Is neurology research finally breaking the resolve of MND?

Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrig disease.

By Goudey [Public domain], via Wikimedia Commons
By Goudey [Public domain], via Wikimedia Commons

MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.

Associations: Thiamine deficiency and Diabetes 

By Jynto [CC0], via Wikimedia Commons
By Jynto [CC0], via Wikimedia Commons
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.

Another reported association, more difficult to fathom, is the one between MND and diabetes mellitus. The report in the European Journal of Neurology is titled Association between diabetes and amyotrophic lateral sclerosis in Sweden. Why am I sceptical?

Risk factor: Human endogenous retrovirus K (HERV K) 

Retrovirus capsid. A J Cann on Flikr.
Retrovirus capsid. A J Cann on Flikr.

The cause for MND remains unknown. Risk factors however abound such as smoking and other environmental risk factors. You may now add human endogenous retrovirus K (HERV K) to that list. This is according to a recent paper in Science Translational Medicine titled Human endogenous retrovirus-K contributes to motor neuron disease. The authors report that HERV K is activated in some people with MND, and it is the envelope proteins that cause damage to tissues. The US National Institutes of Health (NIH) think this is an important development, and it released a press statement titled Dormant viral genes may awaken to cause ALS. Scary! Is this important, or just another risk factor? Only time will tell.

Pathology: Neuromuscular junction inflammation 

By Elliejellybelly13 - Own work, CC BY-SA 4.0,
By Elliejellybelly13Own work, CC BY-SA 4.0,

This sounds almost sacrilegious- the thought that inflammation may really play a role in MND. And at the neuromuscular junction (NMJ), not the anterior horn cells. Well, some researchers are ready to commit blasphemy; publishing in Experimental Neurology, the authors showed evidence of inflammation in the muscles and NMJs of rat models of MND. They went further to show that injecting a growth factor called GDNF reduced this inflammation. Do I perceive a potential treatment pathway? Read all about it if you dare, its titled Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).

Treatment target: TDP-43 protein 

By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….

Diagnostic test: Nerve ultrasound

By Oleg Alexandrov - self-made with MATLAB, Public Domain,
By Oleg Alexandrov – self-made with MATLAB, Public Domain,

Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.

Researchers have now reported that ultrasound may be more sensitive in distinguishing MND from MMN. Another sacrilegious thought! They published their paper in Journal of Neurology with a rather long title: Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). Could the diagnosis of MND really be this simple? I am concerned that there were only 16 subjects with MND in the study, all from one centre. Perhaps a randomised, multi-centre, trial will come to the rescue?

Diagnostic biomarker: Brain iron deposition 

By Oleg Alexandrov - self-made with MATLAB, Public Domain,
By Oleg Alexandrov – self-made with MATLAB, Public Domain,

Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.

Prognostic biomarker: Neurofilament light chain (NfL) 

Neurofilament and MBP. Dan O'Shea on Flikr.
Neurofilament and MBP. Dan O’Shea on Flikr.

The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.

Prognostic scale: ALS-MITOS predictive system

A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!

Treatment: Copper 

By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)"derivative work: Materialscientist (talk) - Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0,
By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)”derivative work: Materialscientist (talk) – Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0,

There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of  mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.

The paper has a rather cumbersome title: Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. The result is however anything but. The technique extended the lives of the mice by an average of 18 months. Unbelievable it seems. Any doubts however vanished when, on stopping the treatment, the mice died within 3 months. The finding is exciting enough for Eureka Alert to run the story with the headline New therapy halts progression of Lou Gehrig’s disease in mice. ‘Halt’ sounds very much like ‘cure’, but lets put the brakes on and wait for confirmation in human trials .

Treatment: Gene therapy

Gene_therapy. 1Droid JamLos on Flikr.
Gene_therapy. 1Droid JamLos on Flikr.

Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex. The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.

Treatment: Stem cell therapy

By Ryddragyn at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain,
By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain,

Where gene therapy goes, stem cell therapy seems to follow. And this comes from JAMA Neurology with a classic unwieldy academic title: Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis. The content isn’t any easier to interpret, and I will not pretend I get it at all. I comfort myself that it’s all at the ‘open-label, proof of concept‘ stage, and only the very brainy brains need to delve further. But it seems to offer hope.

By Jim Campbell/Aero-News Network - /, Public Domain,
By Jim Campbell/Aero-News Network – /, Public Domain,


The sky is surely the limit. Here are a couple of other headlines if you wish to explore further:




How bright is the future for Alzheimer’s disease?

Alzheimer’s disease (AD) is scary. It is the most prevalent cause of dementia, and the name strikes terror, especially to those with a close family history of the condition. It is disturbing when a person loses the concept of ‘self’. It is devastating when parents fail to recognise their children.

Any progress in finding the cause or the cure for this neurodegenerative disease should therefore be celebrated. Following on my previous post, Alzheimer’s disease: a few curious things, here are my top 10 breakthroughs giving hope for Alzheimer’s disease.

Deep brain stimulation (DBS)

By Andreashorn - Own work, CC BY-SA 4.0,
By AndreashornOwn work, CC BY-SA 4.0,


I have waxed lyrical on the widening influence of neurostimulation in the context of epilepsy, stroke and vagus nerve stimulation (VNS). I was however taken aback by the potential role of deep brain stimulation (DBS) in dementia. This headline from reports the Benefits of Deep Brain Stimulation for Alzheimer’sand refers to a study published in eLife. This doesn’t sound a very ‘peer-reviewed’ source, but the title is scientific enough: Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats. I should warn you here that most of the studies in this post involve furry little creatures! The study reports that chronic electrical stimulation of the brain increases the activity of memory-related genes, and this in turn increases the number of memory nerves in the hippocampus. puts it bluntly-Using Deep Brain Stimulation to Create New Brain Cells.

Iron-reducing treatments

By Vaccinationist - PubChem, CC BY-SA 4.0,
By VaccinationistPubChem, CC BY-SA 4.0,


Based on a premise that high brain iron levels are related to the pathology in Alzheimer’s disease, researchers have looked at iron reducing therapies. This isn’t a new idea because an article in Lancet from 1991 was titled Intramuscular desferrioxamine in patients with Alzheimer’s disease. This study showed that the progression of Alzheimer’s disease could be slowed down by reducing the iron levels in the brain. New Scientist has brought this therapeutic strategy back into contention in its article titled Iron levels in brain predict when people will get Alzheimer’s. The article tantalisingly refers to a link between high iron levels and ApoE4, a gene associated with Alzheimer’s disease. Watch this space.

Ultrasound therapy

By Unknown - Popular Science Monthly Volume 13, Public Domain,
By UnknownPopular Science Monthly Volume 13, Public Domain,


New Alzheimer’s treatment fully restores memory function, so blares this headline in Science Alert. It refers to a study in mice which shows that focused therapeutic ultrasound stimulates microglia, the cells responsible for clearing the brain’s waste products. The paper, published in Science Translational Medicine, is titled Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. The authors report that that by clearing amyloid, this technique restored memory in about 75% of mice models of Alzheimer’s disease. Human trials must surely beckon.

Dampening amyloid production

By Nephron - Own work, CC BY-SA 3.0,
By NephronOwn work, CC BY-SA 3.0,


The idea of dampening the production of amyloid comes from the discovery of a new chemical pathway in the brain; I didn’t realise there were any more pathways left to discover! My ignorance was dispelled by this article in MNT titled A newly discovered molecular feedback process may protect the brain against Alzheimer’s. The article discusses WAVE-1, a protein which is central to a pathway involved in ß-amyloid production. How could scientists could suppress this pathway and improve the clearance of ß-amyloid? By somehow enhancing an inhibitory feedback loop thereby reducing WAVE-1 production. The scientific details are published in Nature Medicine titled APP intracellular domain–WAVE1 pathway reduces amyloid-β production

Monoclonal antibodies

B0007277 Monoclonal antibodies Anna Tanczos. Wellcome Images
B0007277 Monoclonal antibodies
Anna Tanczos. Wellcome Images


It would be surprising if monoclonal antibodies did not crop up in this post, being the rage in many other diseases. The monoclonal antibody raising hopes in Alzheimer’s disease is Solanezumab. I came across this in Russia Today (yes…RT) in an article titled Alzheimer’s breakthrough? First ever drug found that may slow disease. ‘First ever’ is obviously hype, but there does seem to be some benefit of Solanezumab, even if this is restricted to those with early disease.  The phase 3 trial of Solanezumab, called EXPEDITION 3, will study this effect further. More hope, less hype!

Boosting the brain’s immune system

B0007277 Monoclonal antibodies Anna Tanczos. Wellcome Images
B0007277 Monoclonal antibodies
Anna Tanczos. Wellcome Images


Microglia, the brain’s waste disposal cells, also play a key role in it’s immune system. In this way they protect the brain from damage by ß-amyloid. This immune function is however countered by EP2, a prostaglandin receptor protein found on the surface of the microglia. In other words EP2 functions to restrict the activity of the microglia. Researchers have now shown that the nuisance effect of EP2 could be blocked, as reported in an article titled Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models, and published in Journal of Clinical Investigation. Enhancing the activity of microglia therefore raises hope for the treatment for Alzheimer’s disease… if it could be translated to humans.

Neurotrophic factors

Brain Aging. Kalvicio de las Nieves on Flikr.
Brain Aging. Kalvicio de las Nieves on Flikr.


What if we could boost the activity of cells that have not yet been affected by Alzheimer’s disease? An experimental drug called J147 might just do that. According to researchers, J147 is a neurotrophic drug which enhances nerve activity in mice. The research, appropriately published in the journal Aging, shows that J147 improves cognitive function in mice which have been modified to age fast. The article is titled A comprehensive multiomics approach toward understanding the relationship between aging and dementia. I personally prefer the headline in Neuroscience News which simply says Experimental Alzheimer’s Drug Slows Clock on Key Aspects of Aging. Too soon to speculate, but could we be talking age reversal here? Perhaps competition for klotho.

Enhancing proteasome activity

By User:KGH - User:KGH, <a href="" title="Creative Commons Attribution-Share Alike 3.0">CC BY-SA 3.0,
By User:KGHUser:KGH, <a href=”; title=”Creative Commons Attribution-Share Alike 3.0 
“>CC BY-SA 3.0,


We can’t get too far away from waste clearance in this post. This time it’s a drug called Rolipram which seems to enhance the brains waste disposal system. It does this by increasing the activity of proteasomes. Neuroscience News describes a proteasome as ‘a hollow, cylindrical structure which chews up defective proteins into smaller pieces that can be recycled into new proteins needed by a cell‘. The scientific paper is published in Nature Medicine titled Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. The authors show that Rolipram also reduces the levels of tau, another toxic product involved in Alzheimer’s disease. For an easier read see the Neuroscience News article titled Slowing Alzheimer’s by Speeding Up Brain’s Waste Disposal.

Gene therapy

There is no getting away from it, and gene therapy had to crop up in this post. And yes, it may have a role in the future of Alzheimer’s disease. Researchers genetically treated 10 Alzheimer’s disease patients using nerve growth factor (NGF) gene, and then waited and waited, …and then studied the brains of the subjects. They reported their findings the Journal of the American Medical Association (JAMA) under the title Nerve Growth Factor Gene Therapy Activation of Neuronal Responses in Alzheimer Disease. The details of the study are rather complicated, but it appears the nerve growth factor treatment triggered nerve growth. Doesn’t sound like rocket science but imagine the potential. I only wished they had used a more straightforward title. I prefer the layman’s version in The Guardian simply titled Gene therapy rescues dying cells in the brains of Alzheimer’s patients. Scientific journals really need better headline writers!

Reprogramming astroglia

A cocktail mixture which transforms the brain’s supporting cells into proper nerve cells? Not science fiction it seems. A group of scientists have developed a mixture which could reprogram glial cells into functional brain cells. I came across this in Neurology Times under the title Transforming Glial Cells. For a change, the original research paper is well headlined; it is published in Cell under the title Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. The authors show that the cocktail of nine small molecules do the trick by inhibiting glial pathways and activating neuronal pathways. And this all happens within 8-10 days! Too good to be true? Hopefully not.


Looking for more? Here are 13 headlines to further raise the spirits of people with Alzheimer’s disease:

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10 remarkable breakthroughs that will change neurology

This is the age of rapidly advancing technology. Blink, and the scene changes unrecognisably. It would be unbelievable if we weren’t actually living it. What technological advances will impact Neurology in the near future? Here are my top 10 neurology-impacting technologies.

1. Nanotechnology to deliver clot-busting drugs

CSIRO [CC BY 3.0 (], via Wikimedia Commons
CSIRO [CC BY 3.0 (, via Wikimedia Commons

Clot-busting or thrombolysis is life saving treatment following stroke. This however requires getting to hospital within 4.5 hours of the event, and is given by intravenous injections. How much better if it would be if thrombolysis could be delivered by mouth, and at the point of contact with paramedics. Indeed this is the idea behind clot-busting nanocapsules. Nanoparticles may also have future applications in prevention of MS relapses.

2. Disease-monitoring wearables

What if people with epilepsy could predict their next seizure? Or if someone with multiple sclerosis (MS) could predict an impending relapse? Well,  wearable technology promises to do just that. This goes beyond the fitbit which measures basic biological processes; these technologies will monitor realtime data such as a watch that measures skin moisture for seizure-prediction, or an iPad strapped to the back to monitor walking speed of patients with MS. I predict this technology will rapidly spread to many other chronic neurological diseases.

3. Nanoscale-resolution brain imaging

From the humble X-ray to the CT scan, brain imaging has progressed in leaps and bounds to a proliferation of MRI modalities with ever-increasing resolution or power. But nanoscale resolution imaging promises to make things more SciFi than healthcare. With the ability to look at ‘every nook and cranny‘ of the brain, this technology will visualise brain connections with incredible detail. Imagine how this will enhance diagnostic accuracy (and diagnostic conundrums in equal measure). This work is still in mice butI’m sure human application will follow shortly.

4. High-resolution eye selfies

Mobile phones are ubiquitous and the camera function seems to be more valuable than the talk mode. What with the number of selfies proliferating like a rah over social media. This may however be of advantage to healthcare. As the camera resolution increases exponentially, eye-selfies may come to the aid of neurologists and  ophthalmologists who treat patients with a condition called idiopathic intracranial hypertension (IIH). In this condition the pressure of the fluid around the brain is elevated. This shows as a blurring of the margins of an area called the disc and this is seen in the back of the eye using an ophthalmoscope. With advanced mobile phone cameras patients with IIH could make an eye-selfie diagnosis or assist in monitoring their eyes themselves.

5. Wireless brain EEG monitoring

Thinker Thing.
Attribution: Thinker Thing.


The electroencephalogram (EEG) is an invaluable tool for making the diagnosis of epilepsy. The process requires a time-consuming application of several electrodes to specific points on the scalp. The electrodes are then connected by wires or leads to a machine which records the brains electrical activity. This cumbersome process is time consuming especially for patients that need to keep the wires on for days. To the rescue is the wireless brain helmetThis will not only make the recording easier, it will send the recording wirelessly to the physiologist who will interpret the test. More interestingly, it will allow receive signals sent by the physiologist which will be targeted to treat epilepsy or other conditions like depression. The NeuroPace’s RNS system is one such device leading the way.

6.Wireless drug delivery

This is another wireless technology which facilitates the direct delivery of drugs into the brainThe device, not thicker than a human hair, is implanted into the brain and wirelessly controlled to deliver the required dose of drug, at specified times. The likely beneficiary diseases are epilepsy and depression (again). It is still in the stage of trials in mice but coming to your neighbourhood hospital very soon. If you want the complicated details then see the journal Cell for the research paper titled Wireless Optofluidic Systems for Programmable In-vivo Pharmacology and Optogenetics. What a mouthful!

7. Suicide-prediction technology

By RyanJWilmot (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
By RyanJWilmot (Own work) [CC BY-SA 4.0 (, via Wikimedia Commons

A blood test to warn of the risk of impending suicide? Wouldn’t that be great? It is not a far-fetched dream if reports that a blood test for RNA biomarkers of suicidal thoughts fulfils its potential. This will have psychiatrists whooping for joy-or out of a job!

 8. Optogenetics

Optogenetics is the use of light to control cells. This has the potential to alter nervous system function with exciting prospects for disease treatment. Again epilepsy appears to be a prime beneficiary if this takes off. Imagine programming a brain cell or neurone to glow red when calcium flows into it. This glow then dampens the activity of neighbouring cells thereby inhibiting any rouge electrical impulse that may result in an epileptic seizure. The process requires the injection of a genetically engineered virus which infects the brain cells. This ability to modify brain cell behaviour also has implications for the treatment of Parkinson’s disease (PD) and depression among other things. More SciFi you say.

9. Gene therapy for muscular dystrophy

Genetic therapy is an old dog that is still barking. This is just as well because it remains the only hope for many genetic conditions.  Genetic therapy has had its ups and downs and a very recent high is the positive outcome in leukaemia. Neurology is however not too far behind if this report that muscular dystrophy gene therapy has been successful in dogs is translated to humans. The research is rather complex but the academically minded may be interested in details of the trial.

10. Molecular spies for early cancer detection

A molecular spy is an antibody probe that is directed at the brain to detect and destroy ‘rogue’ cells. The leading researcher for this is Sam Gembhir who is based at the Canary Center at Stanford for Cancer Early Detection. Best to hear it from the horse’s mouth- speaking here at a TED talk.” target=”_blank”>

Follow the links below for more on this topic: