The Power of Research in the Palm of Your Hands- By Dr. De Leon

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There are many devastating neurological illnesses for which there are no cures as of yet as is the case for PD. However, the future is bright since in the last 3 decades have seen many new discoveries in the field of neuroscience which have led us to a greater understanding of such complex illness as PD. Yet, despite all the advances there are nearly 2 million people living with PD in this country. Many of whom still face difficult challenges daily due to lack of specific treatments for various PD non-motor symptoms.
Part of the problem is difficulty recruiting appropriate patients to even fill clinical trials. It is believed that roughly 80% of trials are delayed due to being unfilled while 30% never even get off the ground. The result is that lack of participants in research trials only leads to slowing down the progress towards a possible cure. For those that do participate only one in four reach completion.
The great news is that you have the power to change the future of research. Subsequently, aiding in improvement of quality of life and discovering breakthroughs from which all could benefit.
So, how can you help?
…by playing a part in Parkinson’s research. Saying Yes! to becoming a volunteer.
You can participate in research as a patient or as a control…….
Now that you have decided to take control and become a research participant, you may be asking yourself the following questions:
I want to participate in a trial but, I am not sure if I qualify?
• First, you must know that there are different types of trials. Some are only interested in collecting data via surveys etc. these often times can be done from comfort of your home. Other studies are interested in evaluation of biomarkers, genetic abnormalities, or discovering other risk factors via laboratory. These do not require taking specific medications and maybe a onetime only test as well but may have a degree of invasion in order to draw blood, spinal fluid, tears, etc. There are also those which involve the evaluation of devices for instance to track tremors, gait instability and so on. Finally, there are the drug trials which everyone thinks about when speaking about participating in a clinical trial.
• Once you have understood the different types you can then actively seek out information regarding the various types you might be interested in.
• The best way to do this is talk to your physician. Other options is contact national organizations for referral to research centers or ask your peers at support groups and conferences.
How do I approach my doctor about participating?
• Begin by asking your physician if he or she thinks you might be a good candidate for participation in a trial. Ask the reasons why or why not? If he/she say yes, then ask if they have a particular trial in mind. If they are not actively doing research would they be willing to refer you to a center that does.
• If they are not the primary investigator would they work closely with researcher and would they still continue treating you or release care to another.
How do I choose the best one for me?
• Assuming you opted to volunteer in a drug trial you must find out the stage of the trial. Is this a drug that is in phase 3 awaiting to see efficacy vs. placebo or another treatment? Or is this an early stage trial where safety and tolerability is only being addressed. Expectations must be clear from the start on both ends in order to have the best outcome.

It is important to remember that by definition a clinical TRIAL is an EXPERIMENT in which the outcome (answer) is not yet known!!!!
As I stated previously, since there are different types of clinical drug trials it would serve you well to discuss in detail with your physician what your participation in a particular trial would mean for your disease state not just in the present but also in the future. This is crucial to remember because circumstances change and disease burden also changes over time (increases) which could impede continued participation in case of a long trial or may even preclude you from obtaining standard of care later on when disease advances, such as having DBS when participated in certain gene therapy studies. Furthermore, is also important to consider that in some instances future participation in other trials may be limited.
Therefore, before making a decision you must always take into account ALL of your current circumstances be it social, financial, physical, emotional, and other comorbidities (e.g. depression).
If your health is precarious like mine you can still participate in certain types of drug trials. For instance, participation in phase 4 drug trials in which drug results are already known but require further information or its being used for a different purpose than its intended original use could be something worthwhile.
In the end, the best way to maximize your success and achieve a positive outcome for you is to consider these things before you engage in any trial:
• Consider your goals and those of the studies, are they in sync?
• Are the expectations realistic?
• Never participate to please your doctor…that will only lead to heart break when results don’t yield what you hope for….
• Consider your physical limitations and capabilities along with those of your caregiver.
• MOST IMPORTANT- YOUR WELL BEING comes FIRST!

Don’t forget research is a TWO-WAY street OPEN communication is VITAL…..let your clinician know your concerns and also what interest and issues you have to better fit a study that suits your needs…..

@copyright 2018
all rights reserved by Maria De Leon

Stem cell therapy in Parkinson’s disease: Promising treatment or Hoax? By Dr. De León

Given the fact that living with a chronic neurological disease like Parkinson’s for which there is no cure can make any of us in a moment of desperation turn to any form of treatments and therapies which promise a cure. I have recently noted an increase of talk about this subject on social media in our PD community. Unfortunately, many good people have been bamboozled into believing the hype on social media about stem cell therapy as a cure all! The people offering stem cell therapy as a cure have prayed upon the fears, and suffering of many in our community. However, it is important for me to outline the facts and discard the myths surrounding these so called new therapies that promise so much.

Let’s first look at what are stem cells and why are we so interested in stem cells as a possible treatment for Parkinson’s disease.

• They can continue to divide for a long time
• Unspecialized
• Can give rise to specialized cells

Back in the 1980’s, there were trials in which fetal dopaminergic neurons were transplanted into the brain of some patients some of who had long lasting effects. It was then proposed that in vitro dopamine cells derived from cells derived from embryonic cells and bone marrow could be harvested to produce same effect. However, as of today, there has been no evidence that in vitro cells injected/transplanted in to animals with experimental PD can then re-innervate the striatum with dopamine neurons in vivo and give rise to a considerable improvement and recovery from deficits resembling human Parkinson’s symptoms. Furthermore, in order for the recovery to be effective one must have a large quantities of dopamine neurons which has not been feasible due to extremely short survival after transplantation.
Since, there is still so much we don’t know about this extremely complex disease, finding ways to modify it has proven to be a daunting task. Nevertheless, back at the beginning of this decade there was a small study with stem cells which showed some modicum of promise. This study used adult stem cells (these can be obtain from same person -autologous or another individual-allogenic). Both have their advantages and disadvantages.

Types of cells
• Embryonic- An embryonic stem cell is one that can differentiate into any cell type of the body this is known as pluripotent these then give rise to multipotent stem cells which can the. Differentiate into specialized terminal cells e.g. nervous system giving rise to different type of neurons
• Adult …they do not regenerate as well and if place in different environment these may or may not develop that areas specialized cells which means these cells have to be placed in basal ganglia to even have a chance …
• Umbilical
• Hematopoietic

Studies involving stem cells have included embryonic cells and placed into brain via olfactory nerve tract
The main problem is that most of the people claiming to have the “cure” using stem cells are using adult stem cells from the skin which remain as skin cells especially since they are given back as an intramuscular injection. Many times these develop into scar tissue or lipomas (fat tumors)causing other problems. It is also important to note that when receiving cells from another individual these must be matched for ABO blood type, Rho factors as well as gender. If implanted outside of the nervous system having a mismatch can result in antibody production as well as decrease in longevity of cells. However, if implanted in the nervous system because of blood brain barrier this is not an issue necessarily. However, the effects of this is not known as of yet because the nervous system also possess cells like macrophages and glia which are the brains immune system which can potentially attack these new cells.

In the study, I mention previously autologous totipotent stem cells were used.
These cells are capable of differentiating into any cell and give rise to an entire human organism. The cells were uncommitted to a particular cell type when used therefore potentially much more likely to develop neurons if placed in nervous system. The reason autologous cells are preferred as I mentioned before we would eliminate the need for autoimmune suppressants necessary in all transplantations when foreign cells used.

Remember not all stem cells are alike…although stem cell research is actively evolving and is currently a very dynamic field. Scientists have discovered that hematopoietic cells can be harnessed to develop into nerve cells. These types of cells have already been used to treat other medical problems. However, cells have to be extracted from bone marrow (-autologous). Plus it need the right location …into the striatum of the brain. Placing outside of basal ganglia will NOt produce the appropriate dopamine producing neurons even if placed in the brain much less if placed outside of the central nervous system. Things like temporal lobe epilepsy could potentially result if cells are placed at random in the brain causing migration to other parts of the brain.

In conclusion, what we want is autologous adult totipotent stem cells not embryonic or fetal to be placed inside the brain cavity meeting all these requirements makes for a higher likelihood of success although yet to be proven. Unless, you are participating in a trial meeting these parameters then you are allowing yourself to be part of sham therapies which on top of being extremely expensive could be deleterious to your own health. Fortunately, because of so many scammers, the FDA recently announced back in march of this year that the “wild west of stem cell therapies” is coming to an end with the introduction of a new frame work and guidelines due to the national and international pandemic of providing treatment which are not only ineffective and costly but also proven harmful. I for one could not be happier about this! People need to be held accountable for their careless actions.

As an aside: An autologous bone marrow adult totipotent stem cell study is currently taking place at UT Houston under Dr. Mya Schiess- The coordinator number to get more information can be reached at 18326329 to see if you qualify.

Copyright@2018
All rights reserved by Maria De Leon

Sources:

Lindvall O., Kokaia Z. Stem cells for the treatment of neurological disorder. Nature June 29, 2006 Vol. 441
https://www.omicsonline.org/open-access/treating-parkinson-disease-with-adult-stem-cells-2329-6895.1000121.pdf
Is the wild west of stem cell therapies coming to an end? American council on science and health http://acsh.org/news/2017/11/17/

New trial: Fetal Transplantation Usage for Treatment of PD: By Dr. De Leon

Nearly 30 years ago, the novel treatment which propel me into medicine but not just medicine but neurology and Parkinson’s disease was fetal brain transplantation into PD person’s brain in an attempt to halt disease. After several decades the procedure was banned here in the States and an unofficial moratorium was placed elsewhere on this type of trial. For those 300 plus patients which did receive this “novel” treatment, the results were a mixed bag. While the procedure showed some improvement in younger and less severely affected Parkinson’s patients, “many patients experienced off-drug ‘runaway‘ dyskenesias which resembled a lot like chorea at times. These patients then had to be treated with Tetrabenazine, Reserpine as well as pallidotomies and DBS to attempt to control symptoms.

Now, using a different technique by researchers with a new PD population a trial is underway to test the cell based therapy, which according to Dr. Roger Baker (lead investigator) professor of clinical neuroscience at Cambridge University in the United Knigdom is by any means designed to be a cure but rather another method by which dopamine is better (hopefully) delivered into the brain.

some of the previous trials problems were believed to be due to site implantation since the fetal nigral cells containing dopamine could not be directly placed into the hosts nigra, they were placed in the near by striatum. Uneven re-enervation of these cells is believed to be one of the causes of ‘runaway’ dyskenesias as well as the presence of serotonergic neurons from the donor raphe nucleus which can also produce dopamine in unregulated fashion. Further problem seen with initial procedure back in the 1980’s and 90’s  is the yet unaccounted reason for  the development of Lewy bodies in the grafted (donor) cells.

Because the European community ( where trials began) have always insisted on the merit of this procedure as a possible treatment a TRANSEURO consortium was gather to further discuss results. they have found there is a specific type of patient that responds best- so now they are recruiting patients between ages of 30-68 who have mild to moderate illness with minimal to no dyskenesias. now these patients will receive 3 fetal nigras on each side vs. the 2 used on each side in the past. these patients will receive a year worth of immunosuppression and be observed for 3 years ( believed to be time frame for maximal effect). they hope to control some of the emergence of dyskenesias by their new harvesting protocol which will decrease or minimize the number of serotonin containing neurons. hope is to improve dopamine related symptoms however, the non-dopaminergic effects will still remain unaffected.

Once again, I see hope ( but a smaller ray of sunshine than when I first began this trajectory) for a future generation of PD patients for a better life as I had once envision as a young neuroscientist. If this proves to be successful it will undoubtedly unleash a whole new era in the science of stem cell therapy research for the treatment of neurological diseases.  However, I along with other more prominent neurologists like Dr. Anthony  Lang  caution those considering participating in such trial for it will be not a cure PD and if it works it will only provide limited  results affecting only the symptoms related to dopamine.  Keep in mind that a big part of the spectrum of PD is non-dopamine related and these are in fact the things which I believe as a doctor and patient which cause most PD persons problems such as gait instability, mood and sleep problem’s, along with declining cognition. so in the end, aside from boosting science in a new direction I don’t foresee this to replace DBS which has a long trajectory of excellent outcome and compared to fetal transplantation a much les invasive and aggressive surgery without the need for whole body immunosuppression which is known to carry many risks of its own accord. perhaps may have a niche for usage if works in those with young onset PD with Parkin gene mutation

Others of course like Dr. Baker are much more optimistic and believe that this may actually some day be first line therapy. highly doubt based on my years of experience with this disease and its complexities but one never knows….

Food for thought….

Sources:

Robinson, R. (October 20, 2016); “Fifteen years later, a new trial set to test fetal transplants again is for Parkinson’s Disease.” Neurology Today. 16(20)13,23.

 

Thinking Outside the Brain for a Parkinson’s Cure : By Dr. De Leon

Thinking Outside the Brain for a Parkinson's Cure : By Dr. De Leon

I don’t think inside the box, I don’t think OUTSIDE the box, I don’t EVEN KNOW where the box is!”- unknown

The other day while I was giving a talk about how to diagnose PD, I was giving my usual spill about ” in the hands of a specialist like myself- accuracy is 95%,” when someone in the audience asked me a very thought provoking question. So, how early can you diagnose with such certainty? Therein lies the BIG Problem in why we need biomarkers and be able to think outside of our current diagnostic criteria!

In reality, I told her it is still very accurate above 90% for someone that has a lot of experience -that’s where art meets medicine …you get your “intuition” about things based on past knowledge and experience and are able to predict with fair accuracy and since at this point there is NO difference in treatment really between one type of Parkinson syndrome or another it does not much matter at the beginning…However, where it becomes a problem is being able to predict outcome and assign patients to studies because you have to follow strict criteria and even if you just KNOW that someone has Parkinson’s or an atypical variant you have to back it up…and as you all know EVERYONE is different so it may take some one ten years to develop all 4 cardinal symptoms of Parkinson’s while someone else only 2. So, it is hard to at present time to make a lot of head way in the discovery of new medications that might be beneficial to slow or stop the progression of early stage of Parkinson’s because unfortunately there is still a lot of variability in early diagnostic accuracy depending on the field. Even among neurologist not Parkinson’s specialist, a published study indicated that for PD patients who had symptoms less than 5 years, they were wrong 50% of the time. These patients turned up to have another reason for their Parkinsonism which translates to automatic failure of any drug being studied since 50% of the patients in any given trial of early PD may not even respond because they don’t have the right diagnosis!

So, I realized that in order for us to start thinking OUTSIDE the BOX we need to FIRST get a CLUE of where the BOX is – what Parkinson’s looks like- acts like, presents like so THAT EVERYONE IS on the same page and able to diagnose with same degree of accuracy!!! This needs of course to go back to medical school, residency and communities and we all as PD advocates can play a role in educating health staff and other health professionals about Parkinson’s. The better we are at recognizing early symptoms the better chance we have for participating in neuro-protective trials as well as be able to determine biomarkers early on.

A lot of money and research is being channeled to the finding of these biomarkers in the recent years. According to research initiated by the MJFOX foundation, we may have insight into possible new biomarkers coming from the retina, colon, or skin which could lead to not early detection but a cure for PD.

For a number of years, neuroscientist have known that alpha-synuclein the abnormal protein seen in Parkinson’s is also found outside of the central nervous system. This protein is a major constituent of Lewy body disease another Parkinson’s like disease. However, alpha-synuclein which is located largely at the ends of neurons plays a part in both familial and sporadic Parkinson’s disease as well.

Through the usage of very powerful machines and equipment known as optical coherence tomography (OCT) which takes high resolution pictures of the retina, scientists and doctors have found that PD patients have thinner retinas compared to healthy individuals.
At this point, they are not sure if there is enough evidence to use as a biomarker because they are not certain how specific it is to Parkinson’s since it also has been seen in Alzheimer’s patients who had Parkinson’s as a co-morbidity.
Alpha-synuclein is normally present in several types of retinal cells…so the possibility of serving as a biomarker exists either by accumulation or (absence) at this time no cells have been found in PD patients.

Another place that accumulates alpha-synuclein outside the brain is the colon. Published studies have revealed that immunostaining for Alpha-synuclein in living Parkinson’s individuals results in a positive outcome in 69-100% of the time but not seen in MSA ( multi -system atrophy) patients. Another study showed that these findings preceded the clinical motor symptoms. So far, results which are small have been mixed. They are easy to attain because of flexible sigmoidoscopy can access distal colon easily plus screening is required of all over 50 years of age. However, not all pd people showed pathology. Some explanations have been given which include variation of tissue involvement, change in pathology over time and perhaps unsuitability of this being used as a biomarker.

The third place where scientists are looking for a possible biomarker outside the central nervous system which is also full of alpha -synuclein is the skin. One reason, people are interested in this area is because of the new wave of knowledge and thinking about the etiology of Parkinson’s. Since, we now know that there is a prodrome period of non- motor & autonomic symptoms that precede the development of the motor symptoms, researchers believe that perhaps alpha-synuclein pathology starts outside the brain and migraines to the brainstem.
Also, studies have suggested that peripheral nervous system is equally involved in Parkinson’s. Evidence of this was suggested in an issue of Brain in 2008 where Parkinson’s patients were found to have cutaneous denervation resulting in higher threshold for heat and touch but decrease for pain.

Because the skin is not only easily accessible but also has a plethora of autonomic involvement, and many autonomic nerves making it a great candidate for study.
A study in the Journal of Neuropathology & Experimental Neurology proposed that the skin may be a beneficial site for diagnostic predictability since 70% of PD cases and 40% of PD with dementia revealed positive alpha-synuclein immunoreactivity while absent in other Parkinson plus syndromes like MSA ( multisystem atrophy) , PSP( Progressive supranuclear palsy), & CBGD (Cortico-basal-ganglia-degeneration). The results are very promising but still need to be validated and compared longitudinally and with autopsy confirmed cases of PD.

Out of all these the most promising is the skin biopsies as a possible biomarker..easy and readily accessible and this far able to differentiate between Parkinson’s and other Parkinson’s plus syndromes.
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For more information on the topic: MJFOX research on biomarkers
Haugh, Zac., Movement Disorder Focus: Alpha-synuclein :Thinking Outside the Brain. Practical Neurology. Vol. 13, No.2, March 2014

Dr. M. De Leon is a movement disorder specialist on sabbatical, PPAC member and research advocate for PDF (Parkinson’s Disease Foundation); Texas State Assistant Director for PAN (Parkinson’s Action Network). You can learn more about her work at http://www.facebook.com/defeatparkinsons101 you can also learn more about Parkinson’s disease at www.pdf.org or at www.wemove.org; http://www.aan.org, http://www.defeatparkinsons.blogspot.com

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