What’s happening at the cutting edge of MSA?

Multiple system atrophy (MSA) is a mimic of Parkinson’s disease (PD). Neurologists suspect MSA in people with apparent PD who, in addition, have other defining features. In many people with MSA their prominent symptoms are cerebellar dysfunction (MSA-C), and these have unsteadiness and incoordination of movements. In other people with MSA the predominant symptoms are of Parkinsonism, and this type is called MSA-P.

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7769113
By Images are generated by Life Science Databases(LSDB). – from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7769113

Making a diagnosis of MSA is gratifying, but treating it is frustrating. Only about a third of people with MSA respond to the standard PD medication, Levodopa. Furthermore, MSA confers a shortened life expectancy. It is therefore important that neurologists resolve the mystery of MSA, and they are indeed hacking away at its cutting-edge.

Genetics

The general assumption is that MSA is acquired rather than inherited. This assumption did not dissuade neurologists from looking for MSA genetic risk factors, and their quest has led to the discovery of a candidate MSA gene. This is called coenzyme Q2 4-hydroxybenzoate polyprenyltransferase, or simply the COQ2 gene. This gene was first touted in a 2013 paper in the New England Journal of Medicine titled Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy. Using whole genome sequencing, the authors identified COQ2 gene mutations in both sporadic and familial cases of MSA. Another paper in Neurology in 2016, titled New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy, reported that the COQ2 gene mutation is more likely in MSA-C than in other types of MSA.

You may explore the genetics of MSA further in this paper in Neurobiology of Aging titled Genetic players in multiple system atrophy: unfolding the nature of the beast.

Differential diagnoses

When neurologists are considering the diagnosis of MSA, they come up against many disorders jostling to confuse them. There are of course PD and related conditions such as progressive supranuclear palsy (PSP). There is also the endless list of conditions which cause either cerebellar or autonomic dysfunction. The neurologist is usually cautious to exclude these known differential diagnoses of MSA. But what happens when they come across a mimic that isn’t in the textbooks? Such is the situation with this case report published in Movement Disorders of Concomitant Facioscapulohumeral Muscular Dystrophy and Parkinsonism Mimicking Multiple System Atrophy.

This case defies the law of parsimony, Occam’s razor. To paraphrase, this law states that a single diagnosis is the most likely cause for a patient’s clinical features. Clearly in some cases such as this, the neurologist must disregard William of Occam, and make multiple diagnoses.

Investigations
Hot cross bun. Liliana Fuchs on Flikr. https://www.flickr.com/photos/akane86/5208128379
Hot cross bun. Liliana Fuchs on Flikr. https://www.flickr.com/photos/akane86/5208128379

Neurologists often request some tests to confirm their suspicion of MSA. The usual investigation is the painless but claustrophobic magnetic resonance imaging (MRI). In MSA, this shows shrinking or atrophy of the cerebellum. It may also show the hot cross bun sign, a characteristic pattern of shrinking of the chunky middle section of the brainstem, the pons.

Big MRI. liz west on Flikr. https://www.flickr.com/photos/calliope/223220955
Big MRI. liz west on Flikr. https://www.flickr.com/photos/calliope/223220955

Some neurologists are not satisfied with this culinary sign and have explored other radiological indicators of MSA. They studied an MRI technique called diffusion tensor imaging tractography (DTI tractography) and reported their findings in the Journal of Neurology. Their paper titled Characteristic diffusion tensor tractography in multiple system atrophy reports that DTI tractography appears to distinguish MSA-C from other causes of cerebellar dysfunction.

Biomarkers

Biomarkers again, so soon after my previous blog post, What is the state of parkinson’s disease biomarkers. The whole idea behind biomarkers is their potential to make for an easier and earlier diagnosis. They are all the rage in neurodegenerative diseases, and MSA can’t be an exception. The first potential MSA biomarker is α-synuclein, the abnormal protein that is found in the brains of people with PD, MSA and Lewy body disease (LBD), the so-called synucleopathies. Researchers have now discovered that α-synuclein also resides in the skin. They carried out skin biopsies in people with PD and MSA and found skin deposits of α-synuclein in both. Writing in the journal Movement Disorders, they showed that in PD, the deposits were mainly in autonomic nerve fibers, whilst in MSA they were in the larger somatic nerves. Time to brush up those skin biopsy skills!

The second potential biomarker is optical coherence tomography (OCT). This is reported in Movement Disorders in a paper titled Progressive retinal structure abnormalities in multiple system atrophy. The authors used OCT to measure the thickness of the retina of the eye. They demonstrated that the retina is thin in both PD and MSA, but the thinning advances more rapidly in MSA than in PD. If confirmed, this would be a handy, and painless, biomarker.

Potential treatments
Syringe and vaccine. Niaid on Flikr. https://www.flickr.com/photos/niaid/14329622976
Syringe and vaccine. Niaid on Flikr. https://www.flickr.com/photos/niaid/14329622976

The objective of all research is to arrive at effective treatments. There is unfortunately no bright treatment looming in the MSA horizon because the research so far have produced disappointing results. Such failures include Rifampicin, Fluoxetine and Lithium. There is however no scarcity of potential therapeutic candidates. The most exciting is a vaccine against MSA. For this and other research efforts read this excellent review in Advances in Clinical Neurology and Rehabilitation (ACNR) titled Updates on potential therapeutic targets in MSA.

 

 

What is the state of Parkinson’s disease biomarkers?

Neurologists are always cautious when making a diagnosis of Parkinson’s disease (PD). This shouldn’t be the case because PD is not difficult to recognise-at least not most of the time. For one, PD has classical clinical signs- the trio of resting tremor, slow movements (bradykinesia), and stiffness (rigidity). For another, it is asymmetrical, starting and remaining worse on one side of the body.

All these features are however vague in the early stages of PD. To make matters worse, there are many other diseases that mimic PD. These include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), corticobasal degeneration (CBD), and even SWEDDS (if it exists at all!). And always lurking in the shadows, waiting to catch the neurologist out, are dystonic tremor and essential tremor.

Marking Parkinson's. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544
Marking Parkinson’s. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544

 

These PD mimics challenge and intrigue neurologists in equal measure. They contribute to the delayed and missed diagnosis of PD in 20% of cases. Are there shortcuts out there to improve our diagnostic accuracy? A simple test perhaps? Maybe some biomarker? Here are 6 budding contestants.

1. Dopamine transporter (DAT) scans

Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD
Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD

DAT scans are now in general, even if not universal, use. They help to distinguish PD from conditions such as essential tremor or drug-induced Parkinsonism. DAT scans are however expensive, and they do not distinguish PD from many of its other mimics such as MSA, PSP, (you know the roll call). There are indications that DAT scans may be normal in cases of PD. We therefore clearly need better, cheaper (and newer!) PD biomarkers than DAT scans.

2. Cerebrospinal fluid (CSF) biomarkers

© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Perhaps the answer is in a spinal tap or lumbar puncture (LP). A lumbar puncture is a simple but dreaded test. It is however useful for giving us access to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Analysis of the CSF often gives the game away in many neurological disorders. It is not surprising therefore that researchers looked at a panel of nine CSF biomarkers that may identify PD. The paper, published in the JNNP, suggests that there may be biomarker roles for neurofilament light chain (NFL), soluble amyloid precursor protein (sAPP), and α-synuclein (of course). CSF α-synuclein is the focus of another paper in BioMedCentral which reports that one form, oligomeric α-synuclein, is the one to watch out for.

Another set of CSF biomarkers is related to blood vessel formation (angiogenesis). I came across this in a paper in Neurology titled Increased CSF biomarkers of angiogenesis in Parkinson disease. The authors are referring to vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. Others are placental growth factor (PlGF), angiopoietin 2 (Ang2), and interleukin-8. Enough to keep researchers busy for a while.

3. Peripheral blood biomarkers

Even the most compliant patient would prefer to have a blood test rather than a spinal tap. Thankfully there are some blood-based biomarkers in the offing. One set are called α-synuclein blood transcripts (SNCA transcripts). The authors of an article published in the journal Brain report that SNCA transcripts are consistently reduced in the blood of people with early PD. The accompanying editorial however cautions on the utility of these SNCA transcripts because low levels are also seen in some people who do not have PD. The true value of SNCA transcripts may lie in their ability to predict cognitive decline, but how many people really want to know that?

Other potential blood based biomarkers mentioned are uric acid and epidermal growth factor (EGF).

4. Retinal optical coherence tomography (OCT)

CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623
CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623

Even better than blood and spinal fluid biomarkers would be something totally painless. And to the rescue comes retinal optical coherence tomography (OCT). OCT uses light waves to take pictures of the retina. This allows measurement of the size of different parts of the retina; the area of interest in PD is called the foveal pit. A paper in Movement Disorders reports that OCT is a sensitive marker of PD. The authors show that the foveal pit in PD has a unique form; it is shallow in the superior-inferior and the nasal-temporal slopes. Perhaps neurologists will soon be running to ophthalmologists, cap-in-hand, to save their blushes.

5. Salivary gland α-synuclein

Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079
Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079

 

Back to painful biomarkers I’m afraid, all in aid of clinching an early diagnosis you must understand. This time it’s salivary gland biopsy. Some eager researchers took biopsy samples of the submandibular salivary glands of people with early PD. They then looked for, and found, α-synuclein in about 75% of them. Their paper is published in Movement Disorders titled Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings. Unfortunately  20% of control subjects without PD also had α-synuclein in their salivary glands. Could these people have pre-manifest PD? We must await larger and longer studies before we start needling away at the salivary glands of the worried-well.

6. Intestinal tract α-synuclein

What if the answer is not in the salivary glands? Then we should be really afraid because α-synuclein has popped up in …the intestines. A review paper in Movement Disorders describes this in the brilliantly titled Gut Feelings About α-Synuclein in Gastrointestinal Biopsies: Biomarker in the Making? Another paper published in PLOS One takes things further, reporting an association between intestinal α-synuclein with increased gut permeability. I’ll make no further comments on the gut; not with the threat of cameras and scopes going up all sorts of body openings.

α-synuclein staining of a Lewy body. By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521
α-synuclein staining of a Lewy body. By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

Below is a link to an open access article in Movement Disorders with more potential PD biomarkers

Are there any other biomarkers out there? Please leave a comment.

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Pareidolias-why we see non-existent faces

Human beings are prone to see patterns where none exist. This concept of pareidolias often has religious connotations, and has led to bouts of religious fervour. Wikipedia describes this as a psychological phenomenon wherein ‘the mind perceives a familiar pattern where none actually exists‘. The BBC recently explored why we see these patterns under the title ‘why we see faces in the hills, the moon and toasties‘.

"Holz Geist Gesicht" by Usien - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.
Holz Geist Gesicht” by UsienOwn work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

It is not surprising that artists have made free use of this human weakness to play mind tricks.

"Picture puzzle". Licensed under Public Domain via Wikimedia Commons.
Picture puzzle“. Licensed under Public Domain via Wikimedia Commons.

There are however more sinister implications of pareidolias (you would expect this from a brain doctor!). This tendency to see patterns may be a manifestation of complex hallucinations, typically seen in Lewy body disease and has been reported in Parkinson’s disease.

The tendency to see patterns has been used to good effect in neurological imaging. Many radiological diagnostic signs have been assigned names that reflect the false patterns they project on the human mind. This concept of neuropareidolia is excellently explored in this paper. Neurologists and radiologists for example talk of the hot cross bun sign in multiple system atrophy, the panda sign in Wilson’s disease, and the hummingbird sign in progressive supranuclear palsy (PSP). It seems we bring our humanity to the workplace!

"Archilochus-alexandri-003". Licensed under CC BY-SA 3.0 via Commons.
Archilochus-alexandri-003“. Licensed under CC BY-SA 3.0 via Commons.
"Steele-olszewski-richardson disease" by Dr Laughlin Dawes - radpod.org. Licensed under CC BY 3.0 via Commons.
Steele-olszewski-richardson disease” by Dr Laughlin Dawes – radpod.org. Licensed under CC BY 3.0 via Commons.

 

You may check out

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Top 10 abstracts from ANA 2015

Finally from ANA 2015, here are my top 10 abstracts/posters. My main criterion is posters that made me go ‘hmmm-that’s interesting!’

  • Musical hallucinosis occur in neurodegenerative disorders especially Lewy body disease (LBD)
  • Transcranial direct current stimulation (tDCS) may improve multiple sclerosis (MS) fatigue
  • Subjects with larger and closely knit social networks present earlier to hospital after ischaemic stroke

 

  • Patients with epilepsy are prone to orthostatic intolerance
  • Medical marijuana may be effective in controlling intractable seizures
  • Dropped head syndrome in multiple system atrophy (MSA) may respond to Amantadine

  • Hyponatraemia may predict in-hospital mortality in myasthenia gravis (MG)
  • Prostate cancer metastases to the ventricles may cause obstructive hydrocephalus
  • Rsing the leg off the couch elicits the Babinski response pyramidal tract dysfunction (the Pasupuleti sign)
  • Retinal fiber layer thickening may be a biomarker of Huntington’s disease (HD)

 

 

Parkinson’s disease-a few curious things

Quite a few neurological disorders remain mysteries even when we know so much about them. Parkinson’s diseases (PD) is one of them. Dopamine deficiency is the established final common pathway, but why this deficiency presents in different ways is unclear. PD variants such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and Lewy body disease (LDB) have distinct clinical features to confound any common cause. What then causes dopamine deficiency in the first place?

Substantia nigrai in PD. By Werner CJ., Heyny-von Haussen R., Mall G., Wolf S. [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons
Substantia nigrai in PD. By Werner CJ., Heyny-von Haussen R., Mall G., Wolf S. [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)%5D, via Wikimedia Commons

One link researchers are looking at is the possibility of a pathogen travelling up to the brain from the gut via the vagus nerve. This report from the Annals of Neurology suggests this hypothesis; the researchers found a reduced risk of PD in patients who have had the main trunk of the vagus nerve severed (vagotomy). For more details see a full analysis of the study here.

 

PD PET scan image.By Jens Maus (http://jens-maus.de/) - Own work. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:PET-image.jpg#/media/File:PET-image.jpg
PD PET scan image.By Jens Maus (http://jens-maus.de/) – Own work. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:PET-image.jpg#/media/File:PET-image.jpg

 

Clearly we can’t recommend vagotomy to our at-risk PD patients, and neither can we recommend gout! Yes, studies have suggested that PD patients have a low uric acid level, and this predates the disease onset. Another study takes things further to suggest that uric acid is neuroprotective because of its antioxidant effect. This long list of PubMed abstracts shows the proliferating research into uric acid.

 

Uric acid crystals. By cnicholsonpath (Uric acid) [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons
Uric acid crystals. By cnicholsonpath (Uric acid) [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)%5D, via Wikimedia Commons

And finally, again from the Annals of Neurology, is a paper reporting increased creativity in people with PD on dopamine replacement treatment. The study compares people with PD on treatment to control subjects. It is however not clear if the creativity is a feature of PD, or of its treatment.

Just a few curious things

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What is the value of celebrity neurology?

It is always headlines when a celebrity comes out with, or dies of, any disease. The disease often gets a boost, its profile raised high. We saw this with the ‘Jade Goody effect‘ which boosted cervical cancer screening. The same occurred with the ‘Angelina Jolie effect‘ which improved the provision of breast cancer services.

Angelina Jolie
Angelina Jolie

The celebrity effect also works in Neurology, although never as successfully as the examples above. Some single-minded neurology celebrities have tackled their diseases head-on, often by funding research. This is the case with the Michael J. Fox Foundation and Parkinson’s disease (PD).

Michael J Fox
Michael J Fox

The celebrity may support a charity on account of a family member with a condition such as JK Rowling aiding the Multiple Sclerosis Society in Scotland on behalf of her mother who had the disease; unfortunately they eventually fell out.

Most recently we learnt that Robin Williams had Lewy Body disease a variant of Parkinson’s disease, and he probably died from the hallucinations common in this disorder. Will this boost the profile Lewy body diseases? Will it improve research into its risk factors and treatment?

Robin Williams
Robin Williams

Sometimes its a celebrity event that does the trick. The ice bucket challenge raised millions for MND. The celebrity endorsements for the campaign was a boost for those fighting to eliminate the disease. And one of the best clips is of Benedict Cumberbatch-worth a look!

https://www.youtube.com/embed/YOa7ZjxRuKM” target=”_blank”>

But how valuable is a one-off benefit such as this? A lot it seems going by the MND Association feedback-£7m is not to be scoffed at!

On the theme of MND we see the example of a celebrity ‘endorsement’ of a different type. Stephen Hawking, the world-renowned theoretical physicist, has not been particularly bullish in his support of MND but his biopic, The Theory of Everything, has had an interesting effect;

https://www.youtube.com/embed/Salz7uGp72c” target=”_blank”>

A grandfather made a self-diagnosis of MND after watching the film. Talk of celebrity influence!

What of naming nerve cells after celebrities? Yes indeed. Heard of the Jennifer Aniston neuron? Neuroscientists have discovered that individual nerve cells learn to recocgnise specific faces, and Jennifer’s was a face they used in their trials. A lot of good it has done for her, but a clever way for neuroscience to embed their lesson in our minds; a very good use of celebrity.

By Angela George, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=6044960
By Angela George, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=6044960

Which other celebrities with neurological diseases have raised the profile of their condition, or influenced it, in any way at all? The subject for a blog sequel!

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What are the links between Prion diseases and Parkinsonian disorders?

Neurologists are familiar with prion diseases. And so is the general public, not least because of the mad cow disease scare. The quintessential prion disease is Creutzfeldt Jakob disease (CJD), and this is readily identified by its rapidly progressive course, and by typical blood, brain imaging, cerebrospinal fluid (CSF), and brain pathology features.

Public Domain, Link
Public Domain, Link

There has however been a lot of whispering speculation that some other neurological disorders are really prion diseases camouflaging as neurodegenerative conditions. Most of the speculation is around Parkinson’s disease (PD), with headlines such as, Is Parkinson’s Disease a Prion Disorder? and The prion hypothesis of Parkinson’s disease.

By Cornu (talk) 19:04, 5 June 2009 (UTC) - Own work, CC BY 2.5, Link
By Cornu (talk) 19:04, 5 June 2009 (UTC) – Own work, CC BY 2.5, Link

Pushing the ‘prion-like’ hypothesis comes a paper straight off the press asserting that multiple system atrophy (MSA) is likely to be a prion disease.Published in Proceedings of the National Academy of Sciences, the study demonstrates that human brain homogenates from MSA patients transmit α-synuclein, and produce neurological disease in susceptible mice. More importantly, specimens from Parkinson’s disease (PD) patients and normal controls did not transmit this activity.

By Marvin 101 - Own work, CC BY-SA 3.0, Link
By Marvin 101Own work, CC BY-SA 3.0, Link

MSA, along with other disorders such as progressive supranuclear palsy (PSP) and Lewy body disease (LBD) are really cousins of Parkinson’s disease (PD). It is interesting therefore that this transmissibility is only seen with MSA, and not even in PD. The findings however seem authentic enough, even if slightly still speculative. The paper however comes from one of the gurus of prion diseases, Stanley Prusiner. There must therefore be something about this prion hypothesis, and the next few papers will surely convert this into established theory. Or perhaps not, I hear you whisper.

Read more about prion diseases from the MRC Prion Unit and the CDC prion disease webpage

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