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.
Mindfulness Training Changes the Structure of PARKINSON’S DISEASE Brains
PARKINSON’S DISEASE is both motor symptoms, including the usual trinity of slowness, rigidity and tremor, and non-motor symptoms, such as depression, anxiety, apathy, cognitive changes and pain. The pathology of PARKINSON’S DISEASE is still not clearly understood; however it is understood that responses to therapies other than the standard dopaminergic agents such as serotonergic or cholinergic agents demonstrate that other parts of the nervous system are also affected. For many people, the non-motor symptoms are harder to live with than the motor symptoms. This could be of importance for their understanding of the disease and for following instructions.
So researchers at the University of Antwerp in Belgium, headed by Barbara A. Pickut, M.D., M.P.H. wanted to know if a meditation therapy might also be helpful to treat the symptoms and slow the progression of PARKINSON’S DISEASE in the brain. A small pilot study had lead the researchers to think that a Mindfulness Based Intervention (MBI) held hope to help people with PARKINSON’S DISEASE improve their coping skills and benefit from group support. The researchers wanted to validate the study by obtaining anatomical MRI brain scans of the participants.
Mindfulness is a method of meditation that involves developing an awareness of the present moment, the moment at hand, without passing judgment on it and accepting it with compassion. There is a growing body of literature that describes the positive effects of Mindfulness on a variety of disease states, such as multiple sclerosis and on pain relief in fibromyalgia. It has been helpful, too, with reducing anxiety and relieving depression. The benefits of Mindfulness meditation appear to manifest in improved quality of life, beyond there actual period of meditation.
Thirty people with PARKINSON’S DISEASE were recruited and evaluated to ascertain their level of anti-Parkinson medication, their cognitive status and that they had never participated in a meditation based therapy. They all received MRI scans and then were then divided into two groups. One group received usual care and the other received the Mindfulness training for eight weeks. Participants in the Mindfulness group had a weekly two and a half hour meeting. During these practice sessions, they learned mindfulness exercises in mindful body scan, mindful movement (mindful yoga) and sitting meditation. They were shown how to continue their practice at home and directions integrating it into everyday activities daily life and especially for coping with stress. They were also given recorded exercises for their own use. During the eight weeks of the study, both the usual care group and the MBI group received regular optimal medical care. At the end of the study, both groups received another MRI scan.
While the authors of this study examined the brain scans in great detail, this will be a simplified version of their findings. In the MBI group, they found the grey matter density to be increased in the regions of the hippocampus and the right amygdala. The right and left caudate nucleus, left occipital lobe and left thalamus also demonstrated greater gray matter density. These regions are all know to be affected by PARKINSON’S DISEASE.
In the group that received only the usual care, only the cerebellum showed an increase in gray matter density. This is the part of the brain that tries to compensate for other areas affected by PARKINSON’S. Amazingly, this was not found in the brain scans of the MBI group, suggesting that mindfulness made the support of compensation less necessary.
This is an early and preliminary study and no solid conclusions should be drawn from it. But it does provide some interesting results that could lead to more research. While increased density in gray matter is indeed, fascinating, more clinical or functional improvement measures would also be important to help understand the relationship of Mindfulness to the lives of people with PARKINSON’S DISEASE.
Barbara A. Pickuta,b,g,h,∗, Wim Van Heckea,c, Eric Kerckhofsd, Peter Mariëne,g,
Sven Vannestea, Patrick Crasa,b,h, Paul M. Parizela,f; Mindfulness based intervention in Parkinson’s disease leads tostructural brain changes on MRI; A randomized controlled longitudinal trial; Clinical Neurology and Neurosurgery , article in press.
Review by Marcia McCall
Clinical Implications Of Pre-Motor Symptoms and PARKINSON’S DISEASE
By the time the symptoms of PARKINSON’S DISEASE are sufficiently significant to make the diagnosis, at least 50% of the dopaminergic neurons have already been lost. There have been early signs, such as loss of sense of smell, gastrointestinal issues, psychiatric issues like depression or anxiety, perhaps sleep disturbances like acting out while in a deep dreaming state. Taken individually, they may not send red lights flashing: Warning–PARKINSON’S DISEASE ahead. And even after dopamine replacement therapy is started, these symptoms do not vanish.
Hindsight being 20-20, these pre-motor symptoms seem to universally affect people who develop PARKINSON’S DISEASE. But people who never develop PARKINSON’S DISEASE also can experience some of these symptoms and they are fairly common among the elderly. Many studies have been conducted to assess various pre-motor symptoms and their relationship to the development of PARKINSON’S DISEASE. Loss of sense of smell has been the focus of several, but preliminary data show that this single symptom is not an adequate predictor, other combinations of symptoms will also need to be considered. Studies that have examined loss of sense of smell together with constipation, slow reaction time and excessive daytime sleepiness found 2 people out of 24 who had at least three of the four symptoms did develop PARKINSON’S DISEASE during a 3 year follow up period. Other researchers have combined pre-motor symptoms including loss of sense of smell with neuroimaging studies, but the results have not been definitive. Studies of subjects with sleep behavior disorder have been more conclusive, but these studies require that subjects undergo polysomnographic studies, which can be awkward to obtain.
At a conference held last year, researchers raised questions and sought better ways to evaluate the relationship of pre-motor symptoms to the development of PARKINSON’S DISEASE. For instance, people who have sleep behavior disorder have also had exposure to pesticides and head trauma, but the degree of relationship between them has not been quantified. People who have gastrointestinal disturbances may also have had an exposure to an environmental agent, or perhaps there is a relationship to the development of alpha-synuclein pathologies. Could an environmental agent that enters through the gastrointestinal tract then be responsible for traversing to the substantia nigra and wiping out the dopaminergic tract? Research done in some mouse models exposed to the pesticide rotenone has demonstrated aggregates of alpha synuclein forming in the gastrointestinal tract and that it then follows an orderly progression. More research on other models is needed to verify that this is indeed happening, but studies such as this could provide a better mechanistic understanding of the gastrointestinal and metabolism systems respond to environmental agents.
Much more research is needed to establish the relationship of pre-motor symptoms to the development of PARKINSON’S DISEASE. Such research could help identify high-risk populations and reveal which environmental agents are involved and the manner of their involvement. This is an exciting area of emerging research that presently is in the early stages but hold promise for helping understand the processes of PARKINSON’S DISEASE.
Honglei Chen,1 Edward A. Burton,2 G. Webster Ross,3 Xuemei Huang,4 Rodolfo Savica,5 Robert D. Abbott,6 Alberto Ascherio,7 John N. Caviness,8 Xiang Gao,7 Kimberly A. Gray,1 Jau-Shyong Hong,1 Freya Kamel,1 Danna Jennings,9 Annette Kirshner,1 Cindy Lawler,1 Rui Liu,1 Gary W. Miller,10 Robert Nussbaum,11 Shyamal D. Peddada,1 Amy Comstock Rick,12 Beate Ritz,13 Andrew D. Siderowf,14Caroline M. Tanner,15,16 Alexander I. Tröster,17 and Jing Zhang18; ; Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications; Environ Health Perspect; DOI:10.1289/ehp.1306967
Review by Marcia McCall
One Mutated Gene Causes Multiple Neurodegenerative Disorders
A single mutated gene targets cells in the basal ganglia and disrupts the cells’ abilities to function normally. The gene, HPRT short for Hypoxanthine Guanine Phosphoribosyltransferase,, is considered a “housekeeping gene”, responsible for cellular maintenance and repair. When it is mutated, it affects the neurotransmitter dopamine and dopamine neurons and results in many neurological diseases including Alzheimer’s, PARKINSON’S DISEASE, Lesch-Nyhan, and Huntington’s disease.
Researchers on the study team lead by Theodore Friedmann, M.D., professor of pediatrics at the University of California, San Diego conducted a gene expression study using mouse embryonic stem cells modified to be lacking in HPRT. They found that when HPRT is deficient cells do not develop normally; although they appear as neurons, their functions are impaired. Some of the impaired functions observed were with cell cycles and replication, RNA metabolism, DNA damage and repair as well as cell signaling.
Results of this study provide preliminary results, showing how a defect in this gene leads to the cellular defects found in many neurological diseases. Research can now look for ways to target HPRT genetic mutation possibly leading to specific treatments. It is one of many pathways in the development of neurological disease; the task of future research lies in finding ways to better understand these pathways.
Tae Hyuk Kang, Yongjin Park, Joel S. Bader, Theodore Friedmann. The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation.PLoS ONE, 2013; 8 (10): e74967 DOI:10.1371/journal.pone.0074967
reviewed by Marcia McCall
Walking Speed and PARKINSON’S DISEASE
Researchers at the University of Michigan headed by Nicolaas Bohnen have found that the speed of walking in PARKINSON’S DISEASE depends not only on lack of dopamine but can also be affected by lack of acetylcholine. This suggests that “the clinical heterogeneity of PARKINSON’S DISEASE results from variable involvement of different brain systems”, according to Dr. Bohnen.
In a study that involved 125 subjects with PARKINSON’S DISEASE, they found 38 of them lacked acetylcholine in addition to lack of dopamine. When they compared the speed of walking to a control group of 32 non-Parkinsonian subjects, they found the group lacking dopamine walked only slightly slower than the control group. The speed of the group lacking both acetylcholine and dopamine was markedly slower.
They also compared cognitive function in relation to speed of walking and found that the lack of acetylcholine “may reflect the impact of impaired cognitive processing during ambulation.” The cognitive scores of subjects with lack of acetylcholine and dopamine were lower than those with lack of dopamine only, but non Parkinsonian subjects scored higher than both groups of subjects with PARKINSON’S DISEASE.
The results of this study indicate that people with PARKINSON’S DISEASE whose problems with walking speed do not improve on dopamine replacement therapy may have a form of PARKINSON’S DISEASE that is a multisystem neurodegenerative disorder.
Nicolaas I. Bohnen, MD, PhD, Kirk A. Frey, MD, PhD, Stephanie Studenski, MD, MPH, Vikas Kotagal, MD, Robert A. Koeppe, PhD, Peter J.H. Scott, PhD, Roger L. Albin, MD Martijn L.T.M. Müller, PhD;Gait speed in Parkinson disease correlates with cholinergic degeneration Published online before print September 27, 2013, doi: 10.1212/WNL.0b013e3182a9f558Neurology 10.1212/WNL.0b013e3182a9f558
review by Marcia McCall
Another Link in the Role of Alpha Synuclein in PARKINSON’S DISEASE
Travis Dunckley, Ph.D., an assistant professor and research scientist at the Translational Genomics Research Institute in Arizona has found that the absence of a particular protein, SMG1, may contribute to the accumulation of alpha synuclein in brain cells of people with PARKINSON’S DISEASE, various forms of dementia and multiple system atrophy.
SMG1 is a gene that helps cells in the manufacture and use of energy created in the mitochondria, the little power sources for each cell. Dr. Dunckley and his team found that this protein was either very limited or lacking in post mortem brains of people with PARKINSON’S DISEASE and other neurodegenerative diseases. To arrive at this discovery, they used very advanced genomic techniques to screen hundreds of human chemical regulators of cell function and cell metabolic processes to understand how they relate to the accumulation and aggregation of alpha synuclein. They found that lack of SMG1 was significantly related to the expression of synucleins in cells Knowledge of the specific actions or lack of action of these chemicals may lead to the development of specific drugs to prevent the development of alpha synuclein and its toxicity in brain cells.
The Mayo Clinic in Scottsdale, Arizona and the Banner Sun Health Institute, also in Arizona collaborated with Translational Genomics Research Institute and Dr. Dunckley on this study. Their findings are published in the October 30, 2013 PLOS ONE journal.
Adrienne Henderson-Smith, Donald Chow, Bessie Meechoovet, Meraj Aziz, Sandra A. Jacobson, Holly A. Shill, Marwan N. Sabbagh, John N. Caviness, Charles H. Adler, Erika D. Driver-Dunckley, Thomas G. Beach, Hongwei Yin, Travis Dunckley. SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA Screening. PLoS ONE, 2013; 8 (10): e77711 DOI: 10.1371/journal.pone.0077711
reviewed by Marcia McCall
Falls and PARKINSON’S DISEASE
As people age, falls become a more serious complication and people with PARKINSON’S DISEASE fall three times more often that people without. Consequences of falls can range from minor bruising to fractures and loss of consciousness and account for many trips to the emergency room. Some studies have shown that every third fall results in serious injury and after their fall, people begin to fear going out walking in public.
Several studies have focused on falls in PARKINSON’S DISEASE, most recently published are two papers by a Polish Research team who evaluated the causes and consequences of falls of people with PARKINSON’S DISEASE and looked at the risk factors for falls. Their research found that sudden falls were the most common and were caused by problems related to PARKINSON’S DISEASE, such as freezing, postural instability, or sensory disturbances like vertigo. Other research found that lack of arm movement lead to a higher risk of hip fractures and that stiffness and rigidity lead to falling backward. They also found that subjects who were “multi-tasking” and thinking more about the task than their walking also had a higher incidence of falling. Falls also occur during times when medications are not working properly.
There are many precautions that can be put in place to help make walking in the home safer and prevent falls. Pay attention when in close quarters that require turning around or backing up, such as in bathrooms and kitchens, be extra aware. The installation of grab bars in bathrooms can eliminate some of the problems, especially around showers, bathtubs and toilets. Loose rugs in entryways are another hazard, they need to be smooth and firmly in place so they don’t slip or move around or else removed entirely for safety sake. Long hallways can have hand rails installed the length of them to make waking easier. Look at the arrangement of furniture, the backs of couches and sturdy chairs can serve as extra support for someone walking behind them; but some pieces of furniture, such as tables with sharp edges can be hazards to bump into and should be placed where they won’t cause a problem. Going up and down stairs, whether they be a few or many, require sturdy handrails and step treads to be non-slip and perhaps even edged with reflective tape to make them more visible. Good lighting in all areas is also a safety necessity.
Physical and occupational therapists can also help by showing people with PARKINSON’S DISEASE better ways to get up from chairs and from bed. They can provide exercises to strengthen postural instability and improve gait and balance so walking becomes more natural and less hazardous. People with PARKINSONS DISEASE need to be extra careful on standing up, especially since orthostatic hypotension (low blood pressure on standing) is a frequent problem. Taking a moment to stretch and twist to improve blood flow before walking can also ensure a bit more safety from falling. Following a regular exercise program to strengthen the spine and keep muscles in shape while improving posture is a good idea.
Use of a cane or a walker can also improve balance and is useful especially in crowded areas. A cane or a walker can also signal to other people to stay out of the way and give a little more space to the person using it. If there is a tendency to step or fall backward, a walker can be of use keeping the upper torso forward leaning and the movement going forward.
All falls should be reported to the neurologist, with a note about when and how they occurred. It may be a simple tweaking of medication that can help prevent future falls, depending on when and how they happened. Continuing physical therapy is also beneficial to keeping abreast of exercises and ways to prevent falls and remain independent as long as possible.
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“Mushroom Alcohol”, Neurodegeneration and PARKINSON’S DISEASE
During Hurricane Katrina, researcher Joan Bennett lived in New Orleans and worked at Tulane University. Her home was flooded by the hurricane and during the clean up period, she was plagued with headaches, nausea and dizziness. Her work was as a scientist, and specifically as a plant pathologist, so she collected samples of the molds she found wearing appropriate protective gear and masks and gloves. A bit later, she transferred her job to Rutgers.
There, she met Arati Inamdar, Ph.D., who is a researcher in the School of Environmental and Biological Sciences at Rutgers. Together, they began testing Bennett’s samples of mold in hopes of finding why Bennett had been sickened after Katrina. They discovered that those mold samples contained a volatile organic compound known as 1-octen-3-ol, that is also known commonly as mushroom alcohol. They exposed fruit flies to this compound and found that they developed movement disorders similar to the disorders caused by pesticides such as rotenone or paraquat. Further testing showed that 1-octen-3-ol caused loss of dopamine in two specific genes that lead to a loss of neurons and the development of Parkinson’s like symptoms.
“Parkinson’s has been linked to exposure to environmental toxins, but the toxins were man-made chemicals,” said Inamdar. “In this paper, we show that biologic compounds have the potential to damage dopamine and cause Parkinson’s symptoms.” Many new studies show that Parkinson’s disease is increasing in rural areas, but is often thought to be from exposure to pesticides. Rural areas also have high rates of mold and mushroom exposure. Now there is the possibility that for people with a genetic predisposition, molds and volatile compounds that are produced by molds and fungus may also lead to the development of symptoms like PARKINSON’S DISEASE.
As with most research projects, this work was accomplished by a team. On this team were Muhammad Hossein, Jason Richardson, Alison Bernstein and Gary Miller. Their paper was published this week in the journal Proceedings of the National Academy of Sciences..
Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration
Arati A. Inamdar,Muhammad M. Hossain, Alison I. Bernstein, Gary W. Miller, Jason R. Richardson,and Joan Wennstrom Bennett PNAS 2013 ; published ahead of print November 11, 2013, doi:10.1073/pnas.1318830110
Review by Marcia McCall
The result of a Phase III study that was released on November 1, 2013 demonstrated that Pimavanserin was effective in relieving symptoms of psychosis in people with PARKINSON’S DISEASE without worsening the other symptoms of the disease. Pimavanserin is a new type of anti-psychotic drug that works by blocking the receptors for serotonin in areas of the brain that connect sensory perceptions and conscious thoughts.
Psychosis in people with PARKINSON’S DISEASE is not an uncommon occurrence. It is a very serious issue that makes caregiving in the home nearly impossible and results in the admission of people with PARKINSON’S DISEASE to long term care facilities where they can be monitored day and night. Prognosis is not good, and often marks the beginning of serious decline.
Hallucinations usually manifest as rather benign hallucinations, often of children or seeing “little people”, but can sometimes be much more serious with visions of malevolent intruders or assume sexual overtones. Long time use of anti-parkinson’s medications, such as levodopa replacement therapies is thought to be at least part of the cause as well as the disease pathology itself. Sleep disturbances are also a major contributor to psychotic symptoms. Newer studies have shown there are other irregularities in the white matter fibers of the brain that also contribute to psychoses in people with PARKINSON’S DISEASE, but whether the damage to white matter fibers is caused by the disease or contributes to the disease has not been clearly elucidated.
Neurologists’ usual response to hallucinations is to reduce levodopa to the lowest effective dose possible, and if that does not solve the problem, then to introduce antipsychotic medications. Seroquel (quetiapine) is often the first drug of choice, but clinical trials have shown very limited benefit. Clozaril is also a possible candidate, however it requires bi-weekly blood draws to monitor liver function, a major drawback for the already compromised lives of people with PARKINSON’S DISEASE. Anti-depressants have sometimes shown good results, and certain anti cholinergic medications have also sometimes been effective, but side effects have been problematic.
Pimavanserin has been developed by the pharmaceutical company Acadia. The Food and Drug Administration has agreed that the studies thus far conducted have been favorable and they are allowing Acadia to go forward with filing a New Drug Application. A few more supportive studies must be undertaken before approval can be granted, but the company is focused on moving ahead to obtain FDA approval as quickly as possible.
News release from Acadia Pharmaceuticals
Article by Marcia McCall
PARKINSON RESEARCH FOUNDATION
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“Overview of Parkinson’s Disease and Newer Drugs in the Pipeline”
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