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

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

“The ICU is Not a Pause Button”

Yesterday’s article in “The End” — a New York Times series about end-of-life issues — raises some worthwhile topics.  But I didn’t care for the tone, which I found somewhat inhumane — especially since (or because?) the author is an ICU nurse.  I’ll try to look past that to summarize her key points, in case any of the points resonate with you:

  • if your family member is elderly and frail, avoid the ICU
  • “When a family member is in the I.C.U., it’s not enough to [make a phone] call. You need to drop what you’re doing and be at that person’s side, figuring out what is best for them.”
  • while families think of the ICU as a “pause button,” patients are miserable in the ICU.  The author would probably say that families shouldn’t wait for out-of-town relatives to arrive to decide how to proceed.
  • the ICU is not a nice place to die because of all the unpleasant things happening to the patient:  “mask on, mask off, a feeding tube in his nose, IVs in his arms, having his dry mouth sponged, his throat suctioned, defecating and being cleaned up”

These are probably good things to consider now, not when sitting in the ICU…  If you do end up in the ICU, it seems that we can’t rely on the medical staff to have a conversation with us as to where things are headed, or that efforts are futile or hurtful.  The staff is focused on keeping the patient alive.

Here’s a link to the article:

opinionator.blogs.nytimes.com/2015/08/26/the-i-c-u-is-not-a-pause-button

The End
The I.C.U. Is Not a Pause Button
The New York Times
By Kristen McConnell
August 26, 2015 4:15 am

Robin

 

 

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

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

—————————————————————

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

Exercise and dementia (research updates from Alzforum)

This post may be of general interest since many of us are dealing with dementia or will be dealing with dementia at some point in our lives.

At the recent Alzheimer’s Association International Conference in Washington DC (mid-July), a lot of research was presented on exercise.  The Alzforum has two good summaries of the research.

The first summary is here:

alzforum.org/news/conference-coverage/exercise-boosts-cognition-symptomatic-disease

The first summary examines research into whether Alzheimer’s disease can be tempered by aerobic exercise and whether dementia can be avoided through exercise:

“Speakers…presented new evidence that regular aerobic exercise can help people in prodromal disease stages maintain their cognition, while for those with full-blown dementia it relieves neuropsychiatric symptoms. Some studies provided hints that exercise can also hone thinking at the dementia stage, but only if the participants reach moderate intensity heart rates during their workout. Exactly how exercise helps the brain is still not known, but several talks reported better cerebral blood flow and improved structural and functional connectivity in exercisers, and even some signs that six months or more of physical activity can slow pathology.  Researchers agreed that the duration and intensity of an exercise intervention are crucial to determining its effects. For aerobic exercise in particular, the field is standardizing methods and narrowing in on the appropriate dose to prescribe. Some believe supervised exercise classes could become part of the standard of care for people with cognitive problems. … Researchers have few doubts now that exercise protects normal older adults against brain decline.”

(prodromal = before symptoms appear)

The second summary is here:

alzforum.org/news/conference-coverage/can-exercise-slow-progression-alzheimers-pathology

The second summary explores research into whether exercise can slow the progression of a neurodegenerative process:

“Overall, the findings indicated that working out enhances vascular brain health and connectivity, implying a direct benefit to brain structure and function. Data were mixed on whether exercise slows the progression of underlying Alzheimer’s pathology, however. One six-month study of moderate aerobic exercise reported a drop in cerebrospinal fluid tau in cognitively impaired people, but a shorter intervention failed to budge brain amyloid in people with AD. In general, speakers agreed that the cognitive boost from exercise likely comes from diverse benefits on several different aspects of brain function, something that would be hard to match pharmacologically.”

Both summaries are worth reading if exercise research is of interest.

While this may be a good day to go to the gym, this is probably not a good day to exercise outdoors.

Stay cool,
Robin

Tau imaging research and how tau may spread (Alzforum update)

This post may be of interest to those in the PSP and CBD community who are interested in what’s happening in research, particularly imaging of tau, as well as a hypothesis of how tau spreads in the spread.

Alzheimer’s is a disorder of two kinds of proteins — tau and amyloid (or beta amyloid, Aβ).  PSP and CBD are disorders of one kind of protein — tau.

At the recent Alzheimer’s Association International Conference in Washington DC (mid-July), scientists reported on data from tau PET imaging.  Three ligands or chemical tracers from La Roche are being studied, with one seeing superior results.  The data also provide clues as to how tau may spread in the brain.

The Alzforum has a good summary of the tau imaging research presented at the conference:

“…tau imaging data bolstered the idea that tau sits tight in the medial temporal lobe until Aβ builds up, then it spreads, wreaking havoc on cognition. New imaging data suggests that once it breaks loose, tau spreads through functional networks and impairs brain metabolism. What’s more, unlike Aβ, which appears diffusely throughout the brain, tau deposits seem to map closely onto regions where atrophy occurs and cognitive deficits originate. ‘Unlike amyloid imaging, tau PET seems to strongly correlate with cognition and clinical states,’ said Gil Rabinovici, University of California, San Francisco. Researchers were also excited by a new tau ligand that appears to have better specificity and kinetics than its predecessors.”

Here’s a bit more on tau building up in certain brain regions, as in corticobasal syndrome (CBS), and the relevance of tau as a target:

“Disaster Strikes Wherever Tau Lands
Once outside the medial temporal lobe, tau seems to cause trouble wherever it lands. At AAIC, Daniel Schonhaut, who works with Rabinovici, expanded on the notion that tau builds up in brain regions thought to underlie clinical symptoms in patients with atypical forms of AD. He compared performance on a variety of cognitive tests with T807/AV1451 scans from 19 patients with typical and atypical forms of AD, including posterior cortical atrophy, primary progressive aphasia, and corticobasal syndrome.  Schonhaut reported that people with typical AD who performed more poorly on memory tasks had more tau in the hippocampus and surrounding medial temporal areas, while patients with worse visual function indicative of posterior cortical atrophy had more tau in occipital regions. A third group — those with language difficulties typical of primary progressive aphasia — had more tau in the left temporoparietal region. ‘The distribution patterns of tau we’re seeing with this PET tracer seem to underlie the clinical phenotype of our patients,’ Schonhaut told Alzforum.  ‘These data show nicely that there’s a relationship between where the tau is clinical symptomatology,’ said Jagust. ‘We haven’t seen that with amyloid.’ Rabinovici noted that these results corroborate findings from classic postmortem studies demonstrating that cognitive state correlates much more strongly with tangle than amyloid pathology. They also support tau as a therapeutic target, particularly in the symptomatic phase of AD, he told Alzforum.”

The entire Alzforum research summary is worth reading, if research is of interest:

www.alzforum.org/news/conference-coverage/new-imaging-data-tells-story-travelling-tau

Stay cool,
Robin

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

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

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)

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

—————————————————————

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).

Local Case – Man Diagnosed with MSA During Life But X-ALD Upon Brain Donation

This email may be of most interest if you are dealing with MSA that began younger than average with atypical symptoms.  Or if you are interested in what can be learned from post-mortem studies of brains of people diagnosed with MSA while alive.

This article in the journal Neuropathology was published yesterday.  I’m certain it is about a local support group member whose husband supposedly had MSA but, upon brain donation, it was identified that he had a very rare disorder called X-linked adrenoleukodystrophy (X-ALD).  This is the same disorder as the child in Lorenzo’s Oil had.   I believe this disease may be inherited but the donor had no living relatives to investigate.  Note that there is no treatment for adult-onset X-ALD.

The donor had neurological symptoms for over 30 years, and died last year at the age of 69.  The last several years of his life, he was diagnosed with MSA because of cerebellar ataxia, gait problems, speech problems, and autonomic dysfunction.  “A diagnosis of X-ALD was never entertained during his life. He had long disease duration (35 years) and lacked characteristic MRI findings of X-ALD (and of MSA).”

There are only 33 other cases of cerebello-brainstem dominant X-ALD reported worldwide.  Most of the other cases had a family history of X-ALD or Addison’s Disease, adrenal insufficiency or T2-weighted hyperintensities in certain brain areas on MRI.  Our local support group member’s husband had none of these characteristics.  In his case, the “T2 signal abnormalities were interpreted as being due to microvascular pathology common in aging.”  Note that most of the other cases are from Japan and South Korea.

Despite the rarity of X-ALD, the researchers argue that X-ALD should be considered as a differential diagnosis in MSA, especially in younger patients with atypical symptoms.  This sounds like a red herring to me, but I’m anxious to ask some neurologists about this idea.

The Discussion section of the article is interesting in that it reviews details and comparisons of the 34 confirmed X-ALD cases.  I think this is enough for most of you but if you want more, check out the full article.  I’ve also copied the abstract below.

Robin

——————————-

Neuropathology. 2015 Jul 31.Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review.

Ogaki K, Koga S, Aoki N, Lin W, Suzuki K, Ross OA, Dickson DW.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy-confirmed cases exceedingly rare. We report a 69-year-old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be considered in the differential diagnosis of MSA.

© 2015 Japanese Society of Neuropathology.

PMID:  26227820