The emerging research boosting Parkinson’s disease treatment

Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptoms which rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).

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Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.

1. Increasing evidence for the benefit of exercise

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OK, not every advance has to be groundbreaking. It is self-evident that exercise is beneficial for many chronic disorders, but proving this has been difficult…until now that is. Researchers, publishing in the journal Movement Disorders, looked at the benefits of exercise on cognitive function in PD, and their verdict is-yes, it works! The study, titled Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial, comes with strings attached- you have to keep at the exercise for 2 years! A review  in the same journal indicates that exercise also improves mood and sleep in PD.

2. Lithium for treatment of dyskinesias

By Dnn87 - Self-photographed, CC BY 3.0, Link
By Dnn87Self-photographed, CC BY 3.0, Link

Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.

3. Transcranial magnetic stimulation (TMS)

By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link
By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link

Transcranial magnetic stimulation (TMS) is playing an increasing role in neurology as I discussed in a previous post titled Are magnets transforming neurology? It is almost inevitable therefore that TMS will crop up in attempts to treat PD. And so it has, going by a meta-analysis and systematic review published in JAMA Neurology. The paper is titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease. The reviewers passed the judgement that repetitive TMS improves motor symptoms in PD. Perhaps time to invest in TMS!

4. MRI guided focused ultrasound (MRgFUS)

By Frmir - Own work, CC BY-SA 3.0, Link
By FrmirOwn work, CC BY-SA 3.0, Link

MRI guided ultrasound (MRgFUS) is not new to medicine. It is used, for example, in the treatment of solid tumours and uterine fibroids. It is however innovative in the treatment of tremor and dyskinesia in PD. This came to my attention via a press release from University of Maryland titled Metabolic Imaging Center uses new ultrasound technology to target deep structures of the brain. MRgFUS non-invasively transmits ultrasound waves to the globus pallidus, one of the deep brain structures involved in PD. How this works still remains fuzzy to me, but it is exciting enough to generate a lot of research activity with articles such as MRI guided focused ultrasound thalamotomy for moderate-to-severe tremor in Parkinson’s disease in the journal Parkinson’s Disease; and Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease, published in Neurology. Watch out, deep brain stimulation!

5. Nasal mucosal grafting

Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471
Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471

What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose. It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!

6. Fetal stem cell transplantation

Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806
Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806

It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetal stem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space

7. Pluripotent stem cell transplantation

By Judyta Dulnik - Own work, CC BY-SA 4.0, Link
By Judyta DulnikOwn work, CC BY-SA 4.0, Link

The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beatsopen sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was published in the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.

 

Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595
Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595

There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:

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Calming the rage of brain tumours: hope for a dreaded cancer

"Glioblastoma - MR coronal with contrast" by Christaras A - Created myself from anonymized patient MR. Licensed under CC BY 2.5 via Commons.
Glioblastoma – MR coronal with contrast” by Christaras A – Created myself from anonymized patient MR. Licensed under CC BY 2.5 via Commons.

 

Brain cancer is a horrible disease even among cancers. Apart from benign tumours such as meningioma, very few brain tumours have happy endings. It is however not all doom and gloom- there are many advances raising hope for the future of brain cancer. Here are 10 hope-raisers.

10. Nanotechnology-guided radiation treatment

"Nanob". Licensed under ">CC BY-SA 3.0 via Wikimedia Commons.
Nanob“. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

 

Nanotechnology is promising a lot for neurology, and I discussed this in my previous post on 10 remarkable breakthroughs that will change neurology. It is heart-warming to learn that nanotechnology is stepping into brain cancer treatment. Their role is in reducing the damage that normal tissues sustain when brain cancer is treated with conventional radiation. Scientists hope to minimise this damage by delivering the radiation treatment through nanomolecules; because of their small size it is presumed this approach should cause less harm. In this article in Neuro-Oncology titled Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma, the authors report the efficacy of liposomally encapsulated radionuclides in rat models of glioblastoma. It is complicated stuff but Science Daily’s headline says it all: Treating deadly brain tumors by delivering big radiation with tiny tools.

9. Ultrasonic screwdriver

11th Doctor Who Sonic Screw Driver Open. Tony Buser on Flikr. https://www.flickr.com/photos/tbuser/4778412914
11th Doctor Who Sonic Screw Driver Open. Tony Buser on Flikr. https://www.flickr.com/photos/tbuser/4778412914

 

The challenge for every drug cancer treatment is to deliver the drug as close as possible to the tumour cells. This is particularly difficult for brain cancer because of the protective brain blood barrier (BBB). This shield is composed of the walls of the blood vessels, and the triple-layered sheath covering the brain called the dura.

What if the drugs could be sent across this barrier without breaching it? More Dr. Who than neuroscience, but this is what the ultrasonic screwdriver recently achieved to wide acclaim. Using ultrasound, the scientists successfully delivered chemotherapy drugs across the BBB. This press release from Sunnybrook Health Sciences Centre explains it further. The neurosurgeons used an MRI-guided focused low-intensity ultrasound to force drug microbubbles in the bloodstream across the blood-brain barrier. “The waves repeatedly compress and expand the microbubbles, causing them to vibrate and loosen tight junctions of the cells comprising the BBB. Once the barrier was opened, the chemotherapy flowed through and deposited into the targeted regions”. Very exciting SciFi stuff. Here is a simplified version from IFL Science titled Scientists Have Breached The Blood-Brain Barrier For The First Time And Treated A Brain Tumor Using An “Ultrasonic Screwdriver”.

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8. Electromagnetic field therapy

"Felder um Dipol" by Averse - http://de.wikipedia.org/wiki/Datei:Felder_um_Dipol.jpg. Licensed under CC BY-SA 3.0 via Commons.
Felder um Dipol” by Aversehttp://de.wikipedia.org/wiki/Datei:Felder_um_Dipol.jpg. Licensed under CC BY-SA 3.0 via Commons.

 

Electromagnetic field therapy is a new area of brain tumour treatment and not conventional in any way. It however promises to improve survival of patients with glioblastoma who have received conventional radiotherapy and chemotherapy. I came across this in MNT under the title Use of type of electromagnetic field therapy improves survival for patients with brain tumor. This treatment is a form of tumor-treating fields (TTFields), “a treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency alternating electric fields via transducer arrays applied to the shaved scalp”. The evidence for this is a trial reported in the Journal of the American Medical Association (JAMA) titled Alternating electric fields for the treatment of glioblastoma. It is not a panacea but any light at the end of the dreadful tunnel of brain cancer is worth exploring. It is a good sign that the FDA has approved this technology.

7. Pulsed electric field (PEF)

Electric storm. Romain Guy on Flikr. https://www.flickr.com/photos/romainguy/3712378856
Electric storm. Romain Guy on Flikr. https://www.flickr.com/photos/romainguy/3712378856

 

Another technique that is under investigation for treatment of brain cancer is pulsed electric field (PEF). This was the focus of a recent paper in Scientific Reports titled Targeted cellular ablation based on the morphology of malignant cells. PEF preferentially targets and destroys malignant cells relatively sparing normal cells. The mechanism, if you are curious to know, is called high frequency irreversible electroporation (HFIRE). Or, in plain English, electric disruption of cells. This has reportedly been effective in dogs, and the challenge is to translate the benefits to humans.

6. Vacquinols

"Cancer cells- death (step 1)" by Susan Arnold (Photographer) - This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 2368 (image) (next).This tag does not indicate the copyright status of the attached work. A normal copyright tag is still required. See Commons:Licensing for more information.English | Français | +/−. Licensed under Public Domain via Wikimedia Commons.
Cancer cells- death (step 1)” by Susan Arnold (Photographer) – This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 2368 (image) (next).This tag does not indicate the copyright status of the attached work. A normal copyright tag is still required. See Commons:Licensing for more information.English | Français | +/−. Licensed under Public Domain via Wikimedia Commons.

 

Touted as the drug that makes cancer cells explode, Vacquinols are experimental agents which have shown remarkable efficacy in rat models of glioblastoma. The research reported in the journal Cell is titled Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. The article is quite ‘scientific’ as reflected by the tortuous title, but the whole idea is that vacquinols target some cellular processes and  cause the cell membranes of glioblastoma cells to rupture . There is some way to go but imagine this advance translating into clinical practice!

5. aCT1

"Temozolomide-3D-spacefill" by Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer.. Licensed under CC0 via Wikimedia Commons.
Temozolomide-3D-spacefill” by Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer.. Licensed under CC0 via Wikimedia Commons.

Temozolomide is a conventional treatment for glioblastoma but unfortunately some patients become resistant to this useful drug. Scientist have observed that glioblastoma cells achieve temozolomide-resistance via a protein called connexin 43 (Cx43).  Working on this knowledge, they have developed a Cx43 inhibitor called aCT1. I came across this agent in a piece in EurekaAlert titled Scientists find way to make resistant brain cancer cells sensitive to treatment. The scientific paper, published in Cancer Research, is titled Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. A lucid title for a scientific paper for a change!

4. Propentofylline

"Glioblastoma (1)" by No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims).. Licensed under CC BY-SA 3.0 via Commons.
Glioblastoma (1)” by No machine-readable author provided. KGH assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims).. Licensed under CC BY-SA 3.0 via Commons.

I came across propentofylline in the blog brainmysteries.com under the title Drug that could limit spread of deadly brain tumours. Propentofylline seems to enhance the effects of temozolomide and radiotherapy, the conventional treatments of brain cancer. In this way propentofylline may slow the spread of the brain tumour cells. It seems to work by inhibiting TROY, the protein that enables glioblastomas to spread to healthy brain cells. For the small print you may read the paper published in Journal of Neuro-oncology titled Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway.

3. Medical Marijuana

cannabis-400832_1920

A recent study published in Molecular Cancer Therapeutics appears to show that constituents of cannabis drastically increase the anti-cancer effects of conventional radiotherapy. The authors suggest that ‘these cannabinoids can prime glioma cells to respond better to ionizing radiation’. A couple of caveats; this is an in vitro (in a dish) study, and it was carried out in mice. Some way to go then, but you wouldn’t think so going by this headline from the Huffington Post which says Marijuana drastically shrinks aggressive form of brain cancer.

2. New cellular targets for cancer treatment

"Cell membrane3" by Boumphreyfr - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.
Cell membrane3” by BoumphreyfrOwn work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

 

Two recent papers have reported on cellular proteins which brain tumours depend on. These are therefore potential targets for future therapeutic interventions. The first is hypoxia inducible factor-1 (HIF-1) which cancer cells produce when their oxygen supply is threatened. HIF-1 enables the cancer cells to produce new blood vessels (angiogenesis) thereby maintaining their supply of nourishing oxygen. This process is under investigation by researchers at Emory University.

The second property is related to proteins called sterol regulatory element-binding proteins (SREBPs). SREBP’s control the metabolism of glucose and fat in all cells, and researchers at Ohio State University are looking at ways to inhibit these proteins. This would potentially impair the ability of cancer cells to build their cell walls (membranes). Yes, only in mice again but still, hope. Here is a review of SREBP’s and cancer.

1. Pembrolizumab

"Melanoma" by Unknown - National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184. Licensed under Public Domain via Commons.
Melanoma” by Unknown – National Cancer Institute (AV Number: AV-8500-3850; Date Created: 1985; Date Entered: 1/1/2001), http://visualsonline.cancer.gov/details.cfm?imageid=2184. Licensed under Public Domain via Commons.

 

The news that Jimmy Carter has melanoma, and this had spread or metastasised to his brain, came as a shock to many of his admirers. It was therefore a relief when they learnt later that Carter’s cancer has all but cleared away. Very unusual to say the least, especially with a cancer as dreadful as melanoma. This remarkable achievement is attributable to an immunotherapy drug called Pembrolizumab, one of several types of drugs called humanised monoclonal antibodies.

Pembrolizumab has demonstrated effectiveness in melanoma and there are now NICE Guidelines for Pembrolizumab in melanoma. But how good is it in primary brain cancers? A trial is currently in progress to assess the efficacy of Pembromizumab in glioblastoma, the most dreaded of brain cancers. There are several other immune therapies that may be effective in brain metastases, and these are reviewed in an article in Current Treatment Options in Neurology titled Targeted therapies in brain metastases.

 

Brain tumours rage on, but the science is hopefully catching up. Victory beckons over this dreaded disease.

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