Read about patient concerns, family dilemmas, and the clinical dynamics of a weekly movement disorder clinic. Observe ways a movement disorder neurologist manages patient symptoms with medications, surgical referrals, physical therapy, and caregiver options. Find out more in my Weekly Journal.
Interaction of LRRK2 and Alpha-Synuclein in PARKINSON’S Neurodegeneration
Studies have shown that in PARKINSONIAN brains, the mutated LRRK2 gene causes clumps of protein to form within neurons and an increase of kinases to develop. Ultimately, the cells die. In this particular study, researchers wanted to know if the increase of kinase was the cause of cell death or merely part of the reaction.
Early in his post doctoral work, Steve Finkbeiner, M.D., PhD, was not happy with the slow progress of examining cells and neurons one at a time. So he developed a robotic microscope that could examine multiple cells over periods of time and track their development or reaction to various other factors and agents. By using this unique robotic microscope, Dr. Gaia Skibinski and Dr. Finkbeiner of the Gladstone Institutes in San Francisco, CA, they were able to look at the long term progression within the individual cells rather than simply observing what happened to entire populations of cells.
To study this process, they developed two types of cells, one from rats genetically bred with a mutant LRRK2 gene. The second set came from induced pluripotent stem cells developed from the skin of people with the genetic LRRK2 variation of PARKINSON’S DISEASE. These human cells were a mirror image of what is actually happening in the brain cells of affected people. As they studied the development and progression of these cells, they found that it was neither the kinase activity nor the build up of LRRK2 proteins within the cells that lead to cell death, but rather the diffuse accumulation of the mutant LRRK2 gene.
Then they made an unanticipated discovery. Another protein, alpha-synuclein, long associated with PARKINSON’S DISEASE, was also building up in some of the cells. The relationship between LRRK2 and alpha synuclein has not been clearly understood. Dr. Skibinski found that removing the alpha synuclein proteins from the cells immediately reduced the levels of LRRK2 and brought a dramatic decrease in cell death. This unexpected discovery may well lead to better understanding of the relationship and roles of these proteins in neurodegeneration. Dr. Finkbeiner said “Our discovery of this ‘synergy’ between two proteins long known to play a role in PARKINSON’S is a huge step towards developing drugs that attack the disease’s underlying mechanisms. As we continue to unravel the precise functional relationship between alpha synuclein and LRRK2, we are well on our way to halting the onslaught of PARKINSON’S on the brain.”
G. Skibinski, K. Nakamura, M. R. Cookson, S. Finkbeiner.Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies. Journal of Neuroscience, 2014; 34 (2): 418 DOI: 10.1523/JNEUROSCI.2712-13.2014
Review by Marcia McCall
Non-Motor Symptoms Associated with Sleep Disorder in PARKINSON’S DISEASE
A study done in Great Britain found that patients who reported more severe non-motor symptoms such as depression, constipation, or hallucinations also reported having serious sleep behavior problems. While it is impossible to say that the sleep disorder is causative of the other non-motor symptoms, it appears that there are some common underlying pathologies shared between them.
Rapid Eye Movement Sleep Behavior Disorder (RBD) is usually experienced by men and often is present for many years before any other symptoms of PARKINSON’S DISEASE become apparent. They have frequent terrifying nightmares, such as being chased by wild animals or being pursued by armed thugs and they violently act out their defense, often hurting themselves in the process or actually injuring their bed partners. They may yell or scream, punch or kick and actually jump out of bed during the nightmare. What causes RBD is not really well understood, but it often foreshadows the development of neurodegenerative diseases such as Lewy body dementia or PARKINSON’S DISEASE.
When the study done at the Oxford Parkinson’s Disease Center by researcher Michele Hu, M.D., Ph.D., looked at 475 patients who had been diagnosed with PARKINSON’S DISEASE in the last 3 and a half years, they found that almost half of them had probable RBD based on responses to questionnaires. These same patients also reported more problems with non-motor symptoms and had more orthostatic hypotension (low blood pressure on rising from a sitting or lying position) as well as more depression. They scored lower on Mini-Mental State Examination and while there was no significant difference in cognitive testing scores in the early stages, patients with RBD did show earlier cognitive decline as the disease progressed than non RBD patients. They also reported more problems with swallowing, chewing, turning in bed and walking and balance earlier than patients without RBD.
Patients with RBD saw themselves as having more difficulties with their motor functions and also as having a poorer quality of life. Fortunately, there is a medication that helps at least 90% of the patients affected by RBD. Clonazepam is the drug that has shown effectiveness within less than a week of beginning the medication. It needs to be taken continuously. The advice of a skilled movement disorder specialist is need to determine which medication is appropriate, as some medications can actually cause the condition to develop or worsen over time.
REM Sleep behavior disorder is associated with worse quality of life and other non-motor features in early Parkinson’s disease; Michele Hu et al; J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-306104
Review by Marcia McCall
Researchers in France have injected 15 volunteers who were diagnosed with advanced PARKINSON’S DISEASE with a unique gene cocktail and initial results have been exciting and promising. Using a modified and deactivated virus for a carrier, three genes necessary for the production of dopamine were injected directly into the dopamine deficient brain regions of the subjects and within 12 hours the defective brain cells began producing dopamine.
Subjects were given three different doses of ProSavin® and followed for up to four years. Motor improvements were noted in all of them, with better coordination and balance and speech improvements. The improvements did depend upon the dose, with higher doses giving better response. However there were problems with development of dyskinesias and also periods of “on-off”. The gene injection appears to encourage long term production of dopamine and improvement in motor symptoms, up to four years.
It cannot be considered a cure, as the disease process does continue and symptoms can only be controlled. But even a four year improvement of symptoms would provide an amazing benefit to the quality of life of people with PARKINSON’S DISEASE. This study did not address the non-motor symptoms of PARKINSON’S DISEASE, or the effects of this therapy on cognitive function, apathy or depression.
This therapy was a very preliminary test and shows that gene therapy can be delivered effectively and safely. This was not a clinical trial as none of the subjects were given placebo treatments for comparison. The researchers are excited by the results and have begun preparing a newer version of the therapy, which will provide even more dopamine production. This could last longer than four years and be better tolerated than the first therapy test. This new version is presently being evaluated in animal studies for safety before it can be approved for use in humans.
ProSavin® is a registered trademark for the gene based treatment developed by Oxford BioMedica, a pharmaceutical company from the United Kingdom. It uses a patented process called LentiVector® to deliver the gene based enzymes directly to the striatum to restore dopamine production.
Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial
Prof Stéphane Palfi MD,Jean Marc Gurruchaga MD,G Scott Ralph PhD,Helene Lepetit PhD,Sonia Lavisse PhD,Philip C Buttery PhD,Colin Watts PhD,James Miskin PhD,Michelle Kelleher PhD,Sarah Deeley MSc,Hirokazu Iwamuro MD,Jean Pascal Lefaucheur MD,Claire Thiriez MD,Gilles Fenelon MD,Cherry Lucas BA,Pierre Brugières MD,Inanna Gabriel MD,Kou Abhay MD,Xavier Drouot MD,Naoki Tani MD,Aurelie Kas MD,Prof Bijan Ghaleh MD,Philippe Le Corvoisier MD,Patrice Dolphin MSc,David P Breen MRCP,Sarah Mason BSc,Natalie Valle Guzman MSc,Prof Nicholas D Mazarakis PhD,Pippa A Radcliffe PhD,Richard Harrop PhD,Susan M Kingsman PhD,Prof Olivier Rascol MD,Stuart Naylor PhD,Prof Roger A Barker PhD,Philippe Hantraye PhD,Prof Philippe Remy MD,Prof Pierre Cesaro MD,Kyriacos A Mitrophanous PhD The Lancet - 10 January 2014
Review by Marcia McCall
Pesticides and the Genetic Link
The central valley of California is a major producer of all the fruits and vegetables consumed, not just in the United States, but all over the world. Production of huge yearly crops depends upon serious planning and management, including the use of herbicides and pesticides. So three counties in this major agricultural region (Fresno, Kern and Tulare) became a very appropriate laboratory to study the effects of pesticides for Jeff M. Bronstein, MD, PhD, professor of neurology and director of Movement Disorders at the Geffen School of Medicine, University of California at Los Angeles.
His team developed a study, The Parkinson’s Environment and Genes (PEG) Study that recruited subjects from three of the most agricultural counties in the state of California. In the laboratory they found that many pesticides inhibit aldehyde dehydrogenase (ALDH) activity and this inhibition is also associated with risk of developing PARKINSON’S DISEASE. So the team tested 26 different pesticides and found only four structural classes of ALDH inhibiting pesticides that contribute to the risk of developing PARKINSON’S DISEASE. .
All humans carry a gene for ALDH, but not all humans exposed to pesticides develop PARKINSON’S DISEASE Interestingly, some people carry polymorphisms (slightly different versions) of the ALDH gene, and if they have no exposure to pesticides they do not develop PARKINSON’S DISEASE. Also, the study suggests that only about 6 per cent of people exposed to ALDH inhibiting pesticides actually develop PARKINSON’S DISEASE.
However, if a person carries a polymorphism for the ALDH gene, the, exposure to ALDH inhibiting pesticides increases the risk of developing PARKINSON’S DISEASE proportionately to the number of pesticides to which they are exposed. If a person was exposed to one, there was risk, but if they were exposed to six, the risk would be 6 times higher, and most people exposed to pesticides in the agricultural community are exposed to many. A six fold greater risk is enormous. The study also looked at whether a person was exposed only at work or only at home or at both and found much higher correlations when the exposure was at both work and home.
Inhibition of ALDH is thought to occur thru a chemical, dihydroxyphenylacetaldehyde (DOPAL), which is a dopamine derivative. And therein lies a potential target to lower the risk through inhibiting the enzyme that makes DOPAL. Dr. Bronstein notes that there are already drugs on the market that can protect against pesticide poisoning, but finding the 6 percent of the population that is at risk would be difficult to accomplish.
This study is an early but important step in showing mechanism of action between genetics and the environment in PARKINSON’S DISEASE and also to the number of exposures. It helps explain why the connection between pesticides and PARKINSON’S DISEASE which has long been suspected but was so difficult to prove. This study should bring more interest and research into this area to protect the people that are exposed to pesticides and to perhaps help develop less toxic pesticides that do not inhibit ALDH. It also seriously enforces the attention to regulation and safety issues for storing and handling pesticides as well as the methods of application.
J.M. Bronstein et al; How Pesticides May Boost Parkinson’s Risk; Neurology, 2014; 82:419-126
Review by Marcia McCall
Better Thinking and Less Depression with Higher Levels of Vitamin D
Amie L. Peterson, M.D. is first author on a study that was published in The Journal of Parkinson’s Disease that reports that higher Vitamin D levels in early PARKINSON’S DISEASE improve performance on cognition and mood tests. This study may open new interventions to prevent cognitive decline if started early in the course of the disease. Dr. Peterson is on the staff of Oregon Health and Sciences University.
The study examined vitamin D levels of 286 subjects and tested their performance in a battery of tests designed to measure memory and cognitive skills as well as indications of mood, such as depression. 61 of the subjects were considered to be demented, and their testing scores also showed a correlation to lower levels of vitamin D. For the remainder of the group, higher levels of vitamin D did correlate to better performance with memory and recall tests as well as ability to name images of animals and vegetables. They were also found to be less depressed as measured on a well known depression scale.
It was not known if any of the subjects in the study were currently taking supplements of vitamin D, nor is the authors willing to comment on whether or not vitamin D was the cause of the improvement. They speculate that more advanced subjects who already were slowed by the disease and dementia were less able to get outside and had limited exposure to sunshine, the major source of vitamin D. The results do suggest that there is a strong correlation between higher levels of vitamin D and better cognition with less depression. Because cognitive impairment early in the course of PARKINSON’S DISEASE may predict the development of dementia in later stages, anything that slows the development of cognitive problems could improve the quality of life and slow the course of the disease for people in the early stages.
“Memory, Mood, and Vitamin D in Persons with Parkinson’s Disease,” by Amie L. Peterson, Charles Murchison, Cyrus Zabetian, James Leverenz, G. Stennis Watson, Thomas Montine, Natasha Carney, Gene L. Bowman, Karen Edward, and Joseph F. Quinn. Journal of Parkinson’s Disease, Volume 3/Issue 4, DOI: 10.3233/JPD-130206
Review by Marcia McCall
Apomorphine for Treatment of Advanced Symptoms of PARKINSON’S DISEASE
Apomorphine has been available for many years as a “rescue” drug to help people with symptoms of advanced PARKINSON’S DISEASE, such as becoming frozen or having debilitating “off” periods. Because of its serious side effects has not been a drug of choice for many neurologists or patients. Apomorphine needs to be injected under the skin, which is painful and causes scaring. Once injected, it causes immediate nausea and vomiting; plus it needs to be maintained in an acidic composition. All of these ‘side effects’ make it a difficult remedy for an already too difficult set of symptoms.
Many pharmaceutical companies have tried for many years to find a viable formulation and delivery method to make Apomorphine more convenient and helpful for people with PARKINSON’S DISEASE. It has been put into patches, pumps and suppositories, and none of them have been effective in getting sufficient quantities of the medication into the bloodstream without causing major irritations or side effects.
The Canadian company Cynapsus has now developed a novel packaging and delivery method that avoids the adverse reactions with this medication. They have packaged in in a thin filmstrip that dissolves under the tongue, similar to the strips of mouthwash product, Listerine. The medication is embedded in the filmstrip, called APL-130277, which maintains the acidity until it dissolves in the mouth, and it is able to penetrate into the bloodstream within two minutes. It is not quite as fast acting as the injected form, but if negotiations with the Food and Drug Administration go well, the company will be moving ahead with clinical trials this summer. Because Apomorphine is already a known and approved medication, safety trials will not be necessary, which should also help speed this product to market.
PARKIN Mutation Carriers Progress Slower than Idiopathic PARKINSON’S DISEASE
If there is any such thing as good news in PARKINSON’S DISEASE, perhaps it is that people who have young-onset and carry the autosomal recessive gene for PARKIN mutations have a slower decline of motor symptoms and maintain higher cognitive functioning. While being diagnosed with young onset PARKINSON’S DISEASE is certainly not good news, these people may benefit from the assurance that their disease will progress more slowly and that they are at a lower risk for developing dementia than people diagnosed with idiopathic PARKINSON’S DISEASE.
A study of 44 subjects over a period of 14 years compared 21 subjects who carried the PARKIN mutation to 23 subjects who did not. Those who carried the mutation had an earlier age of onset and were younger than the subjects in the idiopathic cohort. These young onsets performed better on Mini-Mental State Examinations and had lower scores (indicating better performance) in Clinical Dementia Rating tests. They also scored higher in cognitive domains and did better in tests of visuospatial relationships, attention and memory. Motor performances were also better than those in the idiopathic cohort.
Primary researcher Dr. Roy N. Alcalay who is with Columbia University in New York says “our findings have important implications for genetic testing and for the counseling of homozygotes and compound heterozygotes that carry PARKIN mutations.” He also stresses that this was a small, cross sectional study and that more longitudinal studies need to be done to confirm these findings.
Alcalay, R.N, et al; Cognitive and Motor Function in Long-Duration PARKIN-Associated Parkinson Disease; JAMA Neurol 2014; 71(1) 62-67, doi:10.1001/jamaneurol.1023.4498
Review by Marcia McCall
Clinical Trial Considers Inosine Safe and May Lead to Future Treatments to Slow the Progression of PARKINSON’S DISEASE
Michael Schwarzschild, M.D., Ph.D. who is connected to the Harvard School of Public Health and Massachusetts General Hospital has been conducting research with urate levels for many years. In a report issued in May 2012, he stated that they had rather unexpectedly found that people who had higher levels of urate (uric acid) also had a lower than average chance of developing PARKINSON’S DISEASE. In that study, they found that urate served as an antioxidant that could protect cells from cell death, however it required the assistance or cooperation of neighboring cells, called astrocytes. Astrocytes are cells that provide both structural and metabolic support to neurons and it is their intervention that determines how the urate is used within the neural cells. The next question was to find out if urate increased artificially would provide the same protection as urate produced naturally.
The results of that study have found that Inosine, a precursor to uric acid, could be added to increase urate and that the results were safe and tolerable. To accomplish this they enrolled 75 very early onset people with PARKINSON’S DISEASE who had not yet begun taking any dopamine replacement therapy and who also had very low levels of urate in a two year study. Inosine occurs naturally in the human system, as a product of normal metabolism. Inosine given in this study was in pill form, which meant it had to be broken down via the digestive system. Two well known side effects of high uric acid levels are gout and kidney stones, so these potential effects were carefully monitored during the study. While kidney stones were developed in three of the participants, in two of the participants they were not related to the levels of urate and all were resolved successfully. After six months in the study, 95 per cent of the participants had no difficulties taking the Inosine drug.
The strengths of Inosine tested on these participants showed an increase in urate levels in both blood and cerebrospinal fluids. One month after stopping the medication, the urate levels of all participants returned to their pre-study levels. The safety and tolerability data together with some early data on effectiveness looks very encouraging “These results support advancing to a larger trial capable of addressing whether Inosine might fill the critical unmet need for a disease-modifying treatment.” says Dr. Schwarzschild. He and fellow investigators are moving toward the development of a much larger phase 3 trials which will study specifically the benefits and effectiveness of Inosine.
Urate levels increased artificially could have potentially serious side effects, so Inosine is not yet considered a safe treatment for PARKINSON’S DISEASE. “We know that excessively high urate can lead to kidney stones, gout and possibly other untoward effects, which is why attempts to elevate urate are best pursued in carefully designed clinical trials where the risks can be reduced and balanced against possible benefits, ” cautions Dr. Schwarzschild.
Michael A. Schwarzschild, MD, PhD; Alberto Ascherio, MD, DrPH; M. Flint Beal, MD; Merit E. Cudkowicz, MD; Gary C. Curhan, MD; Joshua M. Hare, MD; D. Craig Hooper, PhD; Karl D. Kieburtz, MD; Eric A. Macklin, PhD; David Oakes, PhD; Alice Rudolph, PhD; Ira Shoulson, MD; Marsha K. Tennis, RN; Alberto J. Espay, MD, MSc; Maureen Gartner, RN, MEd; Albert Hung, MD, PhD; Grace Bwala, MBBS; Richard Lenehan, MD; Elmyra Encarnacion, MD; Melissa Ainslie; Richard Castillo; Daniel Togasaki, MD, PhD; Gina Barles; Joseph H. Friedman, MD; Lisa Niles, MS; Julie H. Carter, RN, MN, ANP; Megan Murray, MA; Christopher G. Goetz, MD; Jeana Jaglin, RN, CCRC; Anwar Ahmed, MD; David S. Russell, MD, PhD; Candace Cotto, RN; John L. Goudreau, DO, PhD; Doozie Russell; Sotirios Andreas Parashos, MD, PhD; Patricia Ede, RN; Marie H. Saint-Hilaire, MD; Cathi-Ann Thomas, RN, MS; Raymond James; Mark A. Stacy, MD; Julia Johnson, MD; Lisa Gauger, BA; J. Antonelle de Marcaida, MD; Sheila Thurlow, MSN, BSN; Stuart H. Isaacson, MD; Lisbeth Carvajal; Jayaraman Rao, MD; Maureen Cook, RN, BSN; Charlise Hope-Porche, RN; Lauren McClurg; Daniela L. Grasso; Robert Logan, MS; Constance Orme, BA; Tori Ross; Alicia F. D. Brocht; Radu Constantinescu, MD; Saloni Sharma, MBBS; Charles Venuto, PharmD; Joseph Weber; Ken Eaton. Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease: A Randomized Clinical Trial. JAMA Neurology, December 2013
Review by Marcia McCall
Pharmacoperones – A New Way to Rescue Cells
While it appears to be a new technology, it has been a research project for 13 years and is finally showing beneficial effects in mouse models of disease. The procedure that has taken so long to develop has actually reversed a serious reproductive deficit in male mice. The condition in mice is parallel to the condition in humans, and the method perfected on mouse cells will also translate to human cells. This will be a major advance with wide ranging applications, particularly for neurodegenerative diseases such as PARKINSON’S DISEASE, Huntington’s disease and Alzheimer’s, among others.
When proteins such as alpha synuclein enter cells, they need to form a three dimensional structure in order to properly perform their function within the cell. When they do not form the proper structure, they are considered mis-folded proteins, which ultimately cause the cells to die. What this research has shown is that there are small molecules, which serve as a sort of “quality control” system, and when they encounter the misfolded proteins, they are unable to re-direct them thus causing them to fail. Use of another small molecule, a pharmacoperone, as a chaperone can enter the cell and serve as a scaffold to help the misfolded protein fold into the proper shape and then return to function. What is unique is that now they have found drugs to monitor the “quality control” system that can re-direct the misfolded proteins and rescue the cells. This is a whole new approach that may soon be able to cure a range of diseases
The team of researchers from Oregon Health Sciences University consisted of JoAnn Janovick and Michael Conn both of whom have recently left Oregon to join Texas Tech University Health Sciences. They were assisted in their research on this project by Richard, Behringer, M.David Stewart, Douglas Stocco and Pulak Manna. The research paper will be published in an early online edition of the Proceedings of the National Academy of Sciences.
Having seen such exciting and positive results in the mouse model, Dr. Conn is anticipating that clinical trials with humans will not be far in the future. Similar research is being carried out in other institutions for the treatment of diabetes, inherited cataracts and cystic fibrosis. Look for more exciting news and developments to come from this research in the near future.
Review by Marcia McCall
PARKINSON’S DISEASE Treated via the Computer
How would you like to have your next visit with your PARKINSON’S neurologist in the privacy of your own home? What if you didn’t have to travel to the office and could still have the benefit of an office visit? Or if you were able to have the benefit of consulting a specialist who may be too far away to actually visit in person? It may be coming sooner rather than later.
Allison Willis, M.D. did a chart review of 138,000 people diagnosed with PARKINSON’S DISEASE and was alarmed to find that more than 40% of them never had the benefit of seeing a movement disorder specialist. She also found that 40% of them who did have the benefit of a neurologist had a 22% reduced risk of death and a 21% reduced risk of entering nursing home care. And only about 8% of the people with PARKINSON’S ever saw a movement disorder trained neurologist.
Peter Schmidt, Ph.D., has a degree in biomedical engineering. He was challenged by the numbers in Dr. Willis’ study and thought there must be a better way to connect patients with trained neurologists. So he worked out the technical issues between the math and medicine. Ray Dorsey, M.D. is a movement disorder trained neurologist at the University of Rochester Medical Center. Previously, he and another neurologist had developed and piloted a telemedicine program of PARKINSON’S patients in a nursing home. The next challenge was taking the telemedicine program to other people with PARKINSON’S DISEASE. He used a $50,000 grant from Verizon and was able to consult via high speed internet connection with patients in their homes.
Working together with Dr. Schmidt and other colleagues, they were able to write a proposal that would allow them to connect with about 200 patients in their homes. They received a $1.7 million dollar grant and since May of this year has been able to provide telemedicine care to about 100 people and hope to expand that to 200 people. The project has so far covered only 5 states, and provides a one time telemedicine consultation for free. Considering that there are few PARKINSON’S specialists spread far and wide and many, many people with PARKINSON’S, this may prove to be a much better way to provide people with the benefits of a specialist’s knowledge and use the doctors’ clinical skills more effectively. It may not be quite as good as a visit in person, but it is better than no visit to a specialist at all. The future will surely see many technological improvements. Dr. Dorsey’s vision is that “anyone with PARKINSON’S, anywhere can get the care they need.”
Vinayak Venkataraman, Sean J. Donohue, Kevin M. Biglan, Paul Wicks, E. Ray Dorsey. Virtual visits for Parkinson disease. Neurology: Clinical Practice, December 2013
Wilis, A>W>, Schootman, M., Evanoff, BA, et al. Neurolgist care in Parkinson disease. Neurology, 2011; 77:851-857
Review by Marcia McCall