Stem Cell Breakthrough

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Why don’t brain cells in Parkinson brains communicate better? A team of researchers in Aukland, New Zealand, have been working on that question for the last five years and have found some clues that may help both Parkinson’s and Alzheimer’s.
As new stem cells, immature cells, emerge in the brain, they need to grow into neurons and find their proper place in the brain and begin communicating with other neurons. In order to reach their destination, through a complex and tight inter cellular matrix, they become coated with a slippery substance, polysialic-acid-neutral cell adhesion molecule. This slippery substance reduces the friction so they can migrate and saves cell energy, but once the cell has found the right location, in order to be secured in position, the substance must be removed. Removal of the polysialic acid substance is also necessary for the dendrites (neural appendages) to connect with other neurons and begin to communicate. This process has been well known for many years, but what controls the process has been a mystery.
What happens to the slippery molecules when the cell no longer needs it? This team spent years trying many growth processes under various conditions before finding a clue. Actually, they found two clues. First, they learned that cells internalize the polysialic molecule dependent on cues received from collagen in the extra cellular matrix and gaseous molecules of nitrc oxide.
Then they found that if there is insulin in the matrix, the cell cannot absorb the slippery molecules. Parkinson’s and Alzheimer’s brains are less sensitive to insulin, so insulin is blocking the removal of the polysialic acid causing the cell to be unable to connect or communicate properly with other cells.
Dr. Maurice Curtis was the director of the study, and the experiments were done at the Centre for Brain Research laboratories in Aukland, New Zealand. Other researchers on the team were Dr. Hector Monzo, Distinqguished Professor Richard Fauli, Dr. Thomas Park, Dr. Birger Dieriks, Diedre Jansson and Professor Mike Dragunow. They have now begun testing new drug compounds to target the removal of polysialic acid from cells in hopes of improving the migration and connectivity of new stem cells in the brain.

Insulin and IGF1 modulate turnover of polysialylated neuronal cell adhesion molecule (PSA-NCAM) in a process involving specific extracellular matrix components
Hector J. Monzo1,2, Thomas I. H. Park1,3,Victor Birger Dieriks1,2, Deidre Jansson1,3,Richard L. M. Faull1,2, Mike Dragunow1,3,Maurice A. Curtis1,2,*
DOI: 10.1111/jnc.12363 Article Accepted for Publication

Video Games for Therapy – Nintendo Wii Benefits PD

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Video game aficionados have pretty much abandoned the Nintendo Wii….moving on to the next generation and looking for more action, excitement and better screen images.  Medical doctors, physical therapists and people with Parkinson’s are embracing the Wii…and its ability to improve balance and reduce falls.

Spending just 20 minutes a day playing three different Wii games along with workouts on treadmill and exercycle improved scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Tinnetti Balance Test. Dr. Antonella Peppe, a research professor at the Fondazione Sana Lucia in Rome did a pilot study with people with Parkinson’s and found the Wii balance board stimulated the central nervous system.  Improvements in rigidly, movement fine motor skills and energy levels were reported by all the participants  Dr. Peppe’s study confirms the results of other studies.

A different study was done at the Medical College of Georgia.Twenty people with Parkinson’s used the Wii for an hour, three times a week for four weeks.  They played bowling, tennis and boxing, all of which require balance, quick thinking, movement and exercise.  It not only improved all their motor scores, it improved energy levels and alleviated depression, too.  Dr. Ben Herz was the investigator.  He is program director for the school of occupational therapy at the Allied School of Health Sciences.  This study used people who had never had therapy for Parkinson’s,  so they had no preconceived notions of what therapy should be like.  Finding that it involved video games was a big surprise.  But in the end, it was so useful and made them feel so good that more than half of them bought the Wii to use at home.  Dr. Herz says he thinks game systems like the Wii are the future of occupational rehabilitation.

Medical College of Georgia (2008, April 7). Occupational Therapists Use Wii For Parkinson’s Study. ScienceDaily. Retrieved June 25, 2013, from http://www.sciencedaily.com­/releases/2008/04/080407074534.htm

Alexithymia and Impulsive Behavior in Parkinson’s Disease

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A very interesting preliminary report presented at the annual Movement Disorders Society meeting in Sydney looks at impulsive behavior in people with Parkinsons.  Dr. Katharina Goerlich-Dobre from the Department of Neurology at Christian-Albrechts University in Kiel, Germany studied 91 people with Parkinson’s and tested them for alexithymia and found a close correlation between impulsive behaviors and a risk for pathological additive behaviors in people who scored high in alexithymia.

The word alexithymia comes from the Greek “A” for “lack”, ,”lexis”  for “word” and “thymos” meaning emotion.  It was first described by psychiatrists Peter E. Sifneos and John C. Nemiah in 1972 when patients they were working with displayed a marked difficulty in talking about their emotions.  Since then, it has received more attention in psychology and has come to be understood as difficulty identifying feelings or distinguishing between bodily sensations and emotions, a lack of certain types of imagination and difficulty talking about their own feelings or the feelings of others.  People with alexithymia often are rather rigid in the way they relate to life events, tending to be more focused on the mundane or the minute details of daily living.  They are more externally oriented, and tend to prefer to live with strict rules, social conformity and in predictable patterns and may try to maintain them compulsively.  They may be very intellectually accomplished, but are unable to relate to spontaneously imagined or inspired situations or events.   When presented with situations that they find unpredictable, they may make hasty decisions , impulsively, because they are unable to imagine what the outcome of the decision might be.

Anxiety, compulsivity, impulsivity and depression are often discussed in Parkinson’s literature, but little attention has been given to alexithymia.  Dr. Goerlich-Dobre found that many individuals with Parkinson’s are unable to identify their feelings or may suppress feelings they cannot put into words.  She says “The possibly intense emotional arousal accompanying those feelings may prompt alexthymic individuals to engage in impulsive-compulsive behaviors in order to quickly alleviate their distress, as their access to healthier ways of processing those feelings is compromised.”

Neuropsychiatric assessments of Parkinson’s patients’ emotional awareness with an inclusion of alexithymic evaluations my help identify patients who are at risk of impulsive or compulsive behaviors, including pathological addictive behaviors.

Parkinson’s Symptoms Reduced by Smoking Cannabis

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Ruth Djaldetti, M.D., of Tel Aviv University in Israel, presented the findings of her research at a recent International Congress on Parkinson’s Disease and Movement Disorders.  She reported improvement in tremor, pain, rigidity and bradykinesia (slowness of movement).  Twenty subjects, all in their mid-sixties, and were rated using the Unified Parkinson’s Disease Rating Scale (UPDRS) both before and after smoking.  Their overall “before” scores were over 30 and within 30 minutes of smoking, their scores dropped to 24..  Their tremor scores averaged 7.5 on the UPDRS before and dropped to a score of 3.5 after smoking cannabis.  Bradykinesia scores dropped from 13.2 to 8.6 and rigidity went from 7.4 to 6.4.  Dr. Djaldetti also saw a marked relief in the pain her subjects were experiencing and this relief of pain led to better sleep and feeling more rested.

This bears out the results of other studies.  A study done in Great Britain that was published in 2011 found the principal ingredient in cannabis provided neuroprotection for people with Parkinson’s disease.  Its neuroprotective properties included reduction of inflammation and control of spasms, making it an ideal drug for treating Parkinson’s.  However, its confusing legal status make it very difficult for people to obtain or consider using and for doctors to even recommend to patients.

Another interesting study done in 2010 found that cannabinoid receptors are located in many parts of the brain and that cannabinoids are produced naturally in the brain.  People with Parkinson’s have even higher levels of endocannabinoids (cannabinoids produced within the brain).  The main ingredient in cannabis, Tetrahydrcannibol (THC) actually increases dopamine production temporarily.  Cannabidiol (CBD) another component of cannabis, also provides neuroprotective properties and has been shown to reduce dystonias .  CDB could be a very vital improvement for treating Parkinson’s, and a recent study has shown it useful in treating certain cancers as well.

While there have been many, many people reporting the anecdotal benefits of smoking cannabis, clinical trials are lagging behind.  Laboratory and animal studies have shown many benefits, but perplexing issues around the legality of cannabis are slowing the efforts and impeding progress.

 

For a review on Cannabis for Treatment of Movement Disorders go to:

http://thepotbook.com/potbook/additional_chapters_files/Sanche-Ramos-Final.pdf

More News from the Movement Disorder Society Annual Meeting

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Three more stories from the annual Movement Disorder Society meeting that was held in Sydney, Australia.

Researchers from Lund University in Lund, Sweden and the Van Andel Research Institute in Grand Rapids, Michigan, have developed a potentially useful new mouse model for studying Parkinson’s disease.

The accumulation of α-synuclein is one of the hallmarks of the development of Parkinson’s disease.   If scientists can recreate this process in a mouse model, it will go a long way toward furthering their understanding of the cause of Parkinson’s.  While some mouse models demonstrate certain particular pathologies of PD, they do have limitations.  One such limitation is in demonstrating the progressive development that duplicates the slow accumulation of α-synuclein and loss of motor and non-motor symptoms as it happens in humans.  This team of researchers has developed a new transgenic mouse model that parallels the slow age dependent  accumulation of α-synuclein and demonstrates the behavioral deficits seen in humans.  Understanding how α-synuclein increases in the brains of mice gives research a new tool to study how to treat it in humans and to better understand the causes of PD.

It has been suspected for some time that people with Parkinson’s develop malignant skin cancers more often than the general population.  A study done through the University of Rochester demonstrated that Parkinson’s does bring a four fold greater risk.   A new clinical trial followed 1700 newly diagnosed Parkinson subjects and researchers estimated that in this population there should be about just under four cases of malignant melanoma.  In fact, they found 13 cases of new malignant melanoma.  Why this is so is not yet understood.  These findings prompted Matthew Stern, M.D. the Movement Disorder Society President-elect to say “This study underscores the importance for dermatologic screening in PD patients.  Further, elucidating the relationship between PD and melanoma may shed light on the pathogenesis of both disorder.”

Reducing cognitive impairment in Parkinson’s is the goal of another study out of Newcastle University in Great Britain.  They tested the effects of the drug apomorphine that has been used for over 20 years in Europe to reduce motor fluctuations in advanced PD.  α-Synuclein accumulations are one known cause of dementia in PD, but amyloid -beta  (Aβ) accumulations also contribute to dementia.  This study looked at the brain tissue samples from both cognitively impaired and not impaired deceased Parkinson’s patients.  They found that brain tissues of people treated with apomorphine for motor complications while living and found  lower levels of Aβ.  These findings suggest that apomorphine treatment may have significantly lowered the Aβ burden in the brains of non cognitively impaired individuals and alsomay have reduced the cognitive impairment in the cases of noted dementia.

Researchers stressed that this is an on-going investigation, but that it may be able to lead to a therapeutic treatment for dementia in PD and eventually lead to clinical trials.

Notes from the Movement Disorders Society Annual Meeting

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Sydney_Opera_House_(Vivid_Sydney_2012)

The Movement Disorders Society held its annual convention in Sydney, Australia recently.  Many interesting topics dealing with Parkinson’s disease were discussed.  Some of those topics will be addressed here.

A report on mild cognitive impairment in Parkinson’s by Alison Yarnell, from Newcastle University in the United Kingdom, showed that if cognitive impairment was present at the time of Parkinson’s diagnosis, the patient had a higher risk for developing dementia later in the disease progression.  A clinical trial compared neurological and cognitive assessments of 219 newly diagnosed subjects with Parkinson’ s to 99 age-matched controls.  Cognitive assessments covered global cognition, attention, memory, executive function, visuospatial function and language.  Subjects were classified dependent on their scores.  Memory impairment was the most common, with 15 percent of the subjects affected followed by visuospatial deficit s in 13 percent, attention in 12 percent and executive function at 11 percent.  Other studies have shown cognitive impairment in as many as 25 percent of the Parkinson’s population with many going on to develop dementia within three years of diagnosis  The author of this study stressed that cognitive testing should be done at the time of diagnosis to both get a baseline and also to determine which patients might be in need of closer monitoring.  By determining cognitive status early on in the course of the disease, therapeutic interventions may provide better results.

Clinical trial design was another interesting topic at the MDS meeting.  Dr. Tiago Mestre from Toronto Western General Hospital in Ontario, Canada, raised the question of how participants’ attitudes and reactions to placebos in double blind trials influenced the evaluations of the effectiveness of the therapeutic agent being evaluated.   To try to understand if this is indeed a real effect, a systematic review of double-blind, randomized, controlled trials of dopamine agonists in Parkinson’s that used a placebo or an active control.  The analysis of their preliminary results did show a clinically significant impact of decreased effectiveness of the medication being tested.  Therapeutic effectiveness might be even higher for the drug being tested than trial results indicate.  This negative effect of a placebo in a trial is called the “Lessebo” effect.

One commenter also raised the question of the “nocebo” effect…where if a patient is given a placebo, or non-therapeutic substance, by an authority figure who assures them of the benefit, a benefit will be experienced.  Another patient who is more skeptical and less trusting  might experience a harmful effect, when, indeed, the “active” ingredient is not known to cause harm.

Dr. Rajesh Pahwah , from the University of Kansas Medical center presented research on a new formulation of an older medication has shown promise in controlling levodopa induced dyskinesias in Parkinson’s. There are currently no approved medications to treat levodopa induced dyskinesias.  It is still in the investigational stages, but a timed-release form of amantidine has been successful in a small clinical trial.  Amantidine has been around for a long time, and has been used to reduce dyskinesias but  doses hight enough to be effective have often not been well tolerated.  .The new formulation is designed to gradually increase the availability of the drug in the day time, when the dyskinesias are the most disturbing, and to limit the overnight concentration thereby helping to relieve insomnia and sleep disturbances.  Because higher doses can be administered gradually in timed-release, effectiveness and tolerability are both improved.  The new formulation, called a “chronotherapeutic” pharmacokinetic  profile, is not yet FDA approved and not out of the clinical trial testing stages.  Some mild adverse events have been reported, but the company is seeking the advice of the FDA on continuing development of this medication.

Diffusion Tensor Imaging to Diagnose Movement Disorders

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Tensor Imaging

Tensor Imaging

A team of researchers at the University of Florida used a special imaging technique to identify markers in brain regions to help identify specific movement disorders whose clinical symptoms often appear similar but have different origins in the brain.  Parkinson’s disease, multiple system atrophy, essential tremor or supranuclear palsy have symptoms that are very similar in the early stages of the disease which makes a definite diagnosis very difficult.

David Vaillancourt is the team’s principal investigator.  He is an associate professor in the department of applied physiology and kinesiology.  Over a three year period, he and his team have examined 72 patients with movement disorders using the imaging technique Diffusion Tensor Imaging.  They also anticipate testing between 150 and 180 new subjects in the next few years.

DTI, as it is called, is a non-invasive imaging process that together with magnetic resonance imaging (MRI) is able to examine structures deep within the brain and characterize the properties of those structures on a microscopic scale much more detailed than imagery alone can provide.  By sensitizing the MRI signal, it can analyze the random molecular motion of water molecules which provides insights ot the organization of the micro structures.

Dr. Vaillancourt stated that the primary goal of this study was to be able to use DTI to accurately predict the correct disease.  When a new patient presents with symptoms, this technique will make diagnosing the symptoms possible early in the disease progression.  Diagnosis and treatment can be tailored from the beginning, eliminating possible changes to diagnosis as various symptoms progress or response to medication is inadequate.

Of the 72 subjects they have so far examined, they have been able to diagnose and separate the patients into specific movement disorder groups very accurately.  The results of this study will be published in the journal Movement Disorders.

 

Prodoehl, J., Li, H., Planetta, P. J., Goetz, C. G., Shannon, K. M., Tangonan, R., Comella, C. L., Simuni, T., Zhou, X. J., Leurgans, S., Corcos, D. M. and Vaillancourt, D. E. (2013), Diffusion tensor imaging of Parkinson’s disease, atypical parkinsonism, and essential tremor. Mov. Disord.. doi: 10.1002/mds.25491

What Would YOU Like to Ask the Doctor?

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Medical Director

Medical Director

Every day at the Parkinson Research Foundation’s Parkinson Place is special, but the second Wednesday of every month brings a once a month unique opportunity.  Over lunch, people with Parkinson’s and their friends and caregivers can quiz the medical director about specific issues of Parkinson’s disease.

Juan Sanchez-Ramos, Ph.D., M.D. is happy to give in-depth explanations to concerns and questions of a general nature about Parkinson’s disease.  Do you want to know how Sinemet got its name?  Ask the doctor. Just what is “orthostatic hypotension” and why is it important in Parkinson’s?  Ask the doctor!

Dr. Sanchez-Ramos has been a practicing neurologist specializing in movement disorders for more years that he wants anyone to know. He is fellowship trained, which means he has had extra specialized training in Parkinson’s and other movement disorders. Before he became a movement disorder specialist, he earned his Ph.D. in molecular pharmacology. As the head of his own basic research laboratory, he pioneered the development of neurons for brain repair from stem cells he grew from bone marrow.  This man has a very deep and knowledgeable understanding of Parkinson’s.

There is still another fascinating side to Dr. Sanchez-Ramos…a side he values equally with his science and medicine.  Dr. Sanchez-Ramos is an artist, and he credits his artistic endeavors with making him a better neurologist.

In his youth, he was expected to follow in the footsteps of his father and his older brother, both of whom were doctors.  By his junior year at the University of Chicago, he didn’t think medicine was for him….he wanted to be an artist.  The usual parental admonitions about starving artists followed that announcement.   After arguing convincingly of the sincerity of his desire, his father sent him to study art for a year in Europe.  The year turned into three, with some rather interesting adventures, but ultimately, he returned to the University of Chicago to study the pharmacology of psychoactive substances.

While he continued in the world of science and medicine, he never completely relinquished his love of art and drawing.  It has always been an important part of who he is.  He has shown his artwork in several venues and had some one-man shows.  When asked how his art has impacted on his science he said:  ” It has to do to with seeing things in a different dimension. When you work really up close in the lab, you have to step back and see how the parts relate to the whole. A lot of the work requires visualization of things that are invisible.  The images that I see are so beautiful, that inspires me to draw them out. The science influences the art, the art influences the science. They each influence each other. The art allows you to see things you can’t see, then you can understand, then you can explain and manipulate.”

So, think about it.  When the next session of “Ask the doctor” rolls around, line up your questions and sit back and listen to the fascinating and thorough replies of this very special  specialist.  You will find his depth of knowledge amazing and that he is an inspiring and spirited teacher.  Don’t miss this unique opportunity!

Skin Problems and Care in Parkinson’s

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Parkinson’s disease is usually thought of as a movement disorder, but there are many other symptoms that are not related to movement.  Depression, loss of sense of smell, anxiety, constipation, changes in voice…these symptoms often come to mind with Parkinson’s.  Skin is the largest organ of the body, and yes, Parkinson’s affects skin, too.  It is frequently under-diagnosed or untreated, time with the Parkinson’s neurologist is limited and focus is often on the more troublesome movement problems.  Skin problems can be more than just annoying, and they need to be considered and treated, too.

One of the most troublesome skin issues seen early in the development of Parkinson’s is seborrhea.  Greasy skin and limp, oily hair with dandruff  have been associated with Parkinson’s for many decades now. Areas around the nose and forehead are most affected.  The exact mechanism  which causes seborrhea to develop is not yet understood, but undoubtedly relates to the loss of dopamine on the functions of glands located in the skin.

Chronic problems with seborrhea can lead to dermatitis.  Skin and hair need to be washed frequently and anti-dandruff shampoos may be helpful.  But if dermatitis develops in spite of cleanliness, topical steroids may need to be tried.  Seborrheic dermatitis can also develop around the eyes, causing small patches that form little flakes of skin that can get into the eyelashes and the eyes.  Washing carefully with dandruff shampoos and letting it run gently over tightly closed eyes can often help.  Interestingly, when dopamine replacement is implemented, seborrhea often improves.  It seems to be more active when the disease itself is active.

Sialorrhea, or excessive saliva is a common Parkinson’s symptom.  Sometimes it has been thought that due to the difficulty with swallowing people with Parkinson’s often  have,  excessive saliva accumulates in the mouth from not swallowing often enough. There have been several studies that have found excessive amounts of saliva do appear to be produced in some subjects, so swallowing is not the only issue.

Skin around the lips and mouth can become irritated from excessive saliva, especially if drooling occurs.. The friction of constant wiping  can make it even worse. If not taken care of, the skin can begin to break down and cause even more discomfort.   Lip balms and creams to protect the skin can help.  Medications such as anticholenergics may be used to help dry up the secretions and botulinum toxin injections in salivary glands have helped some patients.

Drenching sweats, or hyperhidrosis, are another majorly discomfiting and embarrassing  problem for people with Parkinson’s. Night sweats which soak all the bed clothes are especially difficult to endure.  The excessive sweating involves mainly the head, including the face, and the trunk while the palms of the hands remain amazingly dry.  Hyperhidrosis  usually occurs if the dose of dopamine is either too high or too low.  If the sweating occurs during off-periods, increasing the dopamine dose can help.  Beta blockers, such as propranolol, are sometimes useful.

Problems with sensations of tingling or pain in the skin are also a common Parkinson’s complaint and are also probably due to the loss of dopamine.  Skin lesions, both cancerous and non- cancerous appear to occur a bit more frequently in the Parkinson’s population than in the general population.  Some studies have found a slight correlation and other studies find the rates about the same.  It is difficult to tell if Parkinson’s and skin lesions are connected, because as people age, both become more prevalent.  Possibly, because people with Parkinson’s often have other sensations in their skin, lesions may not be noticed as quickly.  And additionally, since the skin of people with Parkinson’s  is very sensitive, it may have a stronger reaction to exposure to sun.

A further concern is the implication of levodopa treatment in developing malignant melanoma.  Current guidelines for physicians often state that if a patient has undiagnosed or suspicious skin lesions, dopamine should not be used.  The reason being that both dopamine and melanin share biochemical pathways in their synthesis.  But studies have shown that there is not necessarily a correlation, that the occurrences of  melanoma in Parkinson’s patients may simply be coincidental.

Skin patches for treatment of Parkinson’s offer a more continuous and even delivery of medication without taking so many pills.  While for the most part, it was well liked by people with Parkinson’s, it did have drawbacks of skin irritation.  Although it was recommended that the site of application be changed every day, sometimes the skin reactions lasted too long on  sensitive and fragile skin and caused too much discomfort.  The FDA withdrew their approval, and the patch was re-formulated and has again received FDA approval.  If the patch is used, careful attention must be paid to the skin in the areas of application.

In later stages of Parkinson’s, people may be much more sedentary than in the earlier stages. Off-time, stiffness and immobility as well as difficulty turning in bed can be challenging.  Sitting or lying down for long periods together with the friction of bedclothes can cause pressure sores to develop and ead to the breakdown of sensitive skin.  Add to this, the moisture of either night sweats or urinary incontinence, and the bacteria, and skin damage is inevitable.  In as little as two days, ulcers can develop.  Because immobility and rigidity are usually at the root of these problems, keeping the person with Parkinson’s mobile is the best treatment: making sure that dopamine and other medication is timely and properly regulated.  While it sounds simple, it is very difficult and complex and not easy to effect.  Caregivers, from caring physicians, nurses, spouses and family members all have to be carefully trained.

Fungal infections in incontinent patients are also a high risk.  Fungal infections look like red patches that are moist and itchy.  They can spread across the skin very rapidly.  Treatment consists of an anitfungal cream, such as mycostatin.  Special care must be taken with folds in the skin, to keep them clean and dry.

Parkinson’s affects the skin in many ways.  Sensory perceptions of hot and cold, pain and touch are diminished from nerve loss in the skin..  MicroRNAs (MiRNA) are non-coding RNA that help regulate cell cycles, differentiation and growthare also involved in skin.  In Par4kinson’s, these regulators have been found in an altered state.  Just exactly how the dopamine system affects them and how they affect wound healing is yet to be discovered.  .Together with the other non-motor, autonomic system changes, the skin presents an area for more research and better understanding of how Parkinson’s impacts the whole person.

 

 

 

Beitz, J.M; Skin and Wound Issues in Patients with Parkinson’s Disease: An Overview of common Disorders; Ostomy Wound Manage. 2013;59(6):26–36.

Pan, T; Li, X; Jankovic, J.; The Association between Parkinson’s Disease and Melanoma. Int. J. Cancer; 2011;128(10):2251-2260

Fisher, M., Gemende, I., Marsch, W., Fisher, P.A.: Skin Function and Skind Disorders in Parkinson’s Disease. J. Neur. Trans. 2001:108(2):205-213

Potential Parkinson treatment from Artificial Sweetener

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α-Synuclein has long been known to accumulate in the brains of people with Parkinson’s and cause cognitive changes.  Finding treatment to prevent clumping  of α-synuclein has been very complex and challenging.  But a substance used by surgeons during surgery to open the blood-brain barrier and allow necessary drugs to pass may hold the key.  Mannitol  is also  Federal Drug Administration (FDA) approved as a diuretic, to flush out excess fluids.  And it is a popular artificial sweetener in sugar free gum.

Researchers Ehud Gazit and Daniel Segal identified the structures of α-synuclein that cause it to form clumps and bind together.  Understanding how those structures worked lead them to look for various substances that might prevent the clumps from forming.  It was in that process that they identified Mannitol as being one of the most effective at preventing aggregation of α-synuclein in test tubes.  Making it an even more attractive candidate was the fact  that it was already FDA approved for other medical uses.

They began by testing Mannitol in the brains of very simple creatures: fruit flies that were genetically engineered to express human α-synuclein and ordinary fruit flies without any genetic changes.  Next, they measured the fruit flies ability to climb up the walls of a test tube, a so called “climbing assay”.  In the first trial, 72 percent of the “normal” fruit flies were able to complete the climb up the test tube, but only 38 per cent of the genetically modified fruit flies were able to successfully climb the test tube.

For 27 days they added Mannitol to the food of the genetically altered fruit flies, but not to the food of the control flies.  When the “climbing assay” was again administered, 70 per cent of the genetically altered fruit flies were able to climb the test tube walls.  On examining the brains of these flies, they found  a 70 per cent reduction in α-synuclein.

Dr. Eliezer Masliah of the University of San Diego repeated the experiment, this time using genetically modified mice.  The results showed a dramatic reduction in the aggregates of α-synuclein after four months of injections of Mannitol.

Fruit flies and mice are still a long way from human people with Parkinson’s disease!  The proven reduction of α-synuclein in the brain is exciting, but more studies of behavior in other animal models of Parkinson’s are needed. The researchers are presently searching for ways to modify the Mannitol compound in order to optimize its effectiveness and insure its safety.  Much more animal research will need to be performed before trials for humans can begin.

Dr. Segal does not advise people with Parkinson’s to begin chewing quantities of sugar free gum!  But he does hold hope that because Mannitol is useful in crossing the blood-brain barrier, it may prove useful as a transporter for other medications for Parkinson’s that are now very difficult to get into certain regions of the brain.

This research was done at Tel Aviv University, Depoartment of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience.  Collegue Ronit Shaltiel-Karyo and Ph.D. candidate Moran Frenkel-Pinter were also participants in this study.  The results were presented at the Drosophilia Conference in Washington, D.C. in April.

 

 

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD)J. Biol. Chem. 2013 288: 17579-17588. First Published on May 1, 2013,doi:10.1074/jbc.M112.434787

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