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.
Evaluating DBS: Sooner is Not Always Better
An alliance of researchers in Germany and France recently published the results of a clinical trial that looked at the benefit of using Deep Brain Stimulation for younger people in earlier stages of PARKINSON’S DISEASE. These people have had relatively short term motor complication for less than three years. The subjects were not treated with standard pharmacological treatments, but instead, opted for the surgery earlier in the course of their disease. The study followed them for two years and reported significant improvements for the participants of the early DBS group over a control group receiving only best medical therapy..
The study caught the eye of several Canadian doctors with extensive experience in treating PARKINSON’S DISEASE, including Dr. Tony Lang, whose work with movement disorders and also with deep brain stimulation is very highly regarded in the medical field. He is affiliated with the Movement Disorders clinic at Toronto Western Hospital and also with University Health Network, Department of Neurology, University of Toronto, in Toronto, Canada. The Canadian researchers reviewed the results of the European trial and looked at it from many angles besides the actual clinical improvement of the patients.
The Canadian researchers acknowledged that the results of the surgery on younger subjects over all did result in better quality of life for the patient and reduction of tremor and rigidity.. But the European study also confirmed that DBS can also have serious adverse events, including risk of suicide, which has also been demonstrated in other clinical trials. In addition, the Canadian group feel that offering DBS to patients who have had motor symptoms for fewer than 5 years could include people with atypical parkinsonism that cannot benefit from the surgery. If symptoms are mild, the results from the surgery will also be mile, but the possibility of adverse events related to the surgery, such as infection, reaction to implanted materials or response to neuro-stimulation is the same as for patients with more advanced symptoms who would see greater benefit. Given that symptoms and severity of the symptoms vary for each individual with PARKINSON’S DISEASE, the decision over treatment must consider the seriousness of potential risks of DBS and whether there is an experienced team of practitioners who are able to respond quickly. DBS does not address all the problems of PD; bradykinesia is not helped, gait problems and freezing of gait may be worsened or even be induced by DBS.
The Canadian team pointed out that the European study was an open-label study, meaning that all participants received DBS and there was no control group receiving sham surgeries. Other Parkinson’s studies involving surgical procedures for cell transplantation have shown and extremely high, positive placebo response Expectation of benefit can be very powerful. Since all the participants in the European study willingly submitted to a serious invasive neurological procedure on their brain, it must be assumed that they had an extremely high expectation of benefit. This may have created an overly positive response to the surgery. Subjects that received only best available medical therapy may have also been negatively impacted, the lessebo effect, thinking they were not expected to show the same improvement as subjects receiving the DBS. This is supported by the fact that after the first, blinded part of the trial, most of the subjects in the medical therapy group elected to undergo the DBS. Caution must be used to interpret the results in light of these considerations.
The results from the European study do show some positive responses that are worth re-evaluating with further, better designed clinical trials. This trial was on a younger population, with a shorter duration of motor symptoms who were good candidates for surgery. At also only followed them for a relatively short time, two years. The results cannot necessarily be duplicated for old subjects with other motor or non-motor complications who might not be good candidates for surgery.
DBS can and has helped many people with Parkinson’s, it is not a question of its effectiveness. But it does bring into question the timing for the best applications of DBS for the best results for the individual undergoing the surgery. Many symptoms of Parkinson’s can be controlled for a long time with best medical therapies, without the risks involved with serious, invasive brain surgery. The decision to undergo this surgery, and the expected benefits or potential adverse events, has to be made by each individual. A multidisciplinary team experienced with Parkinson’s Disease as well ad DBS needs to be able to counsel the person and to be there to assist in the decision making as well as in follow up care.
Tiago A. Mestre, Alberto J. Espay, Connie Marras, Mark H. Eckman, Pierre Pollak and Anthony E. Lang
Article first published online: 16 SEP 2014 | DOI: 10.1002/mds.26024
Review by Marcia McCall
Dopamine Replacement and Nutrition in PARKINSON’S DISEASE
As PARKINSON’S DISEASE progresses and affected people age, maintaining proper nutrition becomes more challenging. A group of researchers from Rome, Italy studied a group of elderly people with PARKINSON’S DISEASE (PD) and found that fully one third of them were at risk for malnutrition. The authors are careful to state that they can draw no conclusive results nor establish any cause and effect relationship from their study of so small a sample group. But their observations are serious and pertinent and should be the basis for more extensive studies.
This study embraced a group of 75 elderly people with PD who attended a day care facility in a hospital center in Rome. All the subjects completed an informed consent and voluntarily participated in the study. Medical history and history of PD were carefully taken, together with questionnaires on the quality of life. They were asked about lifestyle habits such as history of smoking tobacco and/or drinking wine and screened for symptoms of depression. Medication history was also documented, with 69 subjects taking L-dopa, 56 were taking dopamine agonists and 50 of them were taking both L-dopa and an agonist.
Nutritional habits were documented using a standardized assessment and subjects were asked about their personal eating preferences. They were also asked if they had difficulty with chewing and if this difficulty had caused them to change their eating habits.
When the data from the study was tabulated, they found that 35% of the subjects taking L-dopa were at risk for malnutrition. Subjects taking higher doses of L-dopa and using only L-dopa were significantly more at risk of nutritional deficiencies. No association between dopamine agonists and malnutrition were established.
Researchers suggest there may be good reasons why the use of L-dopa therapies can contribute to malnutrition. Higher doses and long time use of L-dopa can lead to dyskinesias, which require a higher output of energy, and may also impair the subjects’ ability to chew. L-dopa can cause nausea, which may encourage anorexia. Other research has hypothesized a relationship between L-dopa and fat metabolism as well as on certain hormones that are involved in eating behavior. But they also suggest that perhaps age and duration of the disease contribute to poor nutritional status.
Dopamine agonists, on the other hand, might actually improve nutritional status. Weight gain has been associated with agonists and could actually encourage compulsive eating! Dopamine agonists also may alleviate depression, making eating more pleasurable and thereby improving nutrition and maintaining weight.
This study has been accepted pre-publication as a brief report in in the journal Movement Disorders.
Alice Laudisio MD1,*, Davide L. Vetrano MD2, Eleonora Meloni MD2, Diego Ricciardi PT2, Francesco Franceschi MD3, Anna Rita Bentivoglio PhD4, Roberto Bernabei MD2 and Giuseppe Zuccalà MD3 Dopaminergic agents and nutritional status in Parkinson’s disease; Mov.Dis. Article first published online: 12 SEP 2014 DOI: 10.1002/mds.25991
Review by Marcia McCall
Daytime Sleepiness and Disrupted Circadian Rhythms in PARKINSON’S DISEASE
Sleep problems affect more than half of people with PARKINSON’S DISEASE. Sleep problems may actually be a symptom that predicts the onset of PARKINSON’S DISEASE. People at risk for PARKINSON’S DISEASE have been known to have disturbed sleep and violently act out dreams. But once the disease has been diagnosed, people with PARKINSON’S DISEASE endure even more problems with sleep. Falling asleep may become difficult, staying asleep even more difficult. If sleeping at night is one problem, excessive daytime sleepiness is yet another difficulty. Many articles have been written about sleep and PARKINSON’S DISEASE, yet the underlying causes have resisted simple explanations. PARKINSON’S DISEASE is a very complex neurological disease whose motor symptoms also tend to occur in cycles. Many of the symptoms, no doubt, are interrelated; their effects compounded by each other.
Circadian rhythms define the sleep and wake cycles of all mammals and those rhythms are affected, in part, by the chemical melatonin, which is secreted in cycles by the pineal gland in response to daylight and darkness of the night. Aleksandar Videnovic, M.D. has been studying sleep in PARKINSON’S DISEASE and has released his newest study on the effects melatonin and circadian rhythms on excessive daytime sleepiness in people with PARKINSON’S DISEASE. This study was done at Northwestern University in Chicago, IL and involved 20 subjects with PARKINSON’S DISEASE and 15 age-matched controls. His objective was to determine the relationship between cycles of melatonin and quality of sleep and severity of daytime sleepiness together with other measures of the disease.
All of the subjects were studied in a modified normal environment for over 24 hours with blood samples being taken every 30 minutes. It would be difficult, if not impossible, to do this study without admitting subjects to a clinical setting so every effort was made to maintain as much as possible the normal environmental conditions of their daily lives, including medication schedules, food intake and exercise routines.
While both the control group and the PARKINSON group had no differences in the 24 hour circadian rhythm cycle, the PARKINSON group had diminished rhythms of melatonin release cycles compared to the control group and PARKINSON subjects who reported more daytime sleepiness had significantly lower melatonin rhythm. These results suggest that a dysfunction in circadian rhythms is involved in excessive daytime sleepiness in people with PARKINSON’S DISEASE.
The researchers note that this study is the first to be done in a controlled environment with blood samples taken every 30 minutes, and subjects were able to maintain their regular medications and schedules. They did not find any relationship between the Parkinson medications and the melatonin cycle, but study of people with PARKINSON’S who have taken no medications should also be evaluated. Other areas such as response to light that may be impaired by retinal degeneration due to dopamine or even autonomic dysfunction which is often a part of PARKINSON’S may play a role in the deregulation of the internal “clock” structure. More studies in the future are needed to address these issues.
At the present time, there are therapeutic approaches, such as bright light therapy and melatonin supplements together with structured physical activity programs and good sleep hygiene that may help to regulate the circadian cycles and improve sleep quality to diminish excessive daytime sleepiness.
Videnovic, A., et al; Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson’s disease; JAMA Neurol. 2014 April; 71(4): 463-469;doi:10.1001/jamaneurol.2013.6239
Review by Marcia McCall
Could Migraine Headaches Predict PARKINSON’S DISEASE?
A newly released study has found that people who suffer migraine headaches have an increased risk of developing PARKINSON’S DISEASE later in life. If those migraine headaches are also accompanied by auras, the flashing bright lights seen in the perimeter of their vision, the risk of developing PARKINSON’S DISEASE (PD) is doubled. While there appears to be an association of migraines to the risk of PD, the overall risk factor is quite small.
For some time, neurologists and psychiatrists have thought there may be a relationship between dopamine function and both migraine and PD. Dopamine dysfunction has been associated with both Restless Legs Syndrome and Parkinson’s and is suspected in the cause of migraines. Migraines are the most often reported neurological complaint, but there is still much research needed. An earlier study found that people who had a family history of migraine continued to suffer from migraines after the onset of PD. However, people who did not have a family history found their migraines improved or disappeared after the onset of PD symptoms. This study made no mention of whether the subjects experienced aura, but called for more research into the role of dopamine in both familiar and non familiar types of migraine.
The current study was conducted by Ann Scher, Ph.D. from the Uniformed Services University in Bethesda, MD. This was a 25 year study that followed 5,620 subjects in Reykjavik, Iceland. Of the original study group, 1,028 reported they suffered from headaches; of that group 668 suffered with migraine headaches and 430 of them also had auras with their headaches. Later, all the subjects were examined for symptoms of PD or Restless Legs Syndrome. 2.4 percent of the people who suffered migraines with auras developed PD while only 1.1 percent of people who had no headaches developed PD. The risk of developing PD is double for people who suffer migraines with aura, compared with people who do not suffer any headaches. But keep in mind, this is an estimate of risk, meant to inspire more research and while the actual level of risk is really very low. Interestingly, they also found that women who suffered migraines with aura also were more likely to have a family history of PD.
Migraines with aura have also been associated with risk of stroke or heart disease and are commonly linked with depression. Some studies have suggested that migraines may also affect the structure of the brain. While this research adds PD to the list, the call is for more research and better understanding of how the neurological problem of migraine relates to other neurological disorders such as PD or depression.
A. I. Scher, G. W. Ross, S. Sigurdsson, M. Garcia, L. S. Gudmundsson, S. Sveinbjornsdottir, A. K. Wagner, V. Gudnason, L. J. Launer. Midlife migraine and late-life parkinsonism: AGES-Reykjavik Study. Neurology, 2014; DOI:10.1212/WNL.0000000000000840
Barbanti, P., et al. “Dopamine and migraine: does Parkinson’s disease modify migraine course?.” Cephalalgia 20.8 (2000): 720-723.
Review by Marcia McCall
Assessing the Difficulties of Walking in PARKINSON’S DISEASE
Changes in the way they walk are an early alert that people may be developing some of the symptoms of PARKINSON’S DISEASE. Walking with smaller steps and kind of shuffling along without the rhythm of normal arm swing is a tell tale sign of PARKINSON’S DISEASE. But when does it start and how does it develop? Does dopamine replacement therapy help? Why do some people progress faster than others? Can early detection help slow the progression and help maintain quality of life a little longer? A group of researchers at Newcastle University in the United Kingdom focused on these issues and reported their findings in the journal, Movement Disorders.
Most studies on gait impairment (walking difficulties) have been done on subjects with more advanced disease symptoms and who have been on dopamine replacement therapies, so there has not been much knowledge about the early stages and progression of gait problems. Gait disturbances can be divided into 16 different characteristics, some of which are greatly helped by dopamine replacement therapies and others remain resistant. The researchers set out to establish an understanding of how gait disturbances progress in early PD, which characteristics responded to or were resistant to dopamine and to find if these responses might be useful in helping to make earlier diagnosis and treatments to delay the progression.
One hundred twenty one people newly diagnosed with PD and 184 non-Parkinson controls were recruited. All the participants were tested over the course of 18 months in comprehensive gait studies divided into 5 domains that included pace, variability, rhythm, asymmetry and postural control. Each of these domains were further divided into categories such as step velocity, step length, swing time, stance time and postural control. The PARKINSON’S subjects demonstrated significant impairment in 12 of the 16 characteristics of gait compared to the controls. Based on their symptoms the PD subjects were classified as either Postural Instability Gait Disturbance (PIGD) or Tremor Dominant (TD) with the PGID group showing the most impairment initially but showing minimal progression over the 18 month period while the TD group demonstrated slightly more progression in both step length and swing rhythm.
While gait characteristics such as length of step and swing time did demonstrate a decline over 18 months, PD subjects evaluated on their normal daily dopamine replacement therapy showed improvement, which continued to improve as the daily dopamine dose increased over the 18 month study. Impairment in width of step, particularly in the PGID group indicated problems with balance and postural control. These symptoms were not improved on dopamine replacement therapy.
These results demonstrate the need for early evaluation of gait characteristics to identify both dopamine responsive and dopamine resistant traits in order to initiate therapies that will improve walking and reduce falls from lack of balance. The failure of some characteristics of gait to respond to dopamine replacement therapy indicates a more complex involvement between dopamine and other neurological pathways.
Authors of this study include first author Brook Galna, Ph.D., Sue Lord, Ph.D., David J. Burn, M.D. and Lynn Rochester, Ph.D. all of whom are affiliated with The Newcastle University Institute for Ageing and the Institute of Neuroscience at Newcastle University, Newcastle Upon Tyne, in the United Kingdom.
Galna, B., Lord, S., Burn, D.J., Rochester, L.’ Progression of Gait Dysfunction in Incident Parkinson’s Disease:Impact of Medication and Phenotype. Published online 00 Month 2014 Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.26110
Review by Marcia McCall
A Skin Test to Help Diagnose PARKINSON’S DISEASE
In the early stages, PARKINSON’S DISEASE is difficult to diagnose accurately. There are no laboratory tests of blood or urine to define it and imaging studies such as the Dopamine Transporter or Magnetic Resonance Imaging are not always readily available, nor can they differentiate between other neurological diseases such as Multiple System Atrophy (MSA) or Progressive Supranuclear Palsy (PSP). Finding a biomarker, some substance that will be a reliable, measurable marker of a particular state of the disease that will indicate or predict the onset of PARKINSON’S DISEASE has been elusive but researchers are not giving up easily.
Alpha-synuclein has been the subject of a lot of research in PARKINSON’S DISEASE. It has been found to be one of the defining substances found in many regions in Parkinsonian brains, which unfortunately, can only be measured post mortem. Some studies have found alpha synuclein in other organs, outside of the brain, such as the heart, the digestive tract and even in the skin. It is not yet known if alpha synuclein in these peripheral organs is as destructive as it is in the brain, but it does suggest that PARKINSON’S DISEASE involves multiple organs. Other researchers in many institutions have focused on alpha synuclein found in the skin, and have employed many methods to study it resulting in conflicting results, but still adding to the existing knowledge.
A large consortium of researchers from five different research facilities in Mexico designed a study to examine the skin of people with clinically diagnosed PARKINSON’S DISEASE for the presence of alpha synuclein and to differentiate it from people with atypical PARKINSONISM. They enrolled 67 subjects, 34 with PD and 33 with atypical PD and a non-neurologically affected control group of 20 subjects. The researchers took skin sample biopsies that included three parts: the superficial skin layer called the spinous cell layer, the hair follicles or pilosebaceous unit and the ecrine (sweat producing) glands from all three groups of subjects.
All the samples were specifically stained to look for the presence of alpha synuclein and analyzed with immunohistochemical techniques followed by confocal microscopy and three dimensional imaging techniques. Samples from the control subjects showed there was no alpha synuclein present, but almost 60% of the PD subjects showed a positive presence in their epidermis, but only about 7% of the atypical PD subjects tested positive. In the PD positive group, alpha-synuclein was found in the surface skin, the hair follicle cells and the sweat producing glands. In the atypical PD group, very low amounts were found in the surface skin and hair follicle cells, but none was found in the sweat producing glands.
The investigators feel that this type of testing could be very useful in making the distinction between idiopathic PARKINSON’S DISEASE and atypical Parkinsonisms. Still, they feel that their study involved a limited number of subjects and they would like to see this research repeated with a larger cohort of subjects. The presence of alpha synuclein in the skin regions may well correlate to the changes occurring in the brain due to alpha synuclein, making skin testing a potentially accurate biomarker. It is a minimally invasive testing technique that is safe and affordable making it a practical screening tool to simplify accurate diagnoses.
Rodríguez-Leyva, I., Calderón-Garcidueñas, A. L., Jiménez-Capdeville, M. E., Rentería-Palomo, A. A., Hernandez-Rodriguez, H. G., Valdés-Rodríguez, R., Fuentes-Ahumada, C., Torres-Álvarez, B., Sepúlveda-Saavedra, J., Soto-Domínguez, A., Santoyo, M. E., Rodriguez-Moreno, J. I. and Castanedo-Cázares, J. P. (2014), α-Synuclein inclusions in the skin of Parkinson’s disease and parkinsonism. Annals of Clinical and Translational Neurology, 1: 471–478. doi: 10.1002/acn3.78
Review by Marcia McCall
Does Parkinson’s Disease Make You Afraid To Be Seen in Social Situations
PARKINSONS DISEASE definitely alters the quality of life of those people who are affected and causes them great distress when in social situations. A recently published study says about 42 percent of the PARKINSON’S population they studied did have serious or clinically significant social phobia and that over half of this group expressed varying degrees of anxiety in social situations. This demonstrates that social phobias are widespread in PARKINSON’S DISEASE and constitute a serious concern.
Not all people with PARKINSON’S DISEASE develop social phobias and that raises some questions. Is social phobia part of disease itself or does it develop as a response to the symptoms? Are the anti-Parkinson medications a contributor or is it a pre-existing condition aggravated by the disease symptoms and process? In this study, only a few people said they had serious fears of social situations before they developed PARKINSON’S, but about 25 percent of the people who developed social phobia during the course of the diseases said that they did sometimes feel shy or nervous in social interactions before they developed PARKINSON’S. For the rest, social anxiety emerged with the diagnosis PARKINSON’S. Over half of the people who developed social anxieties also suffered from depression.
Results of this study showed that more, younger men with an earlier onset of the disease developed social phobia than women. Older men were more affected by a longer duration of the disease, and postural instability along with gait disorders contributed to the older men’s fears. The authors speculated that perhaps the difference in social fears between men and women played on the men’s conceptions of their sexual and social roles.
A review of recent studies was not able to establish a positive correlation between social phobia and anti-Parkinson medications. The neurological and neurochemical changes that are part of the disease may also be contributors to the development of anxiety over the course of the disease. Studies in other neuropsychiatric diseases have found that dopamine and dopamine circuits do contribute to some psychiatric and behavioral conditions, but more research directed at PARKINSON’S is needed.
The results of this study together with information from other studies show that age of onset, duration of the disease and severity of the symptoms all are major contributors to social phobias in people with PARKINSON’S DISEASE. At some point in their disease, nearly all people with PARKINSON’S DISEASE develop social phobias. Social phobias together with PARKINSON’S DISEASE dramatically decrease the quality of life for the people who are affected. Partners’ and caregivers’ lives are also negatively impacted.
Withdrawal from social interactions and loss of friendship activities leads to isolation, despair and depression. It can make living with PARKINSON’S DISEASE utterly unbearable…for both patient and caregiver. Social phobias are a major issue that requires serious attention. Visits to the doctor are often focused only on the physical symptoms of the disease and medication regulation. Social phobia may even prevent talk about social phobias. Recognition and treatment for social anxiety needs to be recognized and treated early to improve the quality of life.
A good way to deal with social phobias in PARKINSON’S DISEASE is to get involved with other people who also have PARKINSON’S DISEASE. Join a support group, go to activities designed especially for people with PARKINSON’S DISEASE. PARKINSON’S PLACE offers a rich social involvement and many programs to improve the quality of life for people with PARKINSON’S. There are sessions for asking questions and information for caregivers–in a unique and specialized setting dedicated specifically to helping people learn to cope with this disease. Get Involved!
BK Gultekin, B Ozdilek, EE Bestepe'; Social phobia in Parkinson’s disease:Prevalence and risk factors. Neuropsychiatric Disease Treat., 2014, 10:829-834 Pub. online 5/21/14. doi: 10.20147/NDT.S62942 PMCID4049431
Review by Marcia McCall
A Vaccine for PARKINSON’S DISEASE
According to Wiki-pedia, a vaccine is “a substance used to stimulate production of antibodies and provide immunity against one or several diseases, prepared from the causative agent of a disease, its products or a synthetic substitute, treated to act as an antigen without inducing the disease.” There is no cure for PARKINSON’S DISEASE, and treatments, while helpful to some degree, do not stop the progression of the disease. But Parkinson’s is not like Mumps, Measles, Pertussis, or Rubella, diseases that vaccines have nearly eliminated. But there is hope on the horizon. An Austrian pharmaceutical research company, AFFiRiS AG has just announced that the first trial of a new medication has proven safe and tolerable in a group of 24 test subjects.
PD01A is a new therapeutic drug designed to generate antibodies specific to alpha-synuclein, thought to be a causative agent in PARKINSON’S DISEASE. In this study, two groups of subjects received two different doses once a month for four months. 8 subjects received “best medical care” but no vaccinations and served as control subjects and all the subjects were followed for the course of one year. At the end of the year, they were all evaluated and clinical specimens were obtained. Half of the subjects that received PD01A developed alpha synuclein specific antibodies in both their serum and their cerebrospinal fluid. These subjects also demonstrated a trend toward stabilization of their functional capacities. The company regards these results as very encouraging and plans to begin further clinical trials beginning this September.
PD01A represents a novel approach to the treatment of PARKINSON’S DISEASE. The role of alpha-synuclein is still not clearly understood and researchers do not agree whether its removal would be clinically beneficial or not. The disease pathology of PARKINSON’S DISEASE is still being studied and is by no means clearly established. Alpha synuclein is definitely involved in some genetically inherited forms of the disease and also is found in the post mortem brain tissues of subjects with Lewy body disease. In animal models, added alpha synuclein does cause clinical symptoms and progression similar to those seen in humans.
Much of the neurodegeneration in PARKINSON’S DISEASE occurs well before the symptoms become manifest. By some estimates, as much as 75% of dopamine producing neurons are affected before a subject shows any symptoms. If a vaccination is to be effective in disease modification, intervention would have to come sooner rather than later. A vaccine may not be effective if the disease is already extensive and the neurodegeneration is irreversible. Biomarkers for PARKINSON’S DISEASE might provide that early warning system, but that also raises ethical issues and much more research is needed Also, the relationship of alpha-synuclein to the later dysfunction of mitochondria and oxidative stress is still under investigation.
The results of this first small trial of PD01A are exciting and encouraging. The next study will address the immunological and clinical effects of a booster vaccination and will be done in Vienna. Development of this vaccine will be slow and cautious. A warning from a similar situation must also be heeded: the development of a vaccine to remove the tau protein from Alzheimer’s brains resulted in development of serious, life threatening side effects and had to be discontinued.
Article by Marcia McCall
Clinical Trials Begin for Novel Administration of Levodopa in Advanced PD
The Israeli pharmaceutical company, NeuroDerm Ltd., has begun clinical trials in human subjects with advanced stages of PARKINSON’S DISEASE who are unable to tolerate oral types of levodopa/carbidopa medications. They expect to have completed the first stage by the end of this year and will make their data public.
As PARKINSON’S DISEASE progresses and patients age, they become less able to tolerate the motor and non-motor fluctuations caused by absorption problems with orally administered levodopa/carbidopa. In advanced stages, oral levodopa no longer seems to be effective, and patients must decide between considering deep brain stimulation or the surgical insertion of an intra-duodenal levodopa/carbidopa pump. Both surgeries are invasive and subject to serious complications and for some people, neither feasible nor desirable.
NeuroDerm has developed a proprietary formulation of liquid levodopa/carbidopa, which they are able to deliver in a continuous dose subcutaneously with a patch and a pump worn on the belt. Delivering a continuous dose of levodopa/carbidopa will eliminate the uneven responses that come from scheduled doses not uniformly absorbed through the digestive tract. Using a pump to deliver a continuous, uniform dose directly under the skin both day and night should improve the effectiveness of levodopa/carbidopa and reduce motor complications and make life easier for people with PARKINSON’S DISEASE.
The present trial is designed to evaluate the response of people with advanced stages of PARKINSON’S DISEASE to various dosage strengths of NeuroDerm’s liquid formula levodopa/carbidopa. Safety and tolerability have already been established, this study will measure drug concentrations in blood levels and motor responses to the doses.
The company has also prepared a low-dose form of liquid levodopa/carbidopa for people with moderate stages of PARKINSON’S DISEASE. A Phase II double blind, randomized, placebo-controlled trial has just finished enrolling all the subjects and completed their treatment. The data is presently being analyzed and the results will soon be made available.
NeuroDerm is a company focused on developing and providing enhanced treatments for major neurodegenerative diseases that will overcome problems encountered with traditional therapies. All of their products are designed to be delivered in a continuous, steady dose delivered subcutaneously by a small pump worn on a belt. They have developed three types of liquid levodopa/carbidopa for patients with moderate to advanced stages of PARKINSON’S and another for an even more severe stage. They are currently developing a formula for liquid apomorphine for patients with severe stages of PARKINSON’S who do not respond to levodopa.
Information provided by NeuroDerm LLC, Rohovot, Israel
Reviewed by Marcia McCall
Klotho, The Genetic Spinner of Aging Destiny
Indeed, we are all destined to age, but some age better than others. Some age faster and some slower. A gene called Klotho appears to be the cause. Klotho seems a rather strange name for a gene, but it comes from the name of one of the triad of Greek Goddesses known as the Fates, those independent controllers of destiny, to whom even the gods must submit. The genetic Klotho was accidentally discovered as the missing gene that caused premature aging in a group of transgenic mutated laboratory mice. Many studies implicated of the lack of Klotho in disease processes, including kidney disease. Newer studies have shown the protective qualities the presence of Klotho provides on reducing oxidative stress, improving blood pressure and preserving the retina in the eye. Klotho can slow aging and prevent loss of mental abilities. Now the newest study shows additional Klotho promotes neuroprotection in the brain.
A team of researchers for Boston University has recently published their study findings in the Journal of Biological Chemistry showing the neuroprotective effect of Klotho against Alzheimer’s disease. They grew nerve cells in petri dishes in the laboratory. Klotho was added to some of the dishes. When amyloid, like that which is found to accumulate in the neurons of Alzheimer’s disease, was added to all the dishes, the ones with the added Klotho showed a much higher survival rate of nerve cells than the untreated dishes. Carmela Abraham, Ph.D.is the principal investigator of this study and a professor of biochemistry and pharmacology at Boston University Medical Center. She says “We now have evidence that if more Klotho is present in the brain, it will protect the neurons from the oxidative stress induced by amyloid and glutamate. Finding a neuroprotective agent that will protect nerve cells from amyloid that accumulates as a function of age in the brain is novel and of major importance.”
However, it is not possible to introduce Klotho directly as a pill or an injection as it is a large molecule that cannot cross the blood-brain barrier. A compound of smaller molecules that can cross the blood-brain barrier and increase the levels of Klotho in the brain is presently under development. Dr. Abraham believes that “increasing Klotho levels with such compounds would improve the outcome for Alzheimer’s patients, and if started early enough would prevent further deterioration. This potential treatment has implications for other neurodegenerative disease such as PARKINSON’S, Huntington’s, ALS and brain trauma, as well.”
E. Zeldich, C.-D. Chen, T. A. Colvin, E. A. Bove-Fenderson, J. Liang, T. B. Tucker Zhou, D. A. Harris, C. R. Abraham. The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System. Journal of Biological Chemistry, 2014; DOI: 10.1074/jbc.M114.567321
Review by Marcia McCall