Alpha-Synuclein Pathology in Parkinson’s Disease

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Alpha-synuclein (α-synuclein) is one of the three members of the synuclein family, small proteins that are present in human brains and whose normal function there is not yet completely known or understood…  What  is known is that accumulations of α-synuclein accumulate in the neurons of Parkinsonian brains over the course of the disease.. The pathological mechanism behind exactly how α-synuclein  forms the aggregates found in Lewy bodies (named for the German neurologist, Friedrich Lewy,  who first described them) has not been understood.  Animal models of this disease have not been found or as yet developed to help researchers study this disease.

But now a group of researchers from the German Center for Neurodegenerative Diseases in Bonn, Germany under the direction of Professor Donato DiMonte have developed an experimental model in rats that may help to explain how α-synuclein, or abnormal forms of α-synuclein, spread throughout the brain, and lead to finding ways to slow or even stop its progression and the progression of Parkinson’s disease.

In human pathology it has been noted that α-synuclein production usually starts in the lower regions of the brain, in the medulla oblongata,  and with the progression of the disease moves to higher regions where it accumulates gradually.  It appears to follow a typical pattern which was thought to pass through a pathway of interconnected neurons, but until now, there was no way to visualize this process.

Dr. DiMonte thinks that since there is good reason to believe that Parkinson’s actually starts in the medulla oblongata and because it is a very difficult region to reach surgically, this rat model would help solve some of the issues.

Dr. DiMonte’s group developed a viral particle carrying a human DNA form of α-synuclein and injected it into the vagus nerve in the rats’ neck.  The genetic code for the human α-synuclein passed into the rats’ neurological system and into the medulla oblongata where it began producing high quantities of human α-synuclein.  After two months, they found the α-synuclein that originated in the medulla oblongata migrated to other higher areas of the rats’ brains. Over more time, the concentrations of α-synuclein actually increased, mimicking the pathology seen in Parkison’s.  They were able to map the specific nerve tracts and note the morphological changes in the nerve projections that absorbed the human α-synuclein.

This is an exciting first study that will lead to better understanding of the progression of not only Parkinson’s disease, but other diseases such as Alzheimers that have an accumulation of α-synuclein.  Future studies could lead to therapeutic treatments that target either the production of α-synuclein or its accumulation and transmission to regions in the brain.

Perception of Speech by Individuals with Parkinson’s Disease: A Review

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This article is a review of literature and studies involving perception in individuals with Parkinson’s. A review of empirical evidence suggests that individuals living with Parkinson’s Disease have possible deficits in the perception of speech concerning loudness, as well as perception of verbal emotions. The casual and nature of perceptual deficit are largely undetermined and need to be further researched.

See the Full article here - Parkinsons Disease Overview

Can a Diabetes Drug Help Parkinson’s?

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The diabetes drug is Byetta and its generic name is exenatide. This drug was developed for Type 2 Diabetes but may be able to improve cognitive and motor function in Parkinson’s disease. A small study of 44 patients conducted by Dr. Thomas Foltynie from the National Hospital for Neurology and Neurosurgery in London has shown promise.

Of the 44 Parkinson’s subjects, 20 received twice daily injections of exenatide.  Byetta (exenatide) is designed as a pen type device for self injection.  Given the expense of manufacturing placebos into such a device, the control group received nothing.  Subjects were followed for a year and evaluated periodically by a blinded investigator. Multiple rating scales were employed and subjects were rated both on and off medication at regular intervals throughout the study.  At the conclusion of the study, investigators found that the subjects who received exenatide showed an almost 3 point improvement in both motor and cognitive function while the control group had a 2 point decline.  Weight loss was the only side effect.  .

But while the benefit and improvement seen in the control group is sufficient reason to initiate more statistically relevant clinical trials, there is another perhaps even larger benefit.  This clinical trial utilized a medication that is already FDA approved and its basic safety and tolerability were already known.  Given the enormous expense, the long period of development and animal studies and the  risks involved in developing and studying new treatments or  drugs for neuroprotection, this study was much more cost efficient as well as being a very rapid way of collecting information about the effectiveness and tolerability of this drug in a new population.    Clearly, the results of this one small study are not sufficient to determine the efficacy of exenatide for Parkinson’s however, it does speed up the process of making more options available for symptomatic relief of Parkinson’s.

Test to Detect Loss of Sense of Smell in Parkinson’s Disease

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Can  a simple test to detect the loss of the sense of smell be useful in making earlier and more accurate diagnoses of Parkinson’s?  A team of Dutch researchers  think so.   At least 90% of all Parkinson’s patients experience loss of their sense of smell, and many studies have verified this.  This study found an easy and inexpensive test  that can be used in a clinical setting to help diagnose PD accurately .

This clinical trial recruited  much larger numbers of participants than many trials which are sometimes limited by having fewer Parkinson’s patients.  This gives this trial’s accuracy a stronger and more favorable outcome.  296 people were enrolled, 148 as age matched healthy controls and 148 Parkinson’s patients.  The PD patients were divided into three groups by symptoms: rigidity as dominant symptom, . tremor as dominant  or other symptoms.

All participants were asked to identify 16 different odors to identify which odors would be appropriate for a more sensitive test.  “Sniffin’ Sticks”, a product specific for olfactory testing, were used enclosed in felt tip pen cases to conceal their identities.   Odors included food odors such as fish, peppermint, coffee, cloves, cinnamon, etc and non food odors such as rose, gardenia, leather, etc.   Food odors had the best sensitivity ratings and were then narrowed down to eight and then again down to three.  Ultimately, the three odors that demonstrated the best sensitivity contrast between healthy controls and Parkinson’s were coffee, peppermint and anise.

All the healthy controls were able to identify these odors and only 10 of 148 in the Parkinson’s group. This appeared to be age related responses from younger members of the Parkinson’s group; however younger members (ages 45 – 65) of the PD  group already showed significant olfactory impairment compared to the age matched controls.  Severity of the disease also was important.  The group that was rigidity-dominant had slightly more olfactory impairment than the tremor group.  Cognition was another  indicator of odor impairment, but the results were sensitive to the type of  cognitive testing used.   Women and smokers showed a somewhat lower risk for impairment.

Results of this trial show a strong correlation between sense of smell and Parkinson’s.    Testing odor identification  can be a useful supportive diagnostic tool for Parkinson’s.   A brief three odor smell test in a clinical setting  is a non-invasive, cost effective tool  that could help both patients and neurologists.

Link Between Parkinson’s and Heart Disease Discovered

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People with Parkinson’s are twice as likely to develop heart disease and have a 50% greater chance of dying from it.  But why?  The perplexing relationship between the two diseases has long troubled scientists.  Now, Gerald W. Dorn II, M.D., and his colleague, Yun Chen, Ph.D. from Washington University in St. Louis have reported their findings in the April 26th edition of the journal “Science”. The path to this discovery was not straight and simple.  For the past six years, this mystery has eluded scientific explanation.

All cells have mitochondria.  Mitochondria are the little “factories” that covert fuel to provide energy to the cells. Brain and heart cells have tremendous needs for fuel and the energy provided by mitochondria.  Cells are also equipped with a mechanism to help rid themselves of mitochondria that have stopped functioning or have become sick.  If the  sick mitochondria are not destroyed and are allowed to accumulate, they no longer manufacture the energy needed by the cell and start using it up themselves thus causing damage or death to the cells.  This type of cell damage is what can lead to Parkinson’s or to heart disease.  Scientists have understood the process, but did not understand the mechanism of how sick mitochondria could signal to the cell that they were in distress.

The researchers were working with the brains of mice and fruit flies and identified a protein known as mitofusion 2 (Mfn2).  The usual role of Mfn2 is to fuse mitochondria together so they can exchange mitochondria DNA, as a form of primitive sexual reproduction.  Now they have discovered that mitofusion 2 can change function under certain circumstances, something that no one has ever suspected.

In normal function to maintain cell integrity,  mitochondria work to import the gene molecule called PINK.  When they collect this PINK molecule, they work to destroy it.  However, if the accumulation of PINK becomes too high, the Mfn2 can then change roles and bind with another gene molecule from within the cell itself called Parkin that signals the cell to destroy the mitochondria. In normal conditions, this is how mitochondria and cells undertake house cleaning to maintain cell health and function.  But….if you have a mutation in the gene PINK or a mutation in the gene Parkin, you will get Parkinson’s.

Gene Transfer Therapy for Parkinson’s

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Ramond T. Bartus, Ph.D. presented the newest findings of a clinical trial utilizing a new trreatment for Parkinson’s disease.  Dr. Bartus is the Chief Scientific Officer and also the Executive Vice President of Ceregene, a San  Diego based biotechnology company that is developing gene transfer treatments for neurodegenerative diseases.  He was an invited speaker at the May 18th annual meeting of The American Society of Gene and Cellular Therapy which was held in Salt Lake City, Utah.

Dr. Bartus spoke about findings from the second and continuing clinical trial of Cere-120, his company’s gene therapy product to deliver the neurotrophic factor neurtuin to people affected by Parkinson’s disease.  Cere-120 is the company’s name for AAV-neurturin.  This is a novel way to deliver a neurotrophic factor the brains of Parkinson’s patients.  Neurturin is a naturally occurring protein that has successfully repaired and restored  injured or dying dopamine producing neurons. In Ceregene’s application, this protein is inserted into a harmless adeno-associated virus (AAV) and  is delivered directly to the putamen or substantia nigra regions of the brain by stereotactic injection.  Degeneration of neurons in these areas of the brain are responsible for the loss of dopamine and the motor impairments associated with Parkinson’s disease.  Neurturin is one of three small proteins that are glial-cell line derived neurotrophic factors (GDNF) that have shown promise in restoring dopamine producing neurons. Neurotrophic factors are proteins responsible for the growth and maintenance of neurons.  In both human autopsy and animal studies, it was found that Cere-120 , once delivered to the brain by this highly targeted injection, provides long term, stable and controlled neurturin expression.

Ceregene completed the first clinical trial of Cere-120 in 2009 that demonstrated safety and tolerability and showed some promise of alleviating some PD symptoms.  This Phase 2b  trial has shown stronger results, but not in all patients.  Patients who have been diagnosed for 5 years or less and have not had any prior treatment had higher scores on the Unified Parkinson’s Disease Rating Scale (UPDRS)  as well as in other measures of Parkinson’s such as quality of life.  Some improvements of overall “off-time” and “on-time without troubling dyskinesias” in patients who had received prior treatment and had been diagnosed for up to 10 years were also noted, but the response was strongest in early-stage patients.

These findings demonstrate that this novel approach to treating neurodegenerative disease deserves more serious consideration and that more carefully planned clinical trials to enroll only early-stage, newly diagnosed and untreated  patients will be necessary..Ceregene has conducted 6 clinical trials in both Parkinson’s and Alzheimers.  Of 200 subjects enrolled, 100 have received gene therapy products with no serious safety issues.  The company plans to continue research in neurotrophic factors via gene therapy delivery for neurodegenerative diseases such as Parkinson’s and Alzheimers.

Human Embryonic Stem Cells without Human Embryos

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Dr. Shoukhrat Mitalipov and his lab at the Oregon Health and Science University announced in the journal “Cell” that they have created human embryonic stem cells without using human embryos..  These cells can be used for various types of therapeutic cell repair without fear of transplant rejection because they will genetically identical to the patient.   This could lead to important future treatments for such neurodegenerative diseases as Parkinson’s, Huntington’s, ALS and Alzheimers as well as heart and liver diseases.

Dr. Mitalipov’s process for creating this cell line uses cells from tissue, such a skin, to encode the genetics of the patient and fuses it with an unfertilized human egg from a female donor. The genetic material is removed from the nucleus of the tissue cell and implanted into the egg from which the nucleus has been removed.   It “tricks” the egg into acting like it has been fertilized, but material in the cytoplasm of the egg causes it to develop into a stem cell.  Initially he thought it might take many eggs to achieve this result, but very few eggs were actually required.  While similar procedures have been known since Dolly, the Scottish sheep, was cloned in 1996, it has taken many years to perfect the technique.  It will now be possible to develop colonies of cell lines which will be able to provide a sufficient quantity of the type of cells that are required for transplantation.  To prove that these stem cells can develop into a variety of cell types, including neurons and heart cells, researchers in this lab have performed many series of tests.  Although this a major break-through in regenerative medicine, a lot of work still remains to develop safe and effective stem cell treatments for human patients.

Convincing the public of the efficacy of this discovery may prove difficult.  Ethical issues abound.  Although no previously fertilized eggs or embryos are destroyed in this process, issues remain about paying women to donate unfertilized eggs.  Encouraging young and possibly poor women to commercialize products of their bodies is  a serious issue.  Worries that transplanted genetically engineered cells might have unintended consequences or create harmful mutations have also been expressed.

Other critics fear that this is yet another step closer to creating human clones and are pushing to halt further research until world standards banning human cloning are enacted.  Mitalipov does not believe this technique will lead to human cloning.  He stressed that cloning of embryos is a dangerous and delicate issue with most artificially created embryos not surviving past implantation.  His technique is simply a more efficient way to create stem cells to replace damaged tissues or neurons.

Still other researchers have turned to less problematic methods of producing cell lines by using .adult cells from the patient and inducing them to become the special cells needed.  However, there are questions that cells of this type may also have unintended consequences or may not achieve the results expected.  Dr. Mitalipov’s lab is currently working on research to directly compare cells derived from both techniques.

New Study Sheds Light on Parkinson’s Patients Ability to Walk

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A fascinatingly simple study from the University of Waterloo in Ontario, Canada, has shed some light on the effect of darkness on people with Parkinson’s ability to walk.  A graduate student completing her Ph.D.  in the department of Psychology, Kaylena Ehgoetz Martens, examined 19 Parkinson’s patients  using new virtual-reality equipment to understand the effect of sensory perception on freezing gait.

Ms. Martens had each of the 19 participants walk through a doorway or walk into open space at various times.  The amount of light available to them was gradually changed each time.  As available light was diminished, freezing gait episodes increased.  It didn’t matter if it was in the doorway or open space.  All participants experienced freezing gait when in complete darkness.  Results of this study indicate that impairment in sensory perception function may be the mechanism behind impairment of movement in Parkinson’s disease.

Lower the risk of developing Parkinson’s with nicotine…A healthier way

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Scientists have long known that nicotine can offer protection from developing Parkinson’s  but the risk of cancer from smoking tends to outweigh the benefits.  Now a study conducted with 1100 subjects has found that edible sources of nicotine from food plants such as potatoes, peppers, eggplant and tomatoes might also lower the risk of developing  Parkinson’s.

Other studies focused on smoking and tobacco use have found nicotine offers some neuroprotection in Parkinson’s.  A few studies have even suggested that second hand smoke might also confer some protection against PD which inspired Dr. Susan Searles Nielsen of University of Washington to see if other  sources of nicotine might also offer some protection.  Tobacco belongs to the solanacea family of plants, as do potatoes, tomatoes, eggplant and peppers.  These vegetables also contain nicotine, however in much smaller amounts than tobacco. They are also an important part of a Mediterranean diet, which has long been considered beneficial for people with Parkinson’s.

Dr Nielsen and associates at the University of Washington in Seattle studied men and women newly diagnosed with Parkinson’s and a comparable group of men and women without neurological diagnoses.   A medical questionnaire was used to evaluate the participants lifetime uses of tobacco and diet.  Use of tobacco included cigarettes, cigars or pipe smoking or smokeless tobacco products.

They found that eating vegetables in general did not confer any risk protection but that eating more vegetables in the solanacea family which contain small amounts of nicotine, did show a trend toward increased protection of risk of Parkinson’s.  People who ate vegetables such as peppers, tomatoes and eggplant at least twice a week were 30% less likely to develop Parkinson’s Disease.  And people who consumed peppers, that have a higher concentration of nicotine, two to four times a week showed an even stronger trend toward risk protection in Parkinson’s.  The effect, however,  was the strongest in people who had used  little or no tobacco in their lives.

But perhaps it is a bit too soon to rush into a diet that is rich in red or green peppers.  While this study may lead to the development of better treatments for Parkinson’s, more research is neede to dtermine the exact mechanism of benefit .

This is the first study to evaluate the benefits of edible nicotine and risk protection in Parkinsons.  While it did show a similarity to studies on the protection offered by tobacco use, more studies are needed to confirm these results.  Finding a less toxic source of nicotine such as peppers could lead to more innovative approaches for the prevention and treatment of Parkinson’s.

Innovative Nerve Damage Repair on the Horizon

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Visualizing nerve damage as an electrical cord with a short in it helped researchers at Tel Aviv University in Israel devise a potential  treatment to reverse nerve damage.  They visualized and then developed a tube running between the damaged nerve ends to restore function and eliminate pain.  This special micro-tube is filled with a gel that contains three special ingredients to encourage the repair and re-growth of the damaged neurons:  Antioxidants that give anti-inflammatory benefits;  synthetic laminum peptides to provide a track along which new neurons can grow and hyaluronic acid to keep the tube from drying out.  The tube itself is biodegradable. The special gel has also been used alone in cell therapy and has been proven to preserve cells and encourage cell growth.

While it is still a ways away from being used in humans, animal studies have been successful and the developers of this technology are hopeful that it will be available within a few years.  They see this development as helping people with paralysis and other nerve damage problems as well as using the gel in cell therapy to help the symptoms of Parkinson’s.

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