Improvement Seen in First Clinical Trial of Magnetic Stimulation for PARKINSON’S DISEASE
A double blind, randomized trial tested two targets of magnetic stimulation as well as a sham stimulation on 60 subjects that had moderate PARKINSON’S DISEASE. They received their usual Parkinson’s medications in addition to the stimulation. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment that researchers hope will augment pharmaceutical treatments for PARKINSON’S DISEASE. This trial has safety and efficacy as its primary outcome measures as well as improving clinical results when the subjects were off their drugs. While other studies have reported mixed results from transcranial magnetic stimulation, this trial used a larger, unique coil with the ability to generate a larger field of stimulation that penetrated deeper into the brain.
Principal investigator of this trial was Mario FIchera, M.D. from the Institute of Experimental Neurology at the Scientific Institute Hospital San Raffaele in Milan, Italy who presented his findings at the 24th Meeting of the European Neurological Society on June 1, 2014. He stated that compared to the group receiving sham stimulation, both groups that received targeted stimulation improved significantly, with no serious adverse events. In addition to reported improvements as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, subjects reported they experienced a better quality of life, but he cautioned that a further trial should be done to “validate the efficacy seen in this trial and to gauge the duration of the effects.”
Transcranial Magnetic Stimulation is a relatively new technique that changes neuronal function by using an electromagnetic field generated by a coil. Electricity passes in opposite directions through the shape of the coil and where the current crosses it generates an electrical field, whose intensity can be modified by regulating the amount of electrical current. Pulses can be applied singly or repetitively and at varying intensities. The strength and frequency of the pulses can determine excitability or inhibition of the target neurons. The coil is placed against the scalp and the magnetic field passes through the skull to change the electrical field of the underlying neurons. In this study TMS was applied in repetitive pulses, timed milliseconds apart. TMS treatment is usually done several times a week for several weeks.
In this study, all groups of subjects received treatment three times a week for four weeks. One group received treatment on the motor cortex region, contralateral to their affected side, and also to the prefrontal cortex. Group two received treatment to the motor cortex region, but sham treatment on the prefrontal cortex. Group three received sham treatments on both treatment sites. Both groups that received actual treatment showed reductions in the motor symptoms and tremors compared to the sham group.
Dr. Josep Valis-Solis, a neurologist and neurophysiologist at the Hospital Clinic in Barcelona, Spain said “I think that we have to promote a bit this kind of treatment that is noninvasive and nonpharmacological, so some hope that we are escaping from toxicity from drugs.” It is still early and there needs to be more investigation into the types and differences of effects from different coils. Cost and availability of the equipment and training and availability of personnel to administer treatment is another issue that needs to be studied together with the rate of retreatment necessary to maintain a positive effect over an as yet unknown, period of time.
Magnetic Stimulation Improves Parkinson’s Symptoms, Medscape Jun 17, 2014
Review by Marcia McCall.
New PARKINSON’S Gene Discovery Could Lead to New Treatment
The new molecular sciences continue to delve deeper into the mysteries of the cellular actions and interactions to unlock the keys to PARKINSON’S DISEASE. A team of genetic researchers at the University of California at Los Angeles headed by Dr. Ming Guo has found one more clue, a gene that mediates the interactions of two mutated genes and helps cells maintain their health to prevent neurodegeneration.
The genes PINK1and Parkin play important roles in protecting the energy producing mitochondria of cells. When these genes are mutated, they do not operate correctly and allow for accumulations of unhealthy cells with damaged mitochondria that leads to the early on-set of PARKINSON’S DISEASE. Working in fruit flies and mouse models of disease, Guo and her team found that a gene called MUL-1 mediated the interaction of PINK-1 and Parkin and contributed to the health of the mitochondria. When MUL-1 was removed from the interaction with PINK-1 and Parkin in the neurons in the mouse model, they found it caused deterioration of the mitochondria, but when an extra amount of MUL-1 was added, the mitochondrial damage was repaired.
The discovery of this new genetic interaction is exciting, showing a new mechanism for improving the function of mitochondria and maintaining the health of the cell, but also because it may lead to the development of a drug that could enhance its presence and prevent neurodegeneration. Such a new drug would be of immense benefit to people with PARKINSON’S DISEASE.
Further studies will test these findings in more complex biological organisms and will help to find more cellular interactions related to MUL-1. Testing for drugs that will enhance MUL-1 and become a basis for treatment is another a priority. The team will also be looking for mutations of the MUL-1 gene and to understand its heritability to see if it exists in all PARKINSON’S patients or if it is found only in the inherited forms of PARKINSON’S.
J. Yun, R. Puri, H. Yang, M. A. Lizzio, C. Wu, Z.-H. Sheng, M. Guo. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife, 2014; 3 (0): e01958 DOI:10.7554/eLife.01958
Review by Marcia McCall
Hopeful New Drug Therapy Being Developed at University of Alabama
Alpha-synuclein is one of the most prevalent proteins found in human brains. It is also the one that when it fails to conform to its normal configuration, or mis-folds, contributes to the neurodegeneration seen in PARKINSON’S DISEASE. Researchers at the University of Alabama led by Andrew West, Ph.D. think they may have found a key to prevent alpha-synuclein from misfolding and aggregating.
The gene LRRK2 has been linked to PARKINSON’S DISEASE and West’s lab demonstrated that the known mutations of this gene all increase its activity. Other studies have shown that it is related to alpha-synuclein in several ways. This study has shown that blocking the expression of LRRK2 in mouse models that are genetically very similar to human models, blocked the over-expression of alpha-synuclein. Blocking alpha-synuclein may prevent the death of dopamine producing cells in the substantia nigra, thus offering a potential treatment to prevent or slow the progress of PARKINSON’S DISEASE. The search for a drug to inhibit the expression of LRRK2 is now underway.
LRRK2 is known to be significantly involved in the genetic forms of PARKINSONS, in populations of Ashkenazy Jews from Eastern Europe and from Mediterranean ethnic populations such as the Berbers of North Africa, but is not as highly involved in non inherited forms of the disease. Still, West’s team thinks LRRK2 has more than one method of action as seen in the genetic forms. It may interact with alpha-synuclein in other ways.
He asks, “What would happen if you simply remove all LRRK2 activity? Modern approaches allow us to approximate what a perfect drug would do in rats and mice. We think LRRK2 is plugging into PARKINSON’S DISEASE in more than one way. It is making the disease more likely to happen and making it progress faster when it does happen. So we think knocking out LRRK2 will do the opposite–slow the disease or make it much less likely to develop.”
Simply slowing the progress of the disease would be a major break through. It could extend the length of time that levodopa effectively alleviates the symptoms and could even reduce or eliminate some of the side effects that can sometimes be worse than the disease.
Southern Research Institute is pharmaceutical research company partnering with Dr. West’s lab to develop a drug to inhibit LRRK2. They hope to be able to test it in humans early next year.
J. P. L. Daher, L. A. Volpicelli-Daley, J. P. Blackburn, M. S. Moehle, A. B. West.Abrogation of -synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1403215111
Review by Marcia McCall
Early Diagnosis of PARKINSON’S DISEASE by a New MRI Process
Early detection of PARKINSON’S DISEASE, before the symptoms become obvious, will lead to early interventions to slow the disease process and improve the lives of people at risk for this disease. While there still is no cure for this disease, it has not been possible to even make a positive diagnosis until after symptoms have already appeared. By then, some estimates indicate that over 75% of the dopamine producing neurons in the patients’ brains have been destroyed. Medications do offer symptomatic relief of some of the symptoms, but early treatment could limit the damage to dopamine producing neurons and dramatically improve the quality of life for people with PARKINSON’S DISEASE.
A research team at Oxford University in the United Kingdom has used a new simple MRI scanning technique that has predicted PARKINSON’S DISEASE with very high accuracy. Standard MRI techniques are not sufficient to detect early changes in the brain that would signal development of the disease. Dr. Clare Mackay found an approach that allowed the team to study the connectivity strength of brain networks in the basal ganglia. Using his technique for resting state functional MRI (fMRI) the researchers compared the connectivity levels of 19 subjects with early stage PARKINSON’S DISEASE and 19 healthy control subjects. With 100% accuracy, they found a much lower level of connectivity in the brains of the subjects with PARKINSON’S DISEASE; it also picked up a small percentage of healthy people. So they repeated the study on a second group of subjects and the results were almost the same, sufficient to validate the results of the first study.
The technique is non-invasive; subjects are simply required to lie still in the scanner. Researchers hope that this new technique will become part of clinical practice and have the ability to allow physicians to predict which of their patients is at risk of developing PARKINSON’S DISEASE before any symptoms arise. The study was done with subjects known to be in the early stages, so more research will be done to refine the technique to be sensitive enough to predict risk for non-symptomatic subjects. Early detection combined with other new research discoveries may hold the key to better and earlier treatment, making life with PARKINSON’S DISEASE much easier.
Clare Mackay et al. Functional connectivity in the basal ganglia network differentiates PD patients from controls. Neurology, June 2014 DOI:10.1212/WNL.0000000000000592
Review by Marcia McCall
Scientists Make Diseased Cells Synthesize Their Own Drug
By Eric Sauter
In a new study that could ultimately lead to many new medicines, scientists from the Florida campus of The Scripps Research Institute (TSRI) have adapted a chemical approach to turn diseased cells into unique manufacturing sites for molecules that can treat a form of muscular dystrophy.
“We’re using a cell as a reaction vessel and a disease-causing defect as a catalyst to synthesize a treatment in a diseased cell,” said TSRI Professor Matthew Disney. “Because the treatment is synthesized only in diseased cells, the compounds could provide highly specific therapeutics that only act when a disease is present. This means we can potentially treat a host of conditions in a very selective and precise manner in totally unprecedented ways.”
The promising research was published recently in the international chemistry journal Angewandte Chemie.
Targeting RNA Repeats
In general, small, low molecular weight compounds can pass the blood-brain barrier, while larger, higher weight compounds tend to be more potent. In the new study, however, small molecules became powerful inhibitors when they bound to targets in cells expressing an RNA defect, such as those found in myotonic dystrophy.
Myotonic dystrophy type 2, a relatively mild and uncommon form of the progressive muscle weakening disease, is caused by a type of RNA defect known as a “tetranucleotide repeat,” in which a series of four nucleotides is repeated more times than normal in an individual’s genetic code. In this case, a cytosine-cytosine-uracil-guanine (CCUG) repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities that, in turn, results in the disease.
In the study, a pair of small molecule “modules” the scientists developed binds to adjacent parts of the defect in a living cell, bringing these groups close together. Under these conditions, the adjacent parts reach out to one another and, as Disney describes it, permanently hold hands. Once that connection is made, the small molecule binds tightly to the defect, potently reversing disease defects on a molecular level.
“When these compounds assemble in the cell, they are 1,000 times more potent than the small molecule itself and 100 times more potent than our most active lead compound,” said Research Associate Suzanne Rzuczek, the first author of the study. “This is the first time this has been validated in live cells.”
Click Chemistry Construction
The basic process used by Disney and his colleagues is known as “click chemistry”—a process invented by Nobel laureate K. Barry Sharpless, a chemist at TSRI, to quickly produce substances by attaching small units or modules together in much the same way this occurs naturally.
“In my opinion, this is one unique and a nearly ideal application of the process Sharpless and his colleagues first developed,” Disney said.
Given the predictability of the process and the nearly endless combinations, translating such an approach to cellular systems could be enormously productive, Disney said. RNAs make ideal targets because they are modular, just like the compounds for which they provide a molecular template.
Not only that, he added, but many similar RNAs cause a host of incurable diseases such as ALS (Lou Gehrig’s Disease), Huntington’s disease and more than 20 others for which there are no known cures, making this approach a potential route to develop lead therapeutics to this large class of debilitating diseases.
In addition to Rzuczek and Disney, the other author of the study, “A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor,” is HaJeung Park of TSRI. For more information on the study, seehttp://onlinelibrary.wiley.com/doi/10.1002/anie.201406465/abstract
The work was supported by the Muscular Dystrophy Foundation, the Myotonic Dystrophy Foundation and the State of Florida.
Article Link: http://www.scripps.edu/newsandviews/e_20140908/disney.html
Do Microbes Rule Your Brain on Food Choices?
People no longer have to blame their food cravings — and giving in to them — on poor self-control.
Now scientists are arguing that microbes living in the gut are responsible for manipulating eating behavior by causing cravings for food they favor for fitness or that suppress their competition. Alternatively, microbiota in the gut may send out signals via the vagus nerve to the brain to induce dysphoria and goad people into eating what the microbe needs whether it’s good for the host or not, a diverse group of researchers are suggesting.
“Bacteria within the gut are manipulative,” Carlo Maley, PhD, director, Center for Evolution and Cancer, University of California at San Francisco, states in a press release. “There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals and others not.”
In their overview of eating behavior and the microbiome published online August 7, 2014 in BioEssays, Joe Alcock, MD, University of New Mexico, Albuquerque, and colleagues argue that certain microbes are highly dependent on the nutrient composition of the diet.
For example, Prevotella grows best on carbohydrates while dietary fiber provides a competitive advantage to Bifidobacteria. “Even microbes with a generalist strategy tend to do better on some combinations of nutrients than others,” the authors write, “and competition will determine which microbes survive.”
Microbes can manipulate host behavior in a variety of ways, but one way may be by “hijacking” the host’s nervous system. As the authors point out, evidence shows that microbes can have dramatic effects on behavior through the microbiome-gut-brain axis.
Other pathways through which microbes may influence host eating behavior is through secretion of hormones involved in mood and behavior, including dopamine and serotonin. Microbes may also manipulate eating behavior by altering receptor expression. Changes in taste receptor expression and activity have been reported following gastric bypass surgery, a procedure that changes gut microbiota and alters satiety and food preference, as the authors point out.
“Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad and releasing chemical rewards to make us feel good,” coauthor Athena Aktipis, PhD, Arizona State University, Phoenix, states in a press release.
“Together, these results suggest that microbes have opportunities to manipulate vagus nerve traffic in order to control host eating. Exerting self-control over eating choices may be partly a matter of suppressing microbial signals that originate in the gut.”
Happily, researcher add, the use of prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes can rapidly alter the microbiome within 24 hours of administration.
The study was funded by the National Institutes of Health, the American Cancer Society, the Bonnie D. Addario Lung Cancer Foundation, and the Institute for Advanced study in Berlin, Germany. The authors have disclosed no relevant financial relationships.
BioEssays. Published online August 7, 2014. Abstract
PARKINSON’S DISEASE – NOT ONE, BUT MANY
A pair of clinical researchers from the Department of Clinical Neurosciences and Mental Health, Faculty of Medicine at the University of Porto, in Porto, Portugal have written a scholarly article that refines and defines how the varying symptoms presented by people with PARKINSON’S DISEASE can be assessed and understood. They make a convincing argument that a “leap in concepts and a shift in research” is needed to enable therapeutic advances toward early treatment with specific neuroprotective agents for each unique presentation of symptoms.
In the past, PARKINSON’S DISEASE was thought to be caused by a loss of dopaminergic neurons in the substantia nigra. Positive diagnosis was delayed until motor symptoms were obvious and depended on the patient’s response to the ‘gold standard’, that is if the patient’s symptoms responded to levodopa. Positive response meant a diagnosis of PARKINSON’S, no response meant PARKINSONISM. Although patients had positive motor improvement responses to dopamine replacement, the results were only temporarily palliative; progression of the disease and the development of non-motor symptoms could not be halted. Many non-motor symptoms such as Rapid Eye Movement Sleep Disorder, loss of sense of smell, cognitive changes and mood problems may be present years before the motor symptoms present, and they involve neurological systems other than the dopamine system of the substantia nigra. These non-motor symptoms may well be precursors to the disease process, and appropriate treatments for them could delay or even halt the development of the motor symptoms.
Studies of the genetics of PARKINSON’S DISEASE have found only a few examples of heritable forms of the disease. But studies of those same genes have yielded further information of the specific roles each of those genes play in modifying or affecting various cellular processes that occur in the development of the disease. The alpha-synuclein gene (SNCA) when mutated, causes aggregations of alpha-synuclein but also has interactions with the PARK genes, with the LRRK2 or the GBA genes. The results of those various and individual interactions contribute significant differences in their presentation in the clinical and neuropathological features of the disease.
Post mortem examinations have shown that patients whose motor symptoms presented early and who had a good response to levodopa but then had a more rapid decline, including dementias, had mutations in the SNCA genes. Patients who had a slower progression of motor symptoms but had more dystonia or tremors usually carried LRRK2 mutations. GBA mutations were found in brains of patients who had early onset with both sides of the body equally affected and also more pronounced neuropsychiatric issues, such as symptoms often being found in Alzheimer’s disease patients. Another unique mutation in the VPS35 gene causes motor complications that get a significant benefit from dopamine replacement and no diminishment of cognitive function. PARK2 carriers had a slower progression of symptoms and responded well to dopamine replacement, but frequently were prone to develop dyskinesias. Dementia was rare in these cases and synucleinopathy was not found in post mortem examinations; however, much deterioration of the substantia nigra was seen.
The above descriptions show that many share multiple symptoms with PARKINSON’S DISEASE, but also demonstrate many differences in clinical presentation, imaging and other neuropathological features. While they may share a common response to dopamine replacement, they may, indeed, be manifestations of other similar but different diseases. There currently are no reliable biomarkers that can accurately predict the onset of the disease or distinguish one form from another, or even monitor its progression. Given the differing symptom presentations, genetics and pathological findings, it is likely that PARKINSON’S DISEASE is not a single disease, but an umbrella that covers multiple, but similar diseases.
Monteiro, A., Massano, J. Parkinson’s disease cluster: the wind of change; Open Access Publication http://ijcnhmh.arc-publishing.org ; 24 March 2014
Review by Marcia McCall
Helpful PARKINSON’S Research from Physics and Astronomy?
A non-traditional physics lab at Michigan State University has been working to advance medical solutions by combining physics and biochemistry. And it is working.
Lisa Lapidus, Ph.D., who is an associate professor of physics and astronomy, was fascinated by the idea that eating spicy food could slow the development of PARKINSON’S DISEASE. So she undertook studies of the spice, curcumin, which is thought to be the major substance in tumeric often used in South East Asian curries and cooking. It has a reputation for being anti-inflammatory and helpful for osteoarthritis. Unfortunately, she found that the molecule of curcumin, while helpful in other diseases, was too large to pass across the blood brain barrier.
In doing that research, she learned about protein aggregations and studied the rate at which proteins mis-fold. Using lasers, she was able to study the rate at which proteins formed aggregates. She found that if the proteins fold either faster or slower than the rate at which they bump into each other, then aggregation is slow. However, if they are bumping into each other at the same rate as when they are reconfiguring, then they will swiftly clump together causing aggregation and neurodegeneration follows.
When a person with PARKINSON’S presents with the symptoms, the process of protein aggregation has already begun. However, there is a patented molecule, called CLR01, which mimics the action of curcumin to prevent protein aggregates from forming. And CLR01 is a small enough molecule that it can cross the blood brain barrier. This small CLR01 molecule can be sent to its target site and will speed up the reconfiguration of the proteins and actually stop the early stages of them forming aggregates. This molecule attaches to the amino acid lysine, which is part of the protein, and acts like a claw or a pair of molecular tweezers to prevent binding with other proteins.
This CLR01 molecule used in this way to prevent aggregations of proteins from forming in the brain is an excellent candidate for a new drug that can be used to stop PARKINSON’S DISEASE early in the game and keep it from becoming the disabling disease. Hopefully, this research will move to the clinical trial stages soon and become a valuable resource for treating not only PARKINSON’S DISEASE, but other neurodegenerative diseases too.
S. Achaya, B.M. Safaie, P Wonkonkathep, M.I. Ivanova, A. Attar, F.G. Klamer, T. Schrader, .J.S. Loo, G. Bitan, L.J. Lapidus. Molecular Basis for Preventing Synuclein Aggregation by a Molecular Tweezer; Journal of Biological Chemistry, 2014, 289 (15); 10727 DOI 10.1074/jbc.M113.524520
Review by Marcia McCall
Mood and Cognition Adversely Affected by Dopamine in Depressed People with PD
A new research study from the University of Kentucky College of Medicine and the Sanders Brown Center on Aging has shown some information about depression and PARKINSON’S DISEASE that was not typically expected. Lee Blonder, Ph.D. used a small group of 28 subjects, all with PARKINSON’S DISEASE, 10 of whom were depressed and 18 who were not to examine the effects of dopamine replacement on cognitive function and depression. HIs expectations were that cognitive function would improve for both depressed and non-depressed subjects with the addition of dopamine. To his surprise, this did not prove to be true.
All of the subjects underwent a baseline series of cognitive testing and tests to measure the severity of their depression. Then they were all retested both with and without their regular dopamine replacement therapies. Subjects who were depressed were found to have poorer performance on three measures of the cognitive testing when taking dopamine replacement than without the dopamine. Mood of the depressed subjects was also worse on dopamine. For subjects that did not have depression, performance on cognitive testing improved on dopamine therapy and their mood was stable.
The results of this study raise concerns about treatment options that may compromise the mental health and cognitive functioning of depressed patients with PARKINSON’S DISEASE. Dr. Blonder cautions that this is a very small preliminary study and should not be used to change treatment plans until additional larger studies confirm his findings. Depression is very common in PARKINSON’S patients, with perhaps 40% of patients affected.
Review by Marcia McCall