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. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/
Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/

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, https://commons.wikimedia.org/w/index.php?curid=40798702
By Elliejellybelly13Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702

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, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

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, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

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. https://www.flickr.com/photos/dan_oshea/4079086197
Neurofilament and MBP. Dan O’Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197

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, https://commons.wikimedia.org/w/index.php?curid=7223304
By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)”derivative work: Materialscientist (talk) – Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304

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. https://www.flickr.com/photos/jamlos/2734418031
Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031

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, https://commons.wikimedia.org/w/index.php?curid=2148036
By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036

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 - http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144
By Jim Campbell/Aero-News Network – http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144

 

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

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What are the most controversial questions in neurology?

Uncertainty and doubt abound in Neurology. There are many evidence-free areas where experts rub each other the wrong way. These controversies are big and occur in all neurology subspecialties. Controversy-busters have tried for about a decade to iron out these wrinkles on neurology’s face, but the unanswered questions remain. This is why there is a 10th World Congress of Controversies in Neurology (CONy) holding in Lisbon this year.

I want to assure you I have no conflict of interest to declare in this blog. My interest is to explore  which questions have plagued this conference over the last 10 years to pick out the most controversial topics in neurology. To do this I reviewed all previous conference programs and focused on the items that were slated for debate. I looked for practical topics that have remained unresolved, or are just emerging. Here are my top controversial neurological questions:

Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402
Raccoon argument II. Tambako The Jaguar on Flikr. https://www.flickr.com/photos/tambako/7460999402

 

1st CONy 2007 (Berlin, Germany)

  • Clinically isolated syndromes (CIS): To treat or not to treat
  • Is stem cell therapy an imminent treatment in advanced multiple sclerosis (MS)?
  • Vascular cognitive impairment is a misleading concept?
  • Is mild cognitive impairment a misleading concept?

 

2nd CONy 2008 (Athens, Greece)

  • Can physical trauma precipitate multiple sclerosis?
  • Should patients with Parkinson’s disease (PD) be treated in the pre-motor phase?
  • What is the first line therapy for chronic inflammatory demyelinating polyneuropathy (CIDP)?
  • Is intravenous immunoglobulin (IVIg) effective in chronic myasthenia gravis (MG)?
  • Tau or ß-amyloid immunotherapy in Alzheimer’s disease (AD)?
  • Chronic fatigue syndrome is an organic disease and should be treated by neurologists?

 

3rd CONy 2009 (Prague, Czech Republic)

  • Should cerebrospinal fluid (CSF) be tested in every clinically isolated syndrome?
  • Can we prevent multiple sclerosis (MS) by early vitamin D supplementation and EBV vaccination?
  • Does Parkinson’s disease (PD) have a prion-like pathogenesis?
  • Patients with medication overuse headache should be treated only after analgesic withdrawal?

 

 

4th CONy 2010 (Barcelona, Spain)

  • Camptocormia in parkinson’s disease (PD): Is this dystonia or myopathy?
  • Does chronic venous insufficiency play a role in the pathogenesis of multiple sclerosis (MS)?
  • IVIg or immunosuppression for long-term treatment of CIDP?

 

5th CONy 2011 (Beijing, China)

  • Is sporadic Parkinson’s disease etiology predominantly environmental or genetic?
  • Is multiple sclerosis (MS) an inflammatory or a primarily neurodegenerative disease?
  • Are the new multiple sclerosis oral medications superior to conventional therapies?
  • Is bilateral transverse venous sinus stenosis a critical finding in idiopathic intracranial hypertension (IIH)?

 

6th CONy 2012 (Vienna, Austria)

  • Will there ever be a valid biomarker for Alzheimer’s disease (AD)?
  • Is amyloid imaging clinically useful in Alzheimer’s disease (AD)?
  • Do functional syndromes have a neurological substrate?
  • Should blood pressure be lowered immediately after stroke?
  • Migraine is primarily a vascular disorder?

 

 

7th CONy 2013 (Istanbul, Turkey)

  • Is intravenous thrombolysis the definitive treatment for acute large artery stroke?
  • Atrial fibrillation related stroke should be treated only with the new anticoagulants?
  • Is the best treatment for chronic migraine botulinum toxin?
  • IS CGRP the key molecule in migraine?
  • Is chronic cluster headache best treated with sphenopalatine ganglion (SPG) stimulation?
  • When should deep brain stimulation (DBS) be initiated for Parkinson’s disease?
  • Do interferons prevent secondary progressive multiple sclerosis (SPMS)?
  • Is deep brain stimulation (DBS) better than botulinum toxin in primary dystonia?
  • Are present outcome measures relevant for assessing efficacy of disease modifying therapies in multiple sclerosis (MS)?
  • Should radiologically isolated syndromes (RIS) be treated?
  • Does genetic testing have a role in epilepsy management?
  • Should cortical strokes be treated prophylactically against seizures?
  • Should enzyme-inducing antiepileptic drugs (AEDs) be avoided?
  • EEG is usually necessary when diagnosing epilepsy

 

8th CONy 2014 (Berlin, Germany)

  • Is late-onset depression prodromal neurodegeneration?
  • Does Parkinson’s disease begin in the peripheral nervous system?
  • What is the best treatment in advanced Parkinson’s disease?
  • Are most cryptogenic epilepsies immune mediated?
  • Should epilepsy be diagnosed after the first unprovoked seizure?
  • Do anti-epileptic drugs (AEDs) contribute to suicide risk?
  • Should the ketogenic diet be prescribed in adults with epilepsy?
  • Do patients with idiopathic generalized epilepsies require lifelong treatment?
  • Cryptogenic stroke: Immediate anticoagulation or long-term ECG recording?
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825
Southern Chivalry: Argument Vs Clubs. elycefeliz on Flikr. https://www.flickr.com/photos/elycefeliz/6271932825

 

9th CONy 2015 (Budapest, Hungary)

  • Is discontinuation of disease-modifying therapies safe in  long-term stable multiple sclerosis?
  • Is behavioral therapy necessary for the treatment of migraine?
  • Which is the first-line therapy in cases of IIH with bilateral papilledema?
  • Should patients with unruptured arterio-venous malformations (AVM) be referred for intervention?
  • Should survivors of hemorrhagic strokes be restarted on oral anticoagulants?
  • Will stem cell therapy become important in stroke rehabilitation?
  • Do statins cause cognitive impairment?

 

10th CONy 2016 (Lisbon, Portugal)

  • Which should be the first-line therapy for CIDP? Steroids vs. IVIg
  • Should disease-modifying treatment be changed if only imaging findings worsen in multiple sclerosis?
  • Should disease-modifying therapies be stopped when secondary progressive MS develops?
  • Should non-convulsive status epilepsy be treated aggressively?
  • Does traumatic chronic encephalopathy (CTE) exist?
  • Does corticobasal degeneration (CBD) exist as a clinico-pathological entity?
  • Is ß-amyloid still a relevant target in AD therapy?
  • Will electrical stimulation replace medications for the treatment of cluster headache?
  • Carotid dissection: Should anticoagulants be used?
  • Is the ABCD2 grading useful for clinical management of TIA patients?
  • Do COMT inhibitors have a future in treatment of Parkinson’s disease?

 

Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203
Debate Energetico. Jumanji Solar on Flikr. https://www.flickr.com/photos/jumanjisolar/5371921203

 

Going through this list, I feel reassured that the experts differ in their answers to these questions? The acknowledgement of uncertainty allows us novices to avoid searching for non-existent black and white answers. It is however also unsettling that I thought some of these questions had been settled long ago. It goes to show that apparently established assumptions are not unshakable?

Do you have the definitive answers to resolve these controversies? Are there important controversies that are missing here? Please leave a comment

 

Will these 10 cutting-edge advances boost stroke care?

Stroke is a global beast. It is a scourge of the young and old. It strikes suddenly, maiming and killing with wanton abandon. So much has been achieved in the attempts to tame the monster, and yet victory still seems a far-off mirage. What are in the pipelines, beyond Aspirin and Statins? What may improve the outlook beyond intravenous clot busters and intensive rehabilitation? What is the likely future of stroke care? Here is a countdown of my top 10 cutting-edge stroke advances. 

10. Uric acid therapy

By AbcdKolya (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons
By AbcdKolya (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)%5D, via Wikimedia Commons

Uric acid is a villain as anyone with gout will attest. And yet there have been recent reports of the benefit of this chemical in neurological diseases. I have previously posted on the protective effect of uric acid on Parkinson’s disease (PD). In its further attempt to change its status from sinner to saint, uric acid is creeping into the world of stroke. A recent article in the journal Stroke is titled Uric Acid Therapy Improves Clinical Outcome in Women With Acute Ischemic Stroke. It was used in conjunction with conventional clot busting of course. Uric acid appears to reduce the growth of the infarct-the part of the brain that is irreversible damaged after a stroke. Why is it only women who benefit? Testament to the fact that it is not so easy to redeem a sullied image.

9. Transdermal glyceryl trinitrate (GTN)

"Nitrogylcerin (3D ball-and-stick model)" by Woodenchemist - Own work. Licensed under Public Domain via Commons.
Nitrogylcerin (3D ball-and-stick model)” by WoodenchemistOwn work. Licensed under Public Domain via Commons.

 

Yes, the simple GTN, popular with those who suffer angina.GTN works in angina by dilating (widening) the arteries thereby improving blood flow to the heart. Why can’t the same effect be expected with the narrow or blocked arteries that lead to stroke? Indeed the effect appears to be the same on the brain as it is on the heart as reported in this article in Stroke titled Effect of Hyperacute Administration (Within 6 Hours) of Transdermal Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome After Stroke. The authors showed that applying GTN through a skin patch within 6 hours of stroke leads to improved outcomes. This intervention lowers the blood pressure, improves functional outcomes, and improves cognition to boot. To good to be true? Perhaps not.

8. Virtual reality augmented rehabilitation

"AC89-0437-20 a". Con licenza Pubblico dominio tramite Wikimedia Commons.
AC89-0437-20 a“. Con licenza Pubblico dominio tramite Wikimedia Commons.

 

There are many advances aimed at improving limb function after stroke. These include techniques such as constraint-induced movement therapy and mirror therapy. The exciting advance for me however is virtual reality. This came to my attention in an article in Augmented Reality Trends titled Virtual Reality Assists Stroke Patients Regain Limb Movement. It took some sleuthing to track down the scientific paper, published in Journal of Neuroengineering and Rehabilitation. Titled, in typical academic obfuscation, The visual amplification of goal-oriented movements counteracts acquired non-use in hemiparetic stroke patients, it showed the benefit of a virtual reality environment on hand-reaching in 20 stroke patients. The authors conclude that “the amplification of the movement of the paretic limb in a virtual environment promotes the use of the paretic limb in stroke patients”. Long words, small sample size, but big progress.

7. Enhanced endovascular therapy

"Merci L5" by Neilbarman at English Wikipedia. Licensed under CC BY-SA 3.0 via Commons.
Merci L5” by Neilbarman at English Wikipedia. Licensed under CC BY-SA 3.0 via Commons.

 

Conventional stroke treatment now relies on injection of clot busting agents into a vein (intravenous thrombolysis). In some cases the clot busting agent is given through an artery (intra-arterial thrombolysis). The immediate future of stroke however is moving towards actual clot removal or mechanical thrombectomy. There have been several studies showing the effectiveness of this technique. These include the appropriately named ESCAPE, MR RESCUEand MR CLEANThrombectomy makes use of devices called stent retrievers such as MerciTrevo Pro and Solitaire™ FR. The results of these trials are overwhelmingly convincing, and the title of a recent review article in Interventional Neurology says it all: Mechanical Thrombectomy Is Now the Gold Standard for Acute Ischemic Stroke: Implications for Routine Clinical Practice. It is such a significant development that a recent Lancet Neurology article was titled Stroke in 2015: the year of endovascular treatment!

6. Neurostimulation

By http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml [Public domain], via Wikimedia Commons
By http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml [Public domain], via Wikimedia Commons

Neurostimulation is having a field day in neurology and I discussed this in my previous post on vagus nerve stimulation. Stroke is going to be no exception. Take this report published in Stroke titled Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. This paper suggests that combining vagus nerve stimulation (VNS) with standard rehabilitation improves upper limb function after stroke. Another report in Neurology is titled Deep brain stimulation of the dentate nucleus improves cerebellar ataxia after cerebellar stroke

5. Remote ischaemic conditioning (RIC)

Could repeatedly inflating and deflating a blood pressure cuff around the arm reduce the brain damage that occurs following stroke? Strange as it may seem, this is the idea behind remote ischaemic conditioning (RIC). A recent paper in Nature Reviews Neurology titled Remote ischaemic conditioning—a new paradigm of self-protection in the brain explains how this works. It says RIC protects organs by triggering protective chemical pathways in their cells. This is neuroprotection when applies to nervous structures such as the brain. This process has the potential not only to limit the damage caused by stroke, but to also reduce the risk of the stroke recurring. One study that has looked at this process in detail is published in Stroke and is titled Remote ischemic per-conditioning: a novel therapy for acute stroke? 

4. PHD oxygen sensor inhibition

When oxygen supply to the brain is restricted, as occurs in stroke, the brain detects this using proteins called PHD (prolyl hydroxylase domain). PHD triggers a change in the metabolism of the brain cells, letting them adapt to the new state of limited oxygen supply. Unfortunately this adaptation leads to the production of toxic oxygen radicals which cause some of the brain damage that results from stroke. A recent study has however shown that mice that are deficient in PHD develop less severe strokes than normal mice. It requires no stretch of the imagination to guess that medications which inhibit PHD may lead to less severe stroke outcomes. And this is what the title of the research paper says: Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal MetabolismA simplified version of the paper is published in News-Medical as Oxygen sensor PHD1 identified as potential target for treatment of ischemic stroke

3. Growth factors 

"NGF Beta 2.5S RCSB 1BET" by RCSB PDB - RCSB PDB. Licensed under CC BY 3.0 via Commons.
NGF Beta 2.5S RCSB 1BET” by RCSB PDB – RCSB PDB. Licensed under CC BY 3.0 via Commons.

 

Recent studies have reported two growth factors with the potential to improve stroke care. The first is growth differentiation factor 10 (GDF10). An article in MNT titled Discovery could lead to drug to enhance recovery from stroke describes GDF10 as a chemical which “signals brain cells to make new connections following a stroke“. The scientific paper is published in Nature Neurology titled GDF10 is a signal for axonal sprouting and functional recovery after stroke. This opens the door for potential drug treatments which will improve recovery after stroke.

The second growth factor is Neurotrophin 3 (NT3). This is one type of nerve growth factor which has been shown, at least in rats, to improve brain function. It however has to be administered within 24 hours of stroke. The report published in Brain is titled Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke. The authors showed that NT3, injected intramuscularly, triggers the sprouting of new nerve cells. This goes beyond neuroprotection and opens a very exiting field for stroke researchers.

2. Stem cell therapy

By Human_embryonic_stem_cells.png: (Images: Nissim Benvenisty)derivative work: Vojtech.dostal (Human_embryonic_stem_cells.png) [CC BY 2.5 or CC BY 2.5], via Wikimedia Commons
By Human_embryonic_stem_cells.png: (Images: Nissim Benvenisty)derivative work: Vojtech.dostal (Human_embryonic_stem_cells.png) [CC BY 2.5 or CC BY 2.5], via Wikimedia Commons

Stem cell therapy is a very promising field of medicine, with exciting reports coming out almost daily. Most recently is the benefit in multiple sclerosis (MS). Recent reports suggest that Stroke is not lagging too far behind. A recent article in The Guardian describes what appears to be a successful trial of stem cell therapy in 5 people with stroke. A review article in International Journal of Preventative Medicine outlines the different types of approaches to stem cell therapy; these include neural, haematopoetic and mesenchymal stem cells. If you are keen on the technical aspects you may look at the research paper in Stem Cells and Translational Medicine titled Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke

1. Brain repair with new nerve cells

Neurones in the brain. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/19923050858
Neurones in the brain. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/19923050858

 

A step which goes beyond neuroprotection, growth factors, and stem cells, is the creation of functioning nerve cells (neurones) from the supporting cells of the brain (glial cells). This technique promises to repair the part of the brain damaged by stroke by simply replacing the dead cells with new nerve cells. I came across  this first in an article in The Guardian titled Brain damage could be repaired by creating new nerve cells. The evidence so far is from studies in mice but the prospects for this are very exciting indeed. For the scientific details, the original research is in Stem Cells Report titled Sox2-Mediated Conversion of NG2 Glia into Induced Neurons in the Injured Adult Cerebral Cortex

These are all very impressive developments, hinting at a bright future for stroke care. It is hopefully not far off when a devastating stroke will be a totally reversible event.