Category: Parkinson’s

The study looked at whether a social and physical activity linked to music, such as tango, could have possible therapeutic value for PD patients who characteristically suffer from motor dysfunctions — tremor, rigidity, gait dysfunction — as well as from non-motor symptoms, such as depression, fatigue and cognitive degeneration. Forty men and women with idiopathic Parkinson's disease participated in the study, which involved studio classes with two professional dance teachers. Patients were from the Movement Disorders Clinics of the McGill University Health Centre.

 

"There's accumulating evidence that habitual physical activity is associated with a lower risk of developing PD, which suggests a potential slowing of PD progression," says Dr. Silvia Rios Romenets, lead researcher in the study with a special interest in Parkinson's disease and dance therapy. Dr. Rios Romenets is a clinical research fellow at the Movement Disorders Clinics at The Neuro and Montreal General Hospital. "In the study, we found the tango was helpful in significantly improving balance and functional mobility, and seemed to encourage patients to appreciate their general course of therapy. We also found modest benefits in terms of patients' cognitive functions and in reducing fatigue. No significant changes were detected in overall motor functions."

 

Argentine tango may be particularly helpful for improving balance and functional mobility in patients with PD. Tango requires specific steps that involve rhythmically walking forward and backward. This may be particularly helpful for walking difficulties especially for freezing of gait and to prevent backward falls. In addition, tango requires working memory, control of attention, and multitasking to incorporate newly learned and previously learned dance elements, to stay in rhythm with the music, and maneuver around others on the dance floor.

Many PD patients find traditional exercise programs unappealing. Over half of PD patients fail to get their recommended daily dose of physical activity. There is however, a connection between music and the dopamine systems in the brain — which are pivotal for establishing and maintaining behavior. So, combining music with exercise in dance such as the tango, can increase accessibility, enjoyability, and motivation, as well as improving mood and stimulating cognition. Also, the social interaction and social support involved in tango have positive results on mood and compliance.

 

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Journal Referance:

1. Silvia Rios Romenets, Julius Anang, Seyed-Mohammad Fereshtehnejad, Amelie Pelletier, Ronald Postuma. Tango for treatment of motor and non-motor manifestations in Parkinson's disease: A randomized control study. Complementary Therapies in Medicine, 2015; 23 (2): 175 DOI: 10.1016/j.ctim.2015.01.015

In collaboration with colleagues at Oxford, a team of researchers at Umeå University in Sweden has now further elaborated its discovery of a way to detect Parkinson's disease at an early stage, and applications in clinical care are not far away.

The project is an example of bridging the gap between basic and clinical research in care environments. The new findings are based on close cooperation between the medical chemist Ludmilla Morozova-Roche's and the neurologist Lars Forsgren's research teams at Umeå University and Jason Davis's team at Oxford University in the UK, who were primarily responsible for the chemical analyses. Their findings are now being published in the journal Chemical Science.

Parkinson's disease attacks the nervous system and, like many other diseases, is caused by proteins that lump together into so-called amyloid. Behind these new findings lies a discovery from the spring of 2011, when the Umeå scientists were able to determine endogenous antibodies against the most important amyloid protein, alpha-synuclein. These antibodies were seen as being able to function as a diagnostic marker, thereby enabling early detection of the disease.

In the new article the discovery is elaborated further in the form of a simplified way to carefully measure the content of antibodies in a blood sample. With the newly developed method — this involves electrochemical analysis of 10 microliters of blood in just a few minutes — it is possible not only to see a clear difference between individuals with incipient Parkinson's disease and healthy controls but also to measure and establish the advance of the disease with great precision.

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson's disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson's and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published September 25 in the online edition of Nature Communications.

Studies of rare, familial (heritable) forms of Parkinson's show that a protein called alpha-synuclein plays a role in the development of the disease. People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson's. Another key feature of Parkinson's is the presence of excess alpha-synuclein aggregates in the brain.

As the vast majority of patients with Parkinson's do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson's nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.

Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson's. "It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and neurology at CUMC. "Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson's. In our study, we show that people with 'bad' variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain."

"An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models," said Dr. Abeliovich. "In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don't really get Parkinson's, which underscores the importance of including the analysis of human brain tissue."

"Furthermore, we found that exposure to toxins associated with Parkinson's can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease," said Dr. Abeliovich.

The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson's. The CUMC team is currently searching for drug candidates and has identified several possibilities.

The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson's, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. "There is a tremendous need for a biomarker for Parkinson's, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups," said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug's effectiveness.

The study was supported by the grants from the Michael J. Fox Foundation, the National Institutes of Health, and the National Institute of Neurological Disorders and Stroke (RO1NS064433).

The scientists found that a common mutation to a gene that produce the enzyme LRRK2, which is responsible for both familial and sporadic cases of Parkinson's disease, deforms the membrane surrounding the nucleus of a neural stem cell. Damaging the nuclear architecture leads to destruction of these powerful cells, as well as their decreased ability to spawn functional neurons, such as the ones that respond to dopamine.

The researchers checked their laboratory findings with brain samples from Parkinson's disease patients and found the same nuclear envelope impairment.

"This discovery helps explain how Parkinson's disease, which has been traditionally associated with loss of neurons that produce dopamine and subsequent motor impairment, could lead to locomotor dysfunction and other common non-motor manifestations, such as depression and anxiety," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory, who led the research team. "Similarly, current clinical trials explore the possibility of neural stem cell transplantation to compensate for dopamine deficits. Our work provides the platform for similar trials by using patient-specific corrected cells. It identifies degeneration of the nucleus as a previously unknown player in Parkinson's."

Although the researchers say that they don't yet know whether these nuclear aberrations cause Parkinson's disease or are a consequence of it, they say the discovery could offer clues about potential new therapeutic approaches.

For example, they were able to use targeted gene-editing technologies to correct the mutation in patient's nuclear stem cells. This genetic correction repaired the disorganization of the nuclear envelope, and improved overall survival and functioning of the neural stem cells.

They were also able to chemically inhibit damage to the nucleus, producing the same results seen with genetic correction. "This opens the door for drug treatment of Parkinson's disease patients who have this genetic mutation," says Belmonte.

The new finding may also help clinicians better diagnose this form of Parkinson's disease, he adds. "Due to the striking appearance in patient samples, nuclear deformation parameters could add to the pool of diagnostic features for Parkinson's disease," he says.

The research team, which included scientists from China, Spain, and the University of California, San Diego, and Scripps Research Institute, made their discoveries using human induced pluripotent stem cells (iPSCs). These cells are similar to natural stem cells, such as embryonic stem cells, except that they are derived from adult cells. While generation of these cells has raised expectations within the biomedical community due to their transplant potential — the idea that they could morph into tissue that needs to be replaced — they also provide exceptional research opportunities, says Belmonte.

"We can model disease using these cells in ways that are not possible using traditional research methods, such as established cell lines, primary cultures and animal models," he says.

In this study, the researchers used skin fibroblast cells taken from Parkinson's disease patients who have the LRRK2 mutation, and they reprogrammed them to iPSC stem cells and developed them into neural stem cells.

Then, by using an approach to model what happens when these neural stem cells aged, they found that older Parkinson disease neural stem cells increasingly displayed deformed nuclear envelopes and nuclear architecture. "This means that, over time, the LRRK2 mutation affects the nucleus of neural stem cells, hampering both their survival and their ability to produce neurons," Belmonte says.

"It is the first time to our knowledge that human neural stem cells have been shown to be affected during Parkinson's pathology due to aberrant LRRK2," he says. "Before development of these reprogramming technologies, studies on human neural stem cells were elusive because they needed to be isolated directly from the brain."

Belmonte speculates that the dysfunctional neural stem cell pools that result from the LRRK2 mutation might contribute to other health issues associated with this form of Parkinson's disease, such as depression, anxiety and the inability to detect smells.

Finally, the study shows that these reprogramming technologies are very useful for modeling disease as well as dysfunction caused by aging, Belmonte says.

The research was supported by Glenn Foundation for Medical Research, G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi, The California Institute of Regenerative Medicine, Ellison Medical Foundation and Leona M. and Harry B. Helmsley Charitable Trust, MINECO and Fundacion Cellex.

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Journal Reference:

1. Guang-Hui Liu, Jing Qu, Keiichiro Suzuki, Emmanuel Nivet, Mo Li, Nuria Montserrat, Fei Yi, Xiuling Xu, Sergio Ruiz, Weiqi Zhang, Ulrich Wagner, Audrey Kim, Bing Ren, Ying Li, April Goebl, Jessica Kim, Rupa Devi Soligalla, Ilir Dubova, James Thompson, John Yates III, Concepcion Rodriguez Esteban, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 2012; DOI: 10.1038/nature11557

A study that used a Utahgenealogic database and a statewide cancer registry to examine the relationship between Parkinson disease (PD) and cancer suggests an increased risk of prostate cancer and melanoma in patients with PD and their relatives, according to a report published Online First by Archives of Neurology, a JAMA Network publication.

Neurodegenerative diseases, in particular PD, may share common pathogenic mechanisms with some cancers, according to the study background.

"Identifying a genetic relationship between PD and cancer is critical to understanding underlying pathophysiologic changes in both diseases. Understanding this relationship could allow clinicians to provide proper assessment of cancer risk in patients with PD and might also have implications for the counseling of relatives of patients," the authors note in the study background.

Seth A. Kareus, M.D., and colleagues from the University of Utah, Salt Lake City, estimated relative risks (RRs) for cancer in individuals with PD listed on their death certificate, and in their relatives. The study identified 2,998 patients with PD listed as their cause of death from 1904 to 2008 and also included information from the Utah Cancer Registry on 100,817 patients diagnosed with cancer.

To validate their observed associations, researchers also estimated the reciprocal RR for PD death among patients diagnosed with melanoma and their relatives, and estimated the RRs for death with PD among patients diagnosed with prostate cancer and their relatives.

"A significantly increased risk for prostate cancer was observed in the PD population as well as among their relatives. A reciprocal significantly increased risk for PD was also found in the 22,147 prostate cancer cases and their relatives," according to the study results.

The study also notes that "a significantly elevated risk for melanoma was found in the Utah PD population as well as in their relatives. A reciprocal significantly increased relative risk for PD was found in 7,841Utahmelanoma cases and their relatives," the study results indicate.

Among the individuals with PD who died, the authors observed 48 cases of melanoma. The estimated RR for melanoma in patients with PD who died was 1.95; and an increased risk for death with PD was noted among the patients with melanoma (RR, 1.65). Researchers also found prostate cancer in 212 patients with PD who died (RR, 1.71) and an increased risk for death with PD was found among the prostate cancer patients (RR, 1.39), according to the results.

"Thus, these data argue strongly for a significant shared genetic risk for specific cancers on the one hand and neurodegeneration on the other. ….These studies provide a framework for future definition of the precise nature of shared genetic variation leading to neurodegeneration in some individuals, but skin or prostate cancers in others, and they may influence strategies for skin and prostate cancer screening," the authors conclude.

Editorial: Families with Parkinson Disease, Cancer

In an editorial, Walter A. Rocca, M.D., M.P.H., of the Mayo Clinic, Rochester, Minn., writes: "The findings from Kareus et al, combined with previous findings in the literature, suggest that some families have a genetic predisposition that can manifest as PD, as other types of parkinsonism, as essential tremor, as cognitive impairment or dementia, as amyotrophic lateral sclerosis, as anxiety disorders, as depressive disorders, or as nonneurological conditions such as melanoma and prostate cancer."

"If the mechanisms are primarily genetic, as suggested by Kareus and colleagues, then it may be possible to identify genetic variants that predispose to accelerated neurodegeneration and to increased oncogenesis in the same individual or among members of some particular families," Rocca continues.

"On the other hand, if PD is multifactorial at the individual level, dimorphic in men and women, and heterogeneous at the population level, the search for one or several genetic variants may not be productive," Rocca concludes.

Scientists at the University of Houston (UH) have discovered what may possibly be a key ingredient in the fight against Parkinson's disease.

Affecting more than 500,000 people in the U.S., Parkinson's disease is a degenerative disorder of the central nervous system marked by a loss of certain nerve cells in the brain, causing a lack of dopamine. These dopamine-producing neurons are in a section of the midbrain that regulates body control and movement. In a study recently published in the Proceedings of the National Academy of Sciences (PNAS), researchers from the UH Center for Nuclear Receptors and Cell Signaling (CNRCS) demonstrated that the nuclear receptor liver X receptor beta (LXRbeta) may play a role in the prevention and treatment of this progressive neurodegenerative disease.

"LXRbeta performs an important function in the development of the central nervous system, and our work indicates that the presence of LXRbeta promotes the survival of dopaminergic neurons, which are the main source of dopamine in the central nervous system," said CNRCS director and professor Jan-Åke Gustafsson, whose lab discovered LXRbeta in 1995. "The receptor continues to show promise as a potential therapeutic target for this disease, as well as other neurological disorders."

To better understand the relationship between LXRbeta and Parkinson's disease, the team worked with a potent neurotoxin, called MPTP, a contaminant found in street drugs that caused Parkinson's in people who consumed these drugs. In lab settings, MPTP is used in murine models to simulate the disease and to study its pathology and possible treatments.

The researchers found that the absence of LXRbeta increased the harmful effects of MPTP on dopamine-producing neurons. Additionally, they found that using a drug that activates LXRbeta receptors prevented the destructive effects of MPTP and, therefore, may offer protection against the neurodegeneration of the midbrain.

"LXRbeta is not expressed in the dopamine-producing neurons, but instead in the microglia surrounding the neurons," Gustafsson said. "Microglia are the police of the brain, keeping things in order. In Parkinson's disease the microglia are overactive and begin to destroy the healthy neurons in the neighborhood of those neurons damaged by MPTP. LXRbeta calms down the microglia and prevents collateral damage. Thus, we have discovered a novel therapeutic target for treatment of Parkinson's disease."

Tokyo Tech's Yoshihiro Miyake and colleagues have developed an innovative, non-invasive therapeutic intervention that may improve the mobility, stability, and quality of life of Parkinson's disease patients.

The technology is also described in the August issue of Tokyo Institute of Technology Bulletin: http://www.titech.ac.jp/bulletin/index.html

The unintentional synchronizing of people's gait as they walk together is a familiar phenomenon. Understanding the mechanisms behind this synchronization could help people with a disturbed gait, such as patients suffering from Parkinson's disease. Research by Yoshihiro Miyake at the Department of Computational Intelligence and Systems Science at Tokyo Institute of Technology has helped to demystify the process and led to a new walking support device — 'Walk Mate'.

Yoshihiro Miyake investigated coupled walking processes between a walking robot and a walking person. The study included people with a healthy gait and people suffering from Parkinson's disease or hemiplegia due to brain infraction. He used the timing of the walking person as a sensory input for the robot and the sound of a walking rhythm as the robot's output. An algorithm based on travelling wave dynamics controlled the timing difference between the Walk Mate's input and output.

The study revealed how people adjust their pace in response to the robot's audible output. Patients' stride patterns were healthier using 'Walk Mate' and they reported a greater stability and "sense of togetherness" compared with more traditional walking aids that have a fixed rhythm. Further studies in collaboration with researchers at the Max Planck Institute for Human Cognitive and Brain Sciences and the Department of Neurology at Kanto Central Hospital have underlined the great potential of the device.

"Our approach offers a flexible, portable, low-cost, non-invasive therapeutic intervention that may improve the mobility, stability, and quality of life of Parkinson's disease patients," say the inventors.

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Journal References:

1. Y. Miyake. Interpersonal Synchronization of Body Motion and the Walk-Mate Walking Support Robot. IEEE Transactions on Robotics, 2009; 25 (3): 638 DOI: 10.1109/TRO.2009.2020350
2. Michael J. Hove, Kazuki Suzuki, Hirotaka Uchitomi, Satoshi Orimo, Yoshihiro Miyake. Interactive Rhythmic Auditory Stimulation Reinstates Natural 1/f Timing in Gait of Parkinson's Patients. PLoS ONE, 2012; 7 (3): e32600 DOI: 10.1371/journal.pone.0032600