Category: Parkinson’s

— REM sleep disturbances constitute an early marker of neurodegenerative diseases. This was demonstrated by the Multidisciplinary Sleep Disturbances Unit of the Hospital Clínic, in an article published in 2006. A new study published by the same team in Lancet Neurology applies neuroimaging techniques to identify patients with REM sleep disturbances who will develop neurodegenerative disorders over the short term.

The first author of both papers is Dr. Àlex Iranzo, a physician belonging to the Neurology Department of the Hospital Clínic in Barcelona, who is also an investigator of the IDIBAPS and a member of the Multidisciplinary Sleep Disturbances Unit. The study has been carried out in the setting of the Neurodegenerative Diseases CIBER (CIBERNED), and has received the collaboration of the Neurology Department of the Innsbruck Medical University (Austria).

One of the challenges of modern medicine is the diagnosis of diseases before they develop clinical manifestations such as tremor or dementia. Neurodegenerative disorders begin in latent periods during which the cells suffer degeneration but clinical manifestations are not yet observed. In this context, the degenerative process advances, and neuropathological changes affect the nervous system. The new data contributed by the investigators of the Hospital Clínic — IDIBAPS make it possible to identify the disease at preclinical stages in patients with REM sleep disturbances.

In the previous work of this same team, 45% of the patients studied had developed a neurodegenerative disorder 5 years after diagnosis of the sleep disturbance. All of them were over 60 years of age and presented REM sleep disturbances in the form of nightmares in which they called out, cried or showed body movements. The new study goes beyond this point and presents the data relating to the follow-up of 43 new patients during two years and a half after undergoing the neuroimaging tests. The 123I-FP-CIT SPECT technique makes it possible to identify striatal dopamine dysfunctions typical of brain substantia nigra pathology, which can degenerate towards Parkinson's disease. Transcranial ultrasound identifies structural alterations of the substantia nigra such as increased iron presence, before Parkinsonism gives rise to clinical manifestations.

The study describes how 19% of the patients had developed a neurodegenerative disorder in the two and a half years following the neuroimaging tests. Of these subjects, 5 developed Parkinson's disease, two developed Lewy body dementia, and one patient developed multisystemic atrophy. All of them belonged to the group of 27 patients (62.8%) showing low FP-CIT uptake at SPECT and/or hyperechogenicity in the substantia nigra in transcranial ultrasound. In other words, none of them had yielded normal results in the neuroimaging tests. In turn, the patients with normal neuroimaging findings showed no neurological disorders after 2.5 years of follow-up.

The investigators have concluded that the neuroimaging tests make it possible to identify patients with REM sleep disturbances who are at high risk of early development of a neurodegenerative disorder such as Parkinson's disease. This will help improve our knowledge of the progression of these diseases, test drugs that might modify their course and initiate early therapy, once the clinical diagnosis is established.

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Journal References:

1. Dr Alex Iranzo et al. Decreased striatal dopamine transporters uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurology, Sep 15, 2010 DOI: 10.1016/S1474-4422(10)70216-7
2. Iranzo et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. The Lancet Neurology, 2006; 5 (7): 572 DOI: 10.1016/S1474-4422(06)70476-8

— A new study led by researchers at Columbia University Medical Center has identified a novel molecular pathway underlying Parkinson's disease and points to existing drugs which may be able to slow progression of the disease.

The pathway involved proteins — known as polyamines — that were found to be responsible for the increase in build-up of other toxic proteins in neurons, which causes the neurons to malfunction and, eventually, die. Though high levels of polyamines have been found previously in patients with Parkinson's, the new study — which appeared in an early online edition of Proceedings of the National Academy of Sciences — is the first to identify a mechanism for why polyamines are elevated in the first place and how polyamines mediate the disease.

The researchers also demonstrated in a mouse model of Parkinson's disease that polyamine-lowering drugs had a protective effect.

"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," says Scott A. Small, MD, the senior author of the study and Herbert Irving Associate Professor of Neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's."

Currently, treatments for Parkinson's can help alleviate some of the disease's symptoms, but they cannot prevent the build-up of toxic proteins and the death of neurons caused by the disease. When polyamines were scrutinized decades ago as a potential therapy against cancer, polyamine-lowering drugs were tested and have completed the Phase 1 and 2 safety stages of clinical trials. However, whether the drugs can pass through the blood-brain barrier remains to be determined and further testing will be needed. If the drugs can reduce the level of polyamines in the brain, they may pave the way for a Parkinson's treatment that can slow the disease's progression.

"This research has the potential to progress quickly," says James Beck, PhD, director of research programs at the Parkinson's Disease Foundation, which helped support the research. "Equally exciting are the new avenues of research this study opens, hopefully leading to better treatments for Parkinson's Disease down the road."

Though many cellular defects have been found to cause rare, inherited forms of Parkinson's disease, most cases of Parkinson's are caused by unknown changes inside the brain's neurons.

The researchers used a wide variety of scientific techniques to search for still unidentified defects in the brain. The suite of techniques — which started with high resolution brain imaging — has been used to reveal previously unknown molecules in the brain that worsen Alzheimer's disease.

Imaging Reveals Brainstem Defect in Parkinson's Patients

The success of the technique depends on identifying regions of the brain affected by the disease and comparing them to unaffected regions.

Using high resolution functional magnetic resonance imaging (fMRI), Nicole Lewandowski, PhD, who is currently a post-doctoral research scientist in Dr. Small's lab, identified such regions in the brainstem of patients with Parkinson's. The scans showed that one region of the brainstem was consistently less active in these patients than in healthy control subjects. Also revealed in the scans was a neighboring region that was unaffected by the disease.

Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences.

"One such protein we found, called SAT1, stood out," said Dr. Small. "Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease."

Three Experiments Confirm Polyamines Are Pathogenic

To validate the finding, three separate studies — in yeast, mice, and people — were performed.

The yeast studies revealed that polyamines promote the accumulation of a toxic Parkinson's-causing protein in living cells, and not just in test tubes, as was known from previous research. Conducted by Gregory Petsko, PhD, the Gyula and Katica Tauber Professor of Biochemistry and Chemistry and Chair of Biochemistry at Brandeis University and Dagmar Ringe, PhD, the Harold and Bernice Davis Professor of Aging and Neurodegenerative Disease Research at Brandeis, the new studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. Furthermore, in a screen conducted for mediators of Parkinson's toxins in the lab of Susan Linquist, PhD, professor of biology in the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute at MIT, other genes related to polyamine transport were identified.

In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the UC San Diego School of Medicine, found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.

Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in nearly 100 patients with Parkinson's and additional genotyping in a further ~800 subjects (389 PD patients and 408 controls), enrolled in the Genetic Epidemiology of Parkinson's disease study at CUMC, Columbia geneticist Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, MPH, who is the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.

"Even though the variant was rare in patients with Parkinson's, finding it was surprising and further strengthens the possibility that defects in the polyamine pathway help to trigger the disease," said Dr. Small.

Dr. Small is now testing current polyamine-lowering drugs to see if the compounds can pass through the blood-brain barrier, or if they can be altered to do so. Drugs that pass through the blood-brain barrier can be administered more easily (e.g., they can be taken by mouth) instead of directly infusing them into the brain.

This work was supported in part by the National Institute of Neurological Disorders and Stroke, the Parkinson's Disease Foundation and Columbia's Irving Institute for Clinical and Translational Research (CTSA).

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Journal Reference:

1. Nicole M. Lewandowski, Shulin Ju, Miguel Verbitsky, Barbara Ross, Melissa L. Geddie, Edward Rockenstein, Anthony Adame, Alim Muhammad, Jean Paul Vonsattel, Dagmar Ringe, Lucien Cote, Susan Lindquist, Eliezer Masliah, Gregory A. Petsko, Karen Marder, Lorraine N. Clark, Scott A. Small. Polyamine pathway contributes to the pathogenesis of Parkinson disease. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1011751107

Yeast could be a powerful ally in the discovery of new therapeutic drugs to treat Parkinson's disease says a scientist presenting his work at the Society for General Microbiology's autumn meeting in Nottingham.

Dr Tiago Fleming Outeiro from the Instituto de Medicina Molecular in Lisbon, Portugal describes how his group is slowly uncovering the molecular basis of Parkinson's disease by studying the associated human protein in yeast cells.

Parkinson's disease is a neurodegenerative disorder without any known cure that affects around 6 million people worldwide. The symptoms, which include rigidity, difficulty in initiating movements and resting tremors, are all related to the specific death of dopamine-producing neurons in the brain. These neurons characteristically contain protein deposits, known as Lewy bodies. A small protein called alpha-synclein is the main component of these deposits.

Dr Outeiro explains how baker's yeast, Saccharomyces cerevisiae, is helping researchers learn how alpha-synuclein might lead to Parkinson's disease. "Yeast is a very simple but powerful model in which to study how alpha-synuclein actually works as, remarkably, many of the biochemical pathways involved are similar between yeast and humans," he said. "There is still a lot we don't know about the function of this protein, but we do know that even small increases in the level of alpha-synuclein in cells lead to cell death."

Dr Outeiro, along with colleagues in the USA, screened a library of 115,000 small compounds to try and identify those that are able to block the toxic effects of alpha-synuclein. Several of these molecules have proved effective in preventing Parkinson's disease in worms and blocking alpha-synuclein toxicity in rat neurons. If developed further, they could form the basis of future drugs to treat Parkinson's disease in humans.

New treatments for neurodegenerative diseases are urgently needed. "With the ageing of the human population the number of people affected by Parkinson's disease will continue to increase. This means the disease will become an even greater problem for modern societies due to the tremendous socio-economic costs associated," Dr Outeiro said. "It's therefore imperative that treatments for such neurodegenerative diseases are developed. Our studies in yeast have enabled us make a step towards this."

Queen's researchers have found that people with Parkinson's disease can perform automated tasks better than people without the disease, but have significant difficulty switching from easy to hard tasks. The findings are a step towards understanding the aspects of the illness that affect the brain's ability to function on a cognitive level.

"We often think of Parkinson's disease as being a disorder of motor function," says Douglas Munoz, director of the Queen's Centre for Neuroscience Studies and a Canada Research Chair in Neuroscience. "But the issue is that the same circuit can affect more cognitive functions like planning and decision-making."

The researchers conducted an experiment using a sample of Parkinson's patients and a control group. When asked to look at a light when it came on, people with Parkinson's responded with greater accuracy than people without the disease. But when asked to change that behavior — to look away from the light, for instance — Parkinson's patients struggled. Even when asked to simply prepare to change their behaviour, people with the disease found it incredibly difficult to adjust their plans.

PhD student Ian Cameron, lead author of the study, says the findings are significant because they highlight how biased Parkinson's patients are towards performing an automated response. It also suggests that medications currently prescribed to treat the symptoms of the disease that affect motor functioning could further upset a patient's cognitive balance.

Mr. Cameron is now conducting functional brain imaging in Parkinson's patients to determine which parts of the brain are affected by medications currently used to treat the symptoms of the disease.

The findings were recently published in Neuropsychologia, an international interdisciplinary journal of cognitive and behavioural neuroscience.

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Journal Reference:

1. Ian G.M. Cameron, Masayuki Watanabe, Giovanna Pari, Douglas P. Munoz. Executive impairment in Parkinson's disease: Response automaticity and task switching. Neuropsychologia, 2010; 48 (7): 1948 DOI: 10.1016/j.neuropsychologia.2010.03.015

A significant number of Parkinson's disease patients have a mutation of the enzyme Leucine-Rich Repeat Protein Kinase 2 (LRRK2, also known as dardarin).

However, little is understood about how it is regulated or functions. In a new paper in the Signal Knowledge Environment of the Biochemical Journal, Dario Alessi and colleagues from the University of Dundee demonstrate that a family of proteins, the 14-3-3 proteins, interact with LRRK2.

Mutations of the gene responsible for expressing LRRK2 have been linked to an increased risk of Parkinson's and Crohn's diseases; the researchers found that five of the six most common pathogenic mutations of LRRK2 affect its ability to bind with 14-3-3 proteins and alter cellular localization — but not kinase activity — of LRRK2. The mutated forms of LRRK2 that fail to bind 14-3-3 proteins accumulate within discrete cytoplasmic pools perhaps resembling inclusion bodies that contain misfolded protein that may be related to the pathology.

This clearer understanding of how LRRK2 is regulated is likely to open promising avenues to Parkinson's disease researchers.

Professor Mark Lemmon, Deputy Chair for BJ Signal, commented that "although this work shows that understanding LRRK2 mutations is definitely not simple, the Alessi group has discovered important new aspects of LRRK2 regulation that help enormously in thinking about what might be going wrong. The path opened up by this study will be very illuminating for understanding LRRK2 itself, which has been something of an enigma, and its role in Parkinson's disease."

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Journal Reference:

1. R. Jeremy Nichols, Nicolas Dzamko, Nicholas A. Morrice, David G. Campbell, Maria Deak, Alban Ordureau, Thomas Macartney, Youren Tong, Jie Shen, Alan R. Prescott, Dario R. Alessi. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochemical Journal, 2010; 430 (3): 393 DOI: 10.1042/BJ20100483

Much like snowflakes, no two neurons are exactly alike. But it's not the size or shape that sets one neuron apart from another, it's the way it responds to incoming stimuli. Carnegie Mellon University researchers have discovered that this diversity is critical to overall brain function and essential in how neurons process complex stimuli and code information.

The researchers published their findings, the first to examine the function of neuron diversity, online in Nature Neuroscience.

"I think neuroscientists have, at an intuitive level, recognized the variability between neurons, but we swept it under the rug because we didn't consider that diversity could be a feature. Rather, we looked at it as a fundamental reflection of the imprecision of biology," said Nathan N. Urban, professor and head of CMU's Department of Biological Sciences. "We wanted to reconsider that notion. Perhaps this diversity is important — maybe it serves some function."

Estimates say that the human brain alone has upwards of 100 billion neurons, which can be broken down into a number of different types. While members of the same type look structurally alike, and, as a group, contribute to completing the same overall task, each individual neuron in that group fires in response to subtle differences in the incoming stimulus. Typically neuroscientists average out this heterogeneity to obtain their results, assuming that the variability is a "bug of biology."

"When we think about computer chips, variability in hardware clearly can be very destructive. Manufacturers spend a lot of time and expense making sure each processor on a chip is identical," Urban said. "The brain is considered to be one of the most sophisticated computers there is. We were intrigued by the idea that the brain might make use of the messy, complex nature of its biological hardware to function more efficiently."

Urban and postdoctoral student Krishnan Padmanabhan, both researchers in CMU's Department of Biological Sciences and the joint CMU/University of Pittsburgh Center for the Neural Basis of Cognition, tested single neurons' responses to a complex stimulus. By placing an electrical probe into individual excitatory neurons called mitral cells and exposing them to a complex computer-controlled noise stimulus, the researchers were able to determine how each cell responded. They found that out of the dozens of neurons they tested, no two had the exact same response. While the researchers believed that these results were striking on their own, it led them to wonder whether or not the neurons were giving a messy version of a single response, or if they were each providing different pieces of information about the stimulus.

To test their hypothesis, the CMU researchers used a tool called spike-triggered averaging that allowed them to determine what feature of the stimulus causes each neuron to respond. They found that some responded to rapid changes in the stimulus and others to slower changes; still other neurons responded when the input signal changed in a regular or rhythmic way. The researchers then computed the information contained in the outputs of highly diverse sets of neurons and compared it to that of groups of more similar neurons. They found that the heterogeneous groups of neurons transmitted two times as much information about the stimulus than the homogeneous group.

"Diversity is an intrinsic good," Urban said. "A population in which each member is a little different in terms of what they can do is a more efficient and more effective population. It's like a baseball team — if you want to win, you shouldn't put nine pitchers on the field."

Aside from its role in information coding, the researchers believe neuronal diversity also could play a role in neurological disorders like epilepsy, Parkinson's disease and schizophrenia. In these conditions, there is a disruption in the synchrony and rhythmicity of neuronal firing. In the case of epilepsy and Parkinson's, groups of neurons fire simultaneously, causing seizures or tremors. In schizophrenia, some neurons have a reduced ability to coordinate firing in certain situations, such as during attention tasks. Changes in the diversity of neuronal populations may alter the ease with which neurons enter into these rhythmic firing patterns.

Additionally, the researchers want to discover how diversity is achieved. Neurons of a given type are typically born at the same stage of development, with many of them coming from the same progenitor cell. Urban hopes to discover how neurons diversify during development, what proteins are involved and if any type of training or exposure enhances diversity.

This research was funded by the National Institute on Deafness and Other Communication Disorders, one of the National Institutes of Health.

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Journal Reference:

1. Krishnan Padmanabhan, Nathaniel N Urban. Intrinsic biophysical diversity decorrelates neuronal firing while increasing information content. Nature Neuroscience, 2010; DOI: 10.1038/nn.2630

Researchers at Johns Hopkins have shown that using specific drugs can protect nerve cells in mice from the lethal effects of Parkinson's disease.

The researchers' findings are published in the August 22 issue of Nature Medicine.

The newly discovered drugs block a protein that, when altered in people, leads to Parkinson's disease. Parkinson's disease causes deterioration of the nervous system that leads to tremors and problems with muscle movement and coordination. There is no proven protective treatment yet. Only recently have genetic causes of Parkinson's disease been identified that have the potential to be used for developing targeted therapies for patients with the disease.

The protein LRRK2 (pronounced lark 2) is overactive in some Parkinson's disease patients and causes nerve cells to shrivel up and die. Why exactly overactive LRRK2 is toxic and leads to Parkinson's disease is still unknown.

Since overactive LRRK2 is deadly, researchers speculated that blocking LRRK2 from acting might protect nerve cells. The research team tested drugs that were commercially available and known to prevent proteins like LRRK2 from acting and adding chemical phosphates to other proteins. Out of 70 drugs tested, eight were found to block LRRK2 from working.

Two of these eight previously were shown by others to be able to cross the blood-brain barrier. So the researchers injected these two drugs twice daily into mice engineered to carry Parkinson-causing LRRK2 changes in their brain. After three weeks, they examined the mouse brains to see if nerve cells had died. One drug provided almost complete protection against nerve cell death. Another drug had about 80 percent fewer dead cells than in mock treated mice. A third drug, which does not inhibit LRRK2 was not effective.

"This data suggests that if you were to develop a safe drug, then you could potentially have a new treatment for Parkinson's disease patients with LRRK2 mutations," says Ted Dawson, M.D., Ph.D., professor of neurology and physiology and scientific director of the Johns Hopkins Institute for Cell Engineering.

The two drugs that blocked LRRK2 and prevented death of nerve cells in mice with Parkinson's disease both had similar chemical structures. "One could envision generating compounds around that core structure to develop a relatively selective and potent inhibitor of LRRK2," says Dawson.

Dawson is collaborating with researchers at Southern Methodist University to design more specific inhibitors of LRRK2 and the group plans to license this technology. Once they identify promising candidate drugs, those candidates still will have to be tested for toxic side effects. The drugs' approval by the FDA for use in humans may still be many years away.

Says Dawson, treatments developed specifically against LRRK2 may even be able to treat other forms of Parkinson's disease — those not caused by LRRK2 alterations — as there may be several alterations in different proteins that can lead Parkinson's disease.

"We're curing Parkinson's disease in a mouse and now we have to discover drugs that actually work in human neurons. Then we'll hopefully be able to make the leap forward to get a treatment to work in humans," says Dawson.

Other authors on the manuscript included Byoung Lee, Joo-Ho Shin, Andrew West, HanSeok Ko, Yun-Il Lee and co-investigator Valina Dawson of Johns Hopkins Medicine; Jackalina VanKampen and Leonard Petrucelli of the Mayo Clinic College of Medicine; Kathleen Maguire-Zeiss and Howard Federoff of the Georgetown University Medical Center; and William Bowers of the University of Rochester Medical Center.

Funding for this research was provided by grants from the National Institutes of Health, the Army Medical Research and Material Command, the Mayo Foundation and the Michael J. Fox Foundation.

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Journal Reference:

1. Byoung Dae Lee, Joo-Ho Shin, Jackalina VanKampen, Leonard Petrucelli, Andrew B West, Han Seok Ko, Yun-Il Lee, Kathleen A Maguire-Zeiss, William J Bowers, Howard J Federoff, Valina L Dawson, Ted M Dawson. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nature Medicine, 2010; DOI: 10.1038/nm.2199

— Individuals with Parkinson's disease were more likely to have a neurochemical response to a placebo medication if they were told they had higher odds of receiving an active drug, according to a report in the August issue of Archives of General Psychiatry.

"The promise of symptom improvement that is elicited by a placebo is a powerful modulator of brain neurochemistry," the authors write as background information in the article. "Understanding the factors that modify the strength of the placebo effect is of major clinical as well as fundamental scientific significance." In patients with Parkinson's disease, the expectation of symptom improvement is associated with the release of the neurotransmitter dopamine, and the manipulation of this expectation has been shown to affect the motor performance of patients with the condition.

Sarah C. Lidstone, Ph.D., of Pacific Parkinson's Research Centre at Vancouver Coastal Health and the University of British Columbia, Vancouver, Canada, and colleagues studied 35 patients with mild to moderate Parkinson's disease undergoing treatment with the medication levodopa. On the first day of the study, a baseline positron emission tomographic (PET) scan was performed, participants were given levodopa and a second scan was performed one hour later to assess dopamine response. On the second day, patients were randomly assigned to one of four groups, during which they were told they had either a 25-percent, 50-percent, 75-percent or 100-percent chance of receiving active medication before the third scan; however, all patients were given placebo.

Patients who were told they had a 75-percent chance of receiving active medication demonstrated a significant release of dopamine in response to the placebo, whereas those in the other groups did not.

Patients' reactions to the active medication before the first scan was also correlated with their response to placebo. "Importantly, whereas prior medication experience (i.e., the dopaminergic response to levodopa) was the major determinant of dopamine release in the dorsal striatum, expectation of clinical improvement (i.e., the probability determined by group allocation) was additionally required to drive dopamine release in the ventral striatum," the authors write. Both areas have been shown to be involved with reward processing; in patients with a chronic debilitating illness who have responded to therapy in the past, expectation of therapeutic benefit in response to placebo has been likened to the expectation of receiving a reward.

"Our findings may have important implications for the design of clinical trials, as we have shown that both the probability of receiving active treatment — which varies in clinical trials depending on the study design and the information provided to the patient — as well as the treatment history of the patient influence dopamine system activity and consequently clinical outcome," the authors conclude. "While our finding of a biochemical placebo response restricted to a 75 percent likelihood of receiving active treatment may not generalize to diseases other than Parkinson's disease, it is extremely likely that both probability and prior experience have similarly profound effects in those conditions."

This study was funded by the Michael Smith Foundation for Health Research, the Canadian Institutes for Health Research and a TRIUMF Life Sciences Grant. Dr. Stoessl is supported by the Canada Research Chairs Program.

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Journal Reference:

1. Lidstone et al. Effects of Expectation on Placebo-Induced Dopamine Release in Parkinson Disease. Archives of General Psychiatry, 2010; 67 (8): 857 DOI: 10.1001/archgenpsychiatry.2010.88

A new study shows that a sleep disorder may be a sign of dementia or Parkinson's disease up to 50 years before the disorders are diagnosed.

The research is published in the July 28, 2010, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Using Mayo Clinic records, researchers identified 27 people who experienced rapid eye movement (REM) sleep behavior disorder for at least 15 years before developing one of three conditions: Parkinson's disease, dementia with Lewy bodies or multiple system atrophy. Multiple system atrophy is a disorder that causes symptoms similar to Parkinson's disease. People with REM sleep behavior disorder often act out their dreams with violent movements, such as punching, which can injure themselves or bed partners.

The study found that the time between the start of the sleep disorder and the symptoms of the neurologic disorders ranged up to 50 years, with an average span of 25 years. Of the participants, 13 were diagnosed with dementia, 13 others were diagnosed with Parkinson's disease and one person was diagnosed with multiple system atrophy.

"Our findings suggest that in some patients, conditions such as Parkinson's disease or dementia with Lewy bodies have a very long span of activity within the brain and they also may have a long period of time where other symptoms aren't apparent," said study author Bradley F. Boeve, MD, with the Mayo Clinic in Rochester, Minn. and a member of the American Academy of Neurology. "More research is needed on this possible link so that scientists may be able to develop therapies that would slow down or stop the progression of these disorders years before the symptoms of Parkinson's disease or dementia appear."

It is not known how many people who experience REM disorder may develop diseases such as Parkinson's or dementia. A corresponding editorial noted there is no evidence that narcolepsy, with or without REM disorder, will later lead to neurodegenerative disorders.

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Journal Reference:

1. D. O. Claassen, K. A. Josephs, J. E. Ahlskog, M. H. Silber, M. Tippmann-Peikert, and B. F. Boeve. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology, 2010; DOI: 10.1212/WNL.0b013e3181ec7fac

Scientists at the Stanford University School of Medicine have identified a molecular pathway responsible for the death of key nerve cells whose loss causes Parkinson's disease. This discovery not only may explain how a genetic mutation linked to Parkinson's causes the cells' death, but could also open the door to new therapeutic approaches for the malady.

In a study to be published July 29 in Nature, investigators used an animal model, the common fruit fly, to show that the mutation results in impaired activity of recently discovered molecules called microRNAs, which fine-tune protein production in cells. This impairment, in turn, leads to the premature death of nerve cells specifically involved in the secretion of the brain chemical dopamine. The degeneration of these so-called dopaminergic nerve cells in the brain is a hallmark of Parkinson's.

"MicroRNA, whose role in the body has only recently begun to be figured out, has been implicated in cancer, cardiac dysfunction and faulty immune response," said Bingwei Lu, PhD, associate professor of pathology and the study's senior author. "But this is the first time it has been identified as a key player in a neurodegenerative disease."

Parkinson's is a movement disorder characterized outwardly by tremor, difficulty in initiating movement, and postural imbalance and, in the brain, by a massive loss of the dopaminergic nerve cells in areas that fine-tune motor activity. It affects an estimated 1 million people in the United States. The incidence of Parkinson's, rare in younger people, increases dramatically with age, although nobody is sure why. Nor is it known why the most common mutation implicated in Parkinson's — LRRK2 G2019S, found in about one-third of all Parkinson's cases occurring among North African Arabs and North American Ashkenazi Jews — increases the likelihood of contracting the disease.

The new findings show that the LRRK2 mutation trips up the normal activity of microRNAs, resulting in the overproduction of at least two proteins that can cause certain cells, like brain cells, to die.

Understanding how microRNA can go wrong requires an understanding of its relationship to its much longer and better-known cousins, "messenger RNA" (or mRNA) molecules. The latter carry genetic recipes from a cell's DNA to specialized molecular machines that translate the instructions into the proteins that make up a cell. In contrast, a microRNA molecule is a very short string of RNA that doesn't contain instructions for making proteins but that can bind to parts of messenger RNA sequences that complement its own. As a result, the messenger RNA's sequence can no longer be read by the cell's protein-manufacturing apparatus, gumming up assembly of the protein it encodes.

It's only recently that scientists have started to understand microRNA's critical role.

The researchers in Lu's lab conducted their experiments in Drosophila, the fruit fly, which has previously proved itself a useful model for several neurodegenerative disorders, yielding substantial insights into Parkinson's, Alzheimer's and Huntington's diseases. They observed that certain proteins were being produced at higher-than-normal levels in the fly LRRK2 model of Parkinson's disease. What particularly drew their attention were two proteins that are important in regulating cell division. Mature nerve cells, which no longer divide, should not have high levels of these proteins; when they do, they are prone to premature cell death.

The researchers looked at the mRNAs containing the genetic recipes for the two overproduced proteins, and predicted that they would be bound by two specific microRNAs: let-7 and miR-184. When they then manipulated the activities of those two microRNA species in flies' brains, they had results consistent with the damage associated with Parkinson's. Diminishing the activity of let-7 in dopaminergic nerve cells, for example, caused both the increased production of one of the suspect proteins and degeneration of the cells.

The researchers showed that toning down the levels of these two proteins, in itself, prevented dopaminergic nerve cell death in the flies. "The flies no longer got symptoms of Parkinson's," said Lu. "This alone has immediate therapeutic implications. Many pharmaceutical companies are already making compounds that act on these two proteins, which in previous studies have been shown to be associated with cancer. It may be possible to take these compounds off the shelf or quickly adapt them for use in non-cancer indications such as Parkinson's."

The researchers then went a step further, showing how the genetic mutation of LRRK2 caused interference of microRNA molecules' ability to inhibit their target mRNAs. It leads to the disruption of a huge complex of molecular machinery that must operate smoothly in order for microRNA to do its job. This link between the common Parkinson's-producing mutation and consequent microRNA malfunction is a new finding.

"The clinical impact of our findings may be five to 10 years down the road," Lu said. "But their impact on our understanding of the disease process is immediate. We can now start testing compounds in mammals and cultured human dopaminergic cells to see if they can inhibit overproduction of these proteins and stave off dopaminergic cell death." Currently available drugs for Parkinson's disease temporarily alleviate its symptoms but can have undesirable side effects, and they don't prevent dopaminergic cells from dying.

The study's first author is Stephan Gehrke, PhD, a postdoctoral researcher in Lu's laboratory. Second author Yuzuru Imai, PhD, a former postdoctoral scientist in Lu's lab, is now an associate professor at Tohoku University in Sendai, Japan. The study received financial support from the National Institutes of Health and the McKnight, Beckman and Sloan foundations.

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Journal Reference:

1. Gehrke et al. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature, 2010; 466 (7306): 637 DOI: 10.1038/nature09191