PSP symptoms (also autopsy-confirmed).  Though “Jackie Riddle” had PSP, since the focus of the case study is on falls and dysphagia, all of our BSN group members, regardless of diagnosis, will find something of value here.

The newsletter is written for healthcare professionals but I’m fairly certain the language is understandable.  We assumed that healthcare professionals are completely un-knowledgeable about PSP, fall prevention, and treatment of dysphagia.

There are also sections in the newsletter specifically for healthcare professionals working at care facilities.  So if any of you has a loved one in a care facility, those sections may be particularly helpful for staff.

The last two pages of the newsletter are my ideas for practical things that can be done about falls and dysphagia.  Again, though it’s titled “in PSP,” these ideas apply to all four disorders in our BSN group.

Check it out; it’s hot off the presses:

www.theaftd.org/wp-content/uploads/2015/07/PinFTDcare_Newsletter_summer_2015.pdf

Robin

Therapeutic advances and research update in MSA and PSP

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This post may be of interest to those wanting to know about what key research in PSP and MSA has taken place in the last few years, and what research is ongoing or recruiting.

This review article on PSP and MSA clinical trials was just published last week.  The article is written for MSA and PSP researchers, explaining how trials since 2013 have been conducted and highlighting priority areas for future therapeutic research.  The lead author is Werner Poewe, MD, an Austrian physician and researcher.  I believe at the most recent Movement Disorder Society meeting in San Diego, he led a discussion with MSA researchers.  Perhaps he reviewed his article at the meeting.

The article notes that an earlier study of riluzole in MSA and PSP proved the feasibility of conducting large controlled trials in these two disorders.  And the study validated disease-specific rating scales for MSA and PSP.  Nearly 800 subjects were enrolled in that study.  The results, published in 2009, were negative for the medication itself.

But that large riluzole study kicked off other trials — two large clinical trials in MSA (rasagiline, rifampicin) and two large clinical trials in PSP (tideglusib, davunetide).  Those four trials failed as well.  The authors describes those trials in detail.

The article lists all of the other trials conducted since 2013 in PSP and MSA, whether results were published or not.  These include a lithium trial in MSA, two droxidopa trials in MSA, a fluoxetine trial in MSA (unpublished), a high-dose CoQ10 trial (2400mg/day) in PSP, and a valproic acid trial in PSP (unpublished).  Unfortunately one rasagiline study in PSP failed to enroll the necessary number of participants.

Though the therapeutic agents being tested in these trials failed, the studies themselves “have made important contributions to our ability to refine designs in future clinical studies targeting these conditions. As a whole they have shown that enrolling sufficient numbers of patients into trials of the less common forms of degenerative parkinsonism is feasible and that this can be accomplished within reasonable time frames.”

The authors note that despite recent trials in PSP and MSA, “there is still a profound lack of symptomatic trials for these disorders.”

The authors state:  “Although autonomic dysfunction is a key driver of disability in MSA, new drugs to treat OH, such as droxidopa, have not been tested in trials specifically enrolling MSA cases only. Likewise, none of the non-pharmacological measures such as exercise-based approaches that are a central part of palliative therapy for patients with MSA or PSP have been tested in properly designed clinical trials.”

The authors call for future research to address two main areas of need:  “improving symptomatic control, independence and well-being of patients by symptomatic interventions, and altering the course of disease by interfering with the mechanisms underlying progressive neurological impairment and disability.”

In case you are interested in exploring the ongoing trials or trials not yet recruiting in MSA and PSP, see the following list:  (If a trial is recruiting, I’ve listed the NIH clinical trial number so that you can look up info on clinicaltrials.gov)

MSA

  • two for droxidopa (one recruiting, NCT02071459, and one isn’t)
  • autologous mesenchymal stem cells (not recruiting)
  • EGCG – a green tea extract (recruiting, NCT02008721)
  • water/peudoephedrine (recruiting, NCT02149901)
  • AFFITOPE – active immunization against alpha-synuclein (recruiting, NCT02270489),
    nebivolol (not recruiting)
  • AZD3241 (the paper says not recruiting but it’s now recruiting, NCT02388295)

PSP

  • bone marrow stem cell therapy (ongoing, NCT01824121)
  • TPI-287 (ongoing, NCT02133846)

I think most of you will want to stop reading here.  Below, I’ve provided the abstract.

Robin

Abstract

Movement Disorders. 2015 Jul 30.
Therapeutic advances in multiple system atrophy and progressive supranuclear palsy.
Poewe W, Mahlknecht P, Krismer F.

Abstract
Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP.

© 2015 International Parkinson and Movement Disorder Society.

PMID:  26227071

 

“Could a vitamin or mineral deficiency be behind your fatigue?” (short article, Harvard)

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Fatigue can be a symptom in all of the disorders in our local support group.  Today’s Healthbeat email from the Harvard Medical School points to one mineral and two vitamin deficiencies that may cause fatigue.  It might be worth having an MD check one’s vitamin levels to rule these out as problems if fatigue is present.

Robin

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Excerpts from

Could a vitamin or mineral deficiency be behind your fatigue?

Healthbeat
Harvard Medical School
August 1, 2015

The world moves at a hectic pace these days. If you feel like you’re constantly running on empty, you’re not alone. Many people say that they just don’t have the energy they need to accomplish all they need to. Sometimes the cause of fatigue is obvious — for example, getting over the flu or falling short on sleep. Sometimes a vitamin deficiency is part of the problem. It might be worth asking your doctor to check a few vitamin levels, such as the three we’ve listed below.

* Iron. Anemia occurs when there aren’t enough red blood cells to meet the body’s need for oxygen, or when these cells don’t carry enough of an important protein called hemoglobin. Fatigue is usually the first sign of anemia. A blood test to measure the number of red blood cells and amount of hemoglobin can tell if you have anemia. The first step in shoring up your body’s iron supply is with iron-rich foods (such as red meat, eggs, rice, and beans) or, with your doctor’s okay, over-the-counter supplements.

* Vitamin B12. Your body needs sufficient vitamin B12 in order to produce healthy red blood cells.  So a deficiency in this vitamin can also cause anemia. The main sources of B12 are meat and dairy products, so many people get enough through diet alone. However, it becomes harder for the body to absorb B12 as you get older, and some illnesses (for example, inflammatory bowel disease) can also impair absorption. Many vegetarians and vegans become deficient in B12 because they don’t eat meat or dairy. When B12 deficiency is diet-related, oral supplements and dietary changes to increase B12 intake usually do the trick. Other causes of B12 deficiency are usually treated with regular injections of vitamin B12.

* Vitamin D. A deficit of this vitamin can sap bone and muscle strength. This vitamin is unique in that your body can produce it when your skin is exposed to sunlight, but there also aren’t many natural food sources of it. You can find it in some types of fish (such as tuna and salmon) and in fortified products such as milk, orange juice, and breakfast cereals. Supplements are another way to ensure you’re getting enough vitamin D (note that the D3 form is easier to absorb than other forms of vitamin D).