research

Turn, stop, then sit: A research-based guide for Parkinson’s patients

Tel Aviv University team studies why patients with Parkinson’s disease have difficulty transitioning from walking to sitting, leading to greater instability and falls

 

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Digital Management of Parkinson Disease: Is Technology the Future?

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Can Imaging Genetics Analysis Effectively Identify Depression In Parkinson Disease?

A model using imaging genetics analysis was able to predict and explain the degree of depression in Parkinson disease (PD) with a lower error and higher correlation than other models over a 5-fold cross-validation, according to the results of a study published in PLoS One.

Ji Hye Won, a PhD student from the Department of Electrical and Computer Engineering, Sungkyunkwan University and the Center for Neuroscience Imaging Research, Institute for Basic Science, Suwon, Korea, and colleagues conducted a retrospective analysis of de-identified data. They used diffusion MRI, T1-weighted MRI, and DNA genotyping data obtained from the Parkinson’s Progression Markers Initiative database for 81 patients with PD. Researchers obtained DNA samples genotyped by NeuroX genotyping arrays from the Parkinson’s Progression Markers Initiative and used the least absolute shrinkage and selection operator (LASSO) algorithm to identify regional imaging features that could characterize depression in Parkinson disease. They assessed depression clinically, using the geriatric depression scale.

The investigators identified imaging features that related significantly to the degree of depression, using the LASSO. The selected imaging features correlated strongly with the geriatric depression scale score. Using the LASSO framework, the researchers selected 3 single nucleotide polymorphisms associated with the geriatric depression scale: exm2267347, exm1187499, and exm-rs9303521. The investigators then created a linear regression model with the genetic features from the imaging genetics approach to describe clinical scores suggesting the degree of depression. They constructed other models using imaging and genetic features based on references to validate their models. These models were tested in a 5-fold cross-validation.

The investigators asserted that imaging genetics represents a powerful bottom-up approach to illuminating the mechanisms involved in psychiatric disease. They suggested that imaging genetics could be used to pinpoint neural circuits that translate genetic influences into behavior.

“Our model combining imaging and genetics information could be applied whenever a patient undergoes new imaging and thus could be used for the early prediction of depression. If detected, patients could be directed to many non-drug therapy options that are only available in the early stages of depression,” the researchers concluded.

Article from PsychiatryAdvisor.

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Exercise can improve non-motor symptoms of Parkinson’s disease

Exercise has potential to improve non-motor as well as motor symptoms of Parkinson’s disease (PD), including cognitive function, report investigators in a review published in the Journal of Parkinson’s Disease.

PD is a slowly progressive disorder that affects movement, muscle control, and balance. While traditionally regarded as a movement disorder, it is now known to be a heterogeneous multisystem disorder — in recognition of the significant impact that non-motor symptoms have on the quality of life of individuals affected by PD. It is widely acknowledged that physical exercise improves motor symptoms such as tremor, gait disturbances, and postural instability. However, the effect of exercise on non-motor symptoms in PD, especially cognitive function, is less clear.

The number of older people with and without PD that experience cognitive impairment is steadily increasing worldwide. It is associated not only with a substantial rise in healthcare costs, but also affects the quality of life of both patients and relatives or carers. Up to 57% of patients suffering from PD develop mild cognitive impairment within five years of their initial diagnosis, and if they survive more than ten years, the majority will eventually develop dementia. The underlying neurophysiological mechanisms for cognitive decline in PD are not completely understood, but an accumulation of amyloid plaques, mitochondrial dysfunction, and neurotransmitter changes are all suggested to contribute.

A comprehensive literature review was conducted by investigators from the Institute of Movement and Neurosciences, German Sport University, Cologne, Germany, and the VasoActive Research Group, School of Health and Sport Sciences, University of the Sunshine Coast, Queensland, Australia. The studies reviewed included investigations of the effects of coordination exercise, resistance exercise, and aerobic exercise on domain-specific cognitive function in patients with PD. “Physical exercise is generally associated with increased cognitive function in older adults, but the effects in individuals suffering from PD are not known,” explained lead investigator Tim Stuckenschneider, MA.

The researchers identified relevant studies published before March 2018. There were 11 studies included with a combined total of over five hundred patients with PD with a disease severity from stages 1 to 4 on the Hoehn & Yahr scale, which is used to describe the symptom progression of PD. In four studies, positive effects of exercise on cognition (memory, executive function, and global cognitive function) were shown with no negative effect of exercise on any cognitive domain. Furthermore, disease severity was generally improved by exercise interventions.

The investigators concluded that all modes of exercise are associated with improved cognitive function in individuals with PD, however, no clear picture of which exercise mode is most effective emerged as they may influence cognitive function differently. Aerobic exercise tended to improve memory best, but different forms of exercises such as treadmill training or stationary bike training may have different effects, although both are considered aerobic exercise. Future studies are needed that directly compare the effects of different exercise modes, as the number of high-quality research projects is still limited.

“The potential of exercise to improve motor and non-motor symptoms is promising and may help to decelerate disease progression in individuals affected by PD,” observed Stuckenschneider. “Exercise therapy needs to be, and often already is, an essential part of therapy in individuals with PD. However, it is mostly used to treat motor symptoms. As part of a holistic therapy, the potential of exercise to maintain or improve non-motor symptoms such as cognitive function in individuals with PD needs to be acknowledged, and the most effective treatment options need to be defined. This will not only help practitioners to recommend specific exercise programs, but also ultimately improve the quality of life of the individual. Our work shows that ‘exercise is medicine’ and should routinely be recommended for people with PD to help combat both the physical and cognitive challenges of the disease.”

Article from ScienceDaily.com.

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Manganese and Parkinson’s: Mechanism may explain link

New research, published in the journal Science Signaling, details the mechanism through which exposure to manganese can trigger protein misfolding in the brain — which may, in turn, lead to Parkinson’s-like symptoms. The findings may enable an earlier diagnosis of the neurological condition.
Manganese is an essential nutrient present in “legumes, pineapples, beans, nuts, tea, and grains.”

In the human body, manganese aids blood sugar regulation, bone formation, and immunity.

However, exposure to excessive levels of manganese may trigger Parkinson’s-like neurological symptoms. Manganese builds up in the basal ganglia area of the brain.

Researchers have known about these links between manganese and Parkinson’s for decades, but new research helps elucidate the mechanisms behind these associations.

Anumantha Kanthasamy, the Linda Lloyd Endowed Chair of Neurotoxicology at Iowa State University in Ames, led the new research.

Manganese helps transfer a faulty protein

Parkinson’s disease is characterized by clumps formed by misfolded alpha-synuclein protein. These protein aggregates are toxic to neurons.

Kanthasamy and colleagues set out to investigate how these misfolding proteins might interact with manganese to trigger the progression of Parkinson’s.

To do so, they examined data from mice and blood serum samples collected from eight welders. As a group, welders have a higher risk of prolonged manganese exposure. The research also examined a control group of 10 people.

The analyses revealed that welders with exposure to manganese had higher levels of misfolded alpha-synuclein, which puts them at a higher risk of Parkinson’s.

Additional cell culture tests showed that misfolded alpha-synuclein was secreted through small vesicles called exosomes into the extracellular space. In other words, the vesicles enabled the proteins to travel from cell to cell and further spread the misfolded protein.

The scientists also isolated alpha-synuclein-containing exosomes from alpha-synuclein-expressing cells that had exposure to manganese and delivered them to a brain area in the mice called the corpus striatum. This induced Parkinson’s-like symptoms in the mice.

Manganese seemed to accelerate the “cell-to-cell transmission” of alpha-synuclein, which, in turn, led to neurotoxicity. Kanthasamy and colleagues explain:

Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.”

“[W]e identified a possible mechanism involving the exosome-mediated, cell-to-cell transmission of [alpha-synuclein] during exposure to the environmental neurotoxicant,” write the authors.

Findings may lead to earlier detection

According to the National Institutes of Health (NIH), around 50,000 individuals in the United States receive a diagnosis of Parkinson’s each year, and 500,000 people currently live with the condition.

Though the condition does not yet have a cure, diagnosing it earlier may prevent irreversible brain damage and help accelerate human clinical trials of new drugs.

The results that Kanthasamy and colleagues have just published may help scientists devise a new diagnostic test for Parkinson’s that could detect the disease much earlier on. The results may also help scientists test how effective new Parkinson’s drugs are.

“As the disease advances, it’s harder to slow it down with treatments,” Kanthasamy says. He adds: “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”

However, the study authors also caution that their findings are still experimental, and that such a diagnostic test may not be available for years.

Article from Medical News Today.

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Can We Repair the Brain?

Cell replacement may play an increasing role in alleviating the motor symptoms of Parkinson’s disease (PD) in future. Writing in an open access special supplement to the Journal of Parkinson’s Disease, experts describe how newly developed stem cell technologies could be used to treat the disease and discuss the great promise, as well as the significant challenges, of stem cell treatment.

The most common PD treatment today is based on enhancing the activity of the nigro-striatal pathway in the brain with dopamine-modulating therapies, thereby increasing striatal dopamine levels and improving motor impairment associated with the disease. However, this treatment has significant long-term limitations and side effects. Stem cell technologies show promise for treating PD and may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.

“We are in desperate need of a better way of helping people with PD. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” explained co-authors Claire Henchcliffe, MD, DPhil, from the Department of Neurology, Weill Cornell Medical College, and Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; and Malin Parmar, PhD, from the Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden. “If successful, using stem cells as a source of transplantable dopamine-producing nerve cells could revolutionize care of the PD patient in the future. A single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications.”

The authors have analyzed how newly developed stem cell technologies could be used to treat PD, and how clinical researchers are moving very quickly to translate this technology to early clinical trials. In the past, most transplantation studies in PD used human cells from aborted embryos. While these transplants could survive and function for many years, there were scientific and ethical issues: fetal cells are in limited supply, and they are highly variable and hard to quality control. Only some patients benefited, and some developed side effects from the grafts, such as uncontrollable movements called dyskinesias.

Recent strides in stem cell technology mean that quality, consistency, activity, and safety can be assured, and that it is possible to grow essentially unlimited amounts of dopamine-producing nerve cells in the laboratory for transplantation. This approach is now rapidly moving into initial testing in clinical trials. The choice of starting material has also expanded with the availability of multiple human embryonic stem cell lines, as well as the possibilities for producing induced pluripotent cells, or neuronal cells from a patient’s own blood or skin cells. The first systematic clinical transplantation trials using pluripotent stem cells as donor tissue were initiated in Japan in 2018.

“We are moving into a very exciting era for stem cell therapy,” commented Dr. Parmar. “The first-generation cells are now being trialed and new advances in stem cell biology and genetic engineering promise even better cells and therapies in the future. There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.”

“With several research groups, including our own centers, quickly moving towards testing of stem cell therapies for PD, there is not only a drive to improve what is possible for our patients, but also a realization that our best chance is harmonizing efforts across groups,” added Dr. Henchcliffe. “Right now, we are just talking about the first logical step in using cell therapies in PD. Importantly, it could open the way to being able to engineer the cells to provide superior treatment, possibly using different types of cells to treat different symptoms of PD like movement problems and memory loss.”

“This approach to brain repair in PD definitely has major potential, and the coming two decades might also see even greater advances in stem cell engineering with stem cells that are tailor-made for specific patients or patient groups,” commented Patrik Brundin, MD, PhD, Van Andel Research Institute, Grand Rapids, MI, USA, and J. William Langston, MD, Stanford Udall Center, Department of Pathology, Stanford University, Palo Alto, CA, USA, Editors-in-Chief of the Journal of Parkinson’s Disease. “At the same time, there are several biological, practical, and commercial hurdles that need circumventing for this to become a routine therapy.”

Article from IOS Press.

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Coffee and Parkinson’s: Protection in the Making?

For years, drinking coffee has been associated with having a reduced risk of developing Parkinson’s disease (PD). In fact, a 1968 study suggested that coffee drinkers were less like to get PD (Nefzger, Quadfasel, & Karl, 1968). Since then, multiple epidemiologic studies have confirmed the PD/coffee connection (Ascherio et al., 2003; Ascherio et al., 2004; Fujimaki et al., 2018). Researchers have mostly attributed the protective effect to the caffeine component (Lee et al., 2013).

However, coffee is more than a caffeine delivery system. Coffee has more than 1,000 different compounds, including organic acids, sugars, amino acids and fatty acids. One such fatty acid called Eicosanoyl-5-hydroxytryptamide (EHT) has been getting quite a bit of buzz in the PD research community; and, for good reason. A recently published study titled, “Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB” (Yan et al., 2018), provides some compelling insights into the possible biochemical protective mechanisms of our cup of joe. A recently published study in the journal, Neuropsychopharmacology, sought to determine if having ADHD and/or its treatment, increases the risk of having basal ganglia and cerebellar diseases. In this 20-year follow-up retrospective cohort study, a total of 190,586 patient records (31,796 with ADHD and 158,790 without ADHD) from Utah were examined. People with no prior PD diagnosis or symptoms, no basal ganglia/cerebellar disease and those with a history of substance abuse were excluded from participating in the study.

Here’s what the researchers did: over a six-month period, they treated groups of two different PD model mice with various combinations of caffeine and EHT (caffeine alone, EHT alone, or caffeine and EHT together) to study their effects on both brain and behavior. There was also a group of mice that received no treatment. Then they performed several behavioral tests to study their movement, as well as study their brains for signs of alpha-synuclein clumps (which result in Lewy bodies, the pathological hallmark of PD), neurodegeneration and inflammation. The study found that the untreated mice had significant amounts of clumped α-synuclein in their brains, increased inflammation and loss of neurons, as well as significant deficits on three different behavioral tests. In general, the mice treated with EHT or caffeine alone showed either no or minimal improvement in any of these measures. However, the mice treated with the combination of EHT and caffeine together showed significant improvements in all of these measures.

Results

  • More specifically, mice treated with both EHT and caffeine together:
  • Had less alpha-synuclein clumping in the brain
  • Maintained better neuron integrity and function
  • Had less brain inflammation
  • Displayed less movement symptoms

What Does This Mean?

In this study, a synergistic combination of EHT and caffeine was shown to slow down the progression of the neurodegeneration associated with PD in mice — which has potentially readily available therapeutic implications. In addition, previous research has demonstrated that caffeine enhances dopamine signaling in the brain (Volkow et al., 2015); and, it’s the death of dopamine-producing cells that results in movement symptoms of PD (and why dopamine replacement medication is the gold standard treating PD symptoms).

For years, coffee consumption has been suggested to play a protective role in developing PD. However, it was never clear what exactly in coffee had this effect. This study suggests that two compounds, caffeine and the fatty acid EHT, work together to protect against alpha- synuclein clumps and dopamine neuron loss in two different PD models of mice. Interestingly, these effects were seen even using very low doses of the compounds. If the results of this study can be replicated by other researchers, then identifying that delicate balance of safety and effectiveness for humans is likely an essential step that researchers will be investigating in the future.

References

Ascherio, A., Chen, H., Schwarzschild, M. A., Zhang, S. M., Colditz, G. A., & Speizer, F. E. (2003). Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology, 60(5), 790-795.

Ascherio, A., Weisskopf, M. G., O’Reilly, E. J., McCullough, M. L., Calle, E. E., Rodriguez, C., & Thun, M. J. (2004). Coffee consumption, gender, and Parkinson’s disease mortality in the cancer prevention study II cohort: the modifying effects of estrogen. Am J Epidemiol, 160(10), 977-984. doi:10.1093/aje/kwh312

Chang, K. L., & Ho, P. C. (2014). Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics for comparison of caffeinated and decaffeinated coffee and its implications for Alzheimer’s disease. PLoS One, 9(8), e104621. doi:10.1371/journal.pone.0104621

Collaborators, G. B. D. P. s. D. (2018). Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 17(11), 939-953. doi:10.1016/S1474-4422(18)30295-3

Fujimaki, M., Saiki, S., Li, Y., Kaga, N., Taka, H., Hatano, T., . . . Hattori, N. (2018). Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. Neurology, 90(5), e404-e411. doi:10.1212/WNL.0000000000004888

Lee, K. W., Im, J. Y., Woo, J. M., Grosso, H., Kim, Y. S., Cristovao, A. C., . . . Mouradian, M. M. (2013). Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson’s disease. Neurotherapeutics, 10(1), 143-153. doi:10.1007/s13311-012-0165-2

Nefzger, M. D., Quadfasel, F. A., & Karl, V. C. (1968). A retrospective study of smoking in Parkinson’s disease. Am J Epidemiol, 88(2), 149-158.

Vicente, S. J., Ishimoto, E. Y., & Torres, E. A. (2014). Coffee modulates transcription factor Nrf2 and highly increases the activity of antioxidant enzymes in rats. J Agric Food Chem, 62(1), 116-122. doi:10.1021/jf401777m

Volkow, N. D., Wang, G. J., Logan, J., Alexoff, D., Fowler, J. S., Thanos, P. K., . . . Tomasi, D. (2015). Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain. Transl Psychiatry, 5, e549. doi:10.1038/tp.2015.46

Yan, R., Zhang, J., Park, H.-J., Park, E. S., Oh, S., Zheng, H., . . . Mouradian, M. M. (2018). Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB. Proceedings of the National Academy of Sciences, 115(51), E12053-E12062. doi:10.1073/pnas.1813365115

Article from Parkinson.org.

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Study Reveals Mechanisms Underlying Pain Processing in PD

Parkinson’s disease is a condition affecting the human brain that becomes worse over time. The most common symptoms are tremors, muscle spasms and movements that are much slower than normal; all of which decrease an individual’s quality of life. Although there is currently no cure, the brain structures involved in Parkinson’s disease are known. These are collectively termed the basal ganglia, and are often targeted to treat the symptoms of Parkinson’s disease. For example, electrically stimulating the subthalamic nucleus (STN), one part of the basal ganglia, reduces muscle tremors and stiffness.

Pain is another common symptom in Parkinson’s disease. Patients often report strange burning or stabbing sensations with no obvious physical cause. They are also likely to be more sensitive to painful stimuli and have a lower pain threshold than normal. This suggested that the brain circuits that allow us to perceive and process pain could be somehow involved in Parkinson’s disease. Indeed, stimulating the STN is known to relieve pain in Parkinson’s disease, as well as the muscle symptoms, but exactly how the STN might link up with the brain’s ‘pain network’ remains poorly understood. Pautrat et al. therefore set out to explore the connection between pain networks and the STN, and determine its potential role in Parkinson’s disease.

First, the electrical activity of nerve cells in the STN of rats was measured, which revealed that these cells do respond to mildly painful sensations. Experiments using dyes to label cells in both the STN and brain structures known to transmit painful signals showed that the STN was indeed directly linked to the brain’s pain network. Moreover, rats with a STN that did not work properly also responded abnormally to painful stimuli, confirming that the STN did indeed influence their perception of pain. Finally, Pautrat et al. repeated their measurements of electrical activity in the STN, this time using rats that lacked the same group of nerve cells affected in the basal ganglia of patients with Parkinson’s disease. Such rats are commonly used to model the disease in laboratory experiments. In these rats, the STN cells responded very strongly to painful stimuli, suggesting that problems with the STN could be causing some of the pain symptoms in Parkinson’s disease.

This work reveals a new role for the STN in controlling responses to pain, both in health and disease. Pautrat et al. hope that their results will inspire research into more effective treatments of nerve pain in both Parkinson’s disease and other neurodegenerative conditions.

To learn more about this work, visit elifesciences.org.

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Protein might become candidate for drug development

Researchers have modified the protein Nurr1 so that it can enter cells from the outside. Nurr1 deficiency may be one of the causes of Parkinson’s disease. Even though Nurr1 has been discussed as a potential target for the treatment of Parkinson’s disease, it is unusable in its normal form, as it cannot penetrate cells. A team from Ruhr-Universität Bochum and the US-American National Institutes of Health (NIH) deployed a bacterial import signal in order to deliver Nurr1 into cells. The researchers also demonstrated that the modified protein may have a positive effect on the survival of dopamine-producing nerve cells. They describe their results in the journal Molecular Neurobiology from 18 August 2018.

For the study, Dennis Paliga, Fabian Raudzus, Dr. Sebastian Neumann, and Professor Rolf Heumann from the work group Molecular Neurobiochemistry collaborated with Professor Stephen Leppla from the NIH.

Bacterial protein building block as import signal

Nurr1 is a transcription factor; this means the protein binds to DNA in the nucleus and regulates which genes get read and translated into proteins. Thereby, it controls many properties in cells that produce the neurotransmitter dopamine and that are affected in Parkinson’s disease. Dopamine withdrawal in certain brain regions is responsible for the slowness of movement that is associated with the disease.

Since the Nurr1 protein does not usually have the capability of entering cells and, therefore, cannot take effect in the nucleus, the researchers were searching for ways of furnishing the protein with an import signal. They found what they were looking for in bacteria and attached a fragment of a protein derived from Bacillus anthracis to Nurr1. In the bacterium, that protein ensures that the pathogen can infiltrate animal cells. “The fragment of bacterial protein that we used does not trigger diseases; it merely contains the command to transport something into the cell,” explains Rolf Heumann. Once the modified protein has been taken up by the cell, the bacterial protein building block is detached, and the Nurr1 protein can reach its target genes by using the cell’s endogenous nuclear import machinery.

Nurr1 has a positive effect on the key enzyme of dopamine synthesis

The researchers measured the effect of functional delivery of Nurr1 by monitoring the production of the enzyme tyrosine hydroxylase. That enzyme is a precursor in dopamine synthesis – a process that is disrupted in Parkinson’s patients. Cultured cells that were treated with modified Nurr1 produced more tyrosine hydroxylase than untreated cells. At the same time, they produced less Nur77 protein, which is involved in the regulation of programmed cell death.

Protein protects from the effects of neurotoxin

Moreover, the researchers tested the effect of modified Nurr1 on cultured cells that they treated with the neurotoxin 6-hydroxydopamine. It causes the dopamine-producing cells to die and is thus a model for Parkinson’s disease. Nurr1 inhibited the neurotoxin-induced degeneration of cells.

“We hope we can thus pave the way for new Parkinson’s therapy,” concludes Sebastian Neumann. “Still, our Nurr1 fusion protein can merely kick off the development of a new approach. Many steps still remain to be taken in order to clarify if the modified protein specifically reaches the right cells in the brain and how it could be applied.”

Article from Ruhr University Bochum.

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Characterization of Parkinson Disease With Restlessness

Highlights

  • A study was conducted of restless leg syndrome, leg motor restlessness, and their variants in Parkinson disease and related disorders.
  • A total of 49.2% of PD patients had any restlessness, including RLS and LMR.
  • LMR variants and RLS variants are rare in PD and related disorders.
  • PD with restlessness was related to autonomic, sleep and depressive symptoms.

Objective
The objective of this study was to investigate the prevalence of restless leg syndrome (RLS), leg motor restlessness (LMR) and RLS/LMR variants and their relationship with clinical factors in patients with Parkinson’s disease (PD) and related disorders.

Methods
Sixty-three PD patients, 17 multiple system atrophy (MSA) patients and 11 progressive supranuclear palsy (PSP) patients were included in this study. Through face-to-face interviews, the patients were diagnosed with RLS/LMR, or with RLS/LMR variants in which the symptoms occur predominantly in body parts other than the legs.

Results
The frequency of RLS, LMR, RLS variants and LMR variants was as follows: PD (12.7%, 11.1%, 0% and 1.6%); MSA (5.9%, 11.8%, 0% and 0%); and PSP (0%, 9.1%, 0% and 0%). Restlessness without the urge to move was observed in 25.4% of the PD patients, 11.8% of the MSA patients and 0% of the PSP patients. The PD patients with restlessness exhibited higher Hoehn and Yahr stages and higher scores on the Scales for Outcomes in PD-Autonomic, PD sleep scale-2 and Beck Depression Inventory-II. The olfactory functioning, 123I-MIBG myocardial scintigraphy uptake and dopamine transporter single photon emission computed tomography findings did not differ between the PD patients with restlessness and those without. The severity of RLS was correlated with the autonomic symptoms among the PD patients with restlessness.

Conclusion
PD with restlessness was characterized by increased autonomic, sleep and depressive symptoms. Further studies including a large sample are warranted to characterize restlessness in PD and related disorders.

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