Cellular Location of Neuroprotective Protein Associated with Parkinson’s Disease Development, Study Finds

Nilotinib Phase 2 trial

Toxic protein aggregates called Lewy bodies sequestrate a protein that is usually found in the cell nucleus and known to protect against neurodegeneration, and change in this protein’s location contributes to the mechanisms underlying Parkinson’s disease, researchers report.

The study, “Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson’s disease patients,” was published in Neuroscience Letters.

Aging is a primary risk factor for Parkinson’s disease as age-related changes in cellular function predispose people to the development of this neurodegenerative disorder.

Evidence suggests a close relationship between neuronal death and toxic protein inclusions, such as Lewy bodies — clumps of alpha-synuclein protein. However, the exact mechanism of how these aggregates result in disease remains to be understood.

“It has been reported that repressor element-1 silencing transcription factor, (also known as) neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes,” the researchers wrote.

Studies have shown that REST expression is decreased in Alzheimer’s disease, but little is known about its role in Parkinson’s disease.

Therefore, researchers from Juntendo University in Japan set to identify the neuroprotective functions of REST in aging and the brains of Parkinson’s disease patients.

The team used post-mortem brain samples of normal aging people (controls), and Parkinson’s or dementia with Lewy bodies patients, and looked at different areas to determine where REST was located within neurons.

In a normal aging (more than 72 years old) brain, REST was present in the nucleus and cytosol (the fluid found inside cells) of dopaminergic neurons present in the substantia nigra — a midbrain area important for muscle control.

This was not the case in the middle-aged brains (age 47 and 61 years), where REST was not observed in the nucleus, and there was a small amount of cytosolic accumulation, suggesting that nuclear entry of REST is dependent on the cellular aging process.

In contrast to healthy controls, REST expression was decreased in patients with Parkinson’s disease and dementia with Lewy bodies, both in the nucleus and cytosol of dopaminergic substantia nigra neurons and cortical neurons. Instead, REST was strongly detected within Lewy bodies.

To dissemble dysfunctional proteins, neurons use two major cellular pathways: the ubiquitin-proteasome system, where short-lived proteins in the cytoplasm and nucleus are degraded by a complex called the proteasome; and the autophagy-lysosome pathway, which digests long-lived proteins and abnormal cellular structures, including mitochondria, the cell’s powerhouse.

The proteasome is a tiny, barrel-shaped cellular structure that degrades toxic non-functional proteins that have been molecularly tagged for destruction.

Disease-related protein aggregates contain ubiquitinated proteins (proteins that have been “tagged” for degradation), and p62 — a molecular receptor that recognizes and shuttles ubiquitinated proteins for degradation.

Researchers wanted to understand whether REST interacted with ubiquitinated protein aggregates. Therefore, they investigated the transcription factor’s location in mouse brain cells that were either normal or were genetically engineered to lack the ability to perform protein degradation (autophagy) specifically in dopaminergic neurons.

In the substantia nigra of normal aging healthy mice (12 months of age), there was no detectable interaction between REST and p62, while in animals with a dysfunctional protein degradation pathway, REST was found in p62-positive aggregates within the cytoplasm. This suggests that REST is incorporated into cytoplasmic aggregates that accumulate as a consequence of autophagy dysfunction.

Therefore, REST aggregating with p62 suggests that it is part of a lesion associated with Lewy body formation.

Scientists then tested if the accumulation of ubiquitinated proteins induced REST gene expression in a human neuroblastoma (a rare type of cancer affecting the nervous system) cell line. Results showed that REST accumulated (was not degraded) in the presence of an autophagy inhibitor called MG132 — which blocks neuronal molecule-degradation systems. However, REST did not accumulate upon the addition of a proteasome-specific inhibitor, called lactacystin, which indicates that REST is dissembled via the autophagy-lysosome pathway.

When researchers added rotenone (a pesticide that inhibits the function of mitochondria) to neurons, REST accumulation increased.

“As rotenone is a possible Parkinson-causing agent, loss of neuronal REST accumulation in aged-neurons may relate to the PD pathology (the typical behaviour of a disease),” the researchers said.

Nuclear accumulation of REST “occurs as a normal aging process and Lewy pathology disturbs the process in dopaminergic neurons by sequestering REST. The alteration of neuronal aging processes including the loss of REST in neurons may associate with the PD pathogenesis,” they concluded.

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Parkinson Voice Project Going Global with Speech Therapy Grant Program

speech therapy grants

This year, Parkinson Voice Project (PVP) is broadening its SPEAK OUT! & LOUD Crowd Grant Program to include support for international speech therapy clinics.

The expanded grant program is intended to help Parkinson’s disease patients around the world gain access to quality speech treatment to maintain their speaking abilities and minimize the threat of swallowing problems.

In addition to facilities in the U.S., grant recipients this year will include five clinics based outside the country. Applications are now being accepted and are due March 1. Recipients will be announced in April during Parkinson’s Awareness Month. Go here for full eligibility requirements, and visit this site to apply.

Nonprofit organizations, universities/graduate students, and hospitals who would like to bring PVP’s speech therapy program to their communities are encouraged to apply. Applicants must have the physical space and clinical staff necessary to provide both individual and group speech therapy. Last year’s winners may reapply for continued support of their programs.

For international applicants, awards are open to any clinic that can use English or Spanish-based therapy materials.

To achieve its mission of making speech treatment widely accessible, PVP recognized a need to support speech language pathologists. These professionals, according to the organization, get low insurance reimbursement for services, and also often have trouble securing funding from employers for specialized training and supplies. The grants are designed to provide pathologists with the knowledge and tools needed to help the Parkinson’s community.

The grant program, which honors the late Parkinson’s speech expert Daniel R. Boone, PhD, was launched last year with 92 grants awarded to speech therapy clinics nationwide. Of them, 34 were university-based clinics.

More than 900 speech language pathologists and graduate students received training in SPEAK OUT! and LOUD Crowd therapy protocols, plus speech therapy supplies, funding support for their organizations, and a trip to PVP’s clinic in Dallas-Fort Worth for hands-on training.

“Our grant program was a huge success in 2018,” said PVP CEO Samantha Elandary, in a press release. “Our goal is to make quality speech treatment available to those living with Parkinson’s around the globe.”

According to Elandary, Parkinson’s affects more than 1 million U.S. residents, and up to 10 million people worldwide. Some 89 percent of patients are likely to develop speech disorders that can lead to swallowing difficulties.

Combining speech, voice, and cognitive exercises, SPEAK OUT! addresses the motor speech issues related to Parkinson’s. LOUD Crowd is a voice maintenance program consisting of speech therapy groups and a singing segment to foster voice strength retention.

Using the two-part trademarked speech therapy program, the patient and a speech language pathologist tackle a series of speech, voice, and cognitive exercises outlined in a specialized workbook. Stressing “speaking with intent,” the program switches speech from an automatic function to a deliberate act. Because speech muscles are also used for swallowing, the benefits of the therapy are twofold.

Grant funding will come from the more than $2 million PVP raised over the past holiday season.

Through intensive speech therapy, follow-up support, research, education and community awareness, the nonprofit aims to preserve the voices of those with Parkinson’s and related disorders. To date, it has trained more than 1,300 speech language pathologists nationwide. Internationally, it has trained therapists in eight countries.

Among other offerings, the organization also hosts an educational lecture series. Earlier this month, Susan Imke, a certified gerontological nurse practitioner who focuses on families living with Parkinson’s disease and other neurodegenerative disorders, discussed “Optimal Nutrition for Living Well with Parkinson’s.”

The next presentation, “Packing Some ‘Punch’ Into Your Parkinson’s Exercise Routine,” will be Feb. 9.

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Study Examines Risk Factors for Impulse Control Disorders in Parkinson’s Patients

impulse control disorders

Use of dopamine agonists, earlier disease onset, being male, and having personality traits such as impulsiveness and high novelty-seeking are among the risk factors for developing impulse control disorders (ICDs) in people with Parkinson’s, according to a review study.

The research, “Impulse control disorders in Parkinson’s disease: A systematic review on risk factors and pathophysiology,” was published in the Journal of the Neurological Sciences.

ICDs are characterized by failure to resist an impulse, drive, or temptation to perform a risky behavior, a growing sense of tension before performing the behavior, and a sense of pleasure while doing it.

In people with Parkinson’s, ICDs may result from treatments intending to increase the levels of dopamine in the brain. Despite their impact on patients’ quality of life, studies about ICDs in this patient population are scarce.

Aiming to address this gap, a research team from IRCCS Centro Neurolesi “Bonino Pulejo”, in Italy, conducted a systematic review of the potential risk factors for the development of ICDs in people with Parkinson’s, including the effects of dopaminergic treatment. Three online databases were used covering studies published from January 2000 to July 2018.

According to research published in 2003 and 2008, the prevalence of gambling, compulsive sexual behavior, and compulsive shopping is 1.7-7.0%, 2.0–4.0%, and 0.4-3.0%, respectively. The 2003 study found one or more ICDs in 13.6% of patients, which included binge eating and hypersexuality. Recent epidemiological studies have indicated that the prevalence of ICDs is 7.2% in patients with Parkinson’s, but only 1% in controls (participants who did not have Parkinson’s.

Specifically, for example, although binge eating typically leads to weight gain, people with Parkinson’s commonly lose weight, which is attributed to swallowing difficulties (dysphagia) and dyskinesia (involuntary, jerky movements).

Slot machine gambling has been identified as the most common form of pathological gambling among these patients. Major depression in middle-aged men has been reported as a comorbidity of pathological gambling, with common genetic factors.

Patients also have an increased risk of developing dopamine dysregulation syndrome, which results from unregulated self-administration and dependence on dopaminergic treatment. “Patients increase drugs doses spontaneously and progressively and this is often associated to behavioral and mood disorders, such as hallucinations, manic states, aggression, psychomotor agitation and delusions,” researchers explained.

Developing addiction-like behavior has been associated with the type, dose and duration of dopaminergic treatment, in particular dopamine agonists.

A 2006 study showed a correlation between earlier onset of Parkinson’s and earlier appearance of motor fluctuations, dyskinesia and psychiatric symptoms. Also, a study with 3,090 patients indicated that greater impulsive choice, faster reaction time and impulsive decisions are among the potential factors for the development of ICDs, although Parkinson’s patients are thought to have increased caution and be risk-averse prior to diagnosis.

Comparing to women, men not only have higher frequency of ICDs, but also show six-times greater difficulty managing them, as shown in a 2012 study. Other factors shown to associate with ICDs in Parkinson’s include sleep impairment, substance abuse, high novelty-seeking, impulsiveness, aggressiveness, cigarette smoking, having more formal education, and being unmarried.

As for brain pathways underlying the development of ICDs, dysregulation of the mesolimbic circuit (responsible for reward learning and the mesocortical pathway (responsible for executive decision-making) leads to impulsive and compulsive behaviors.

Upon exposure to a reward, a brain area called the ventral striatum is activated, prompting a strong emotional response and dopamine release. This behavior ultimately may become compulsive, being reinforced by the dorsal striatum.

Two types of dopamine receptors — D1 and D2 — are involved in the connections between the striatum and the globus pallidus (a part of the brain’s basal ganglia) and subsequently the substantia nigra, a major brain region involved in Parkinson’s disease.

These receptors, and their pathways, have opposing roles in reward-based decision making, either stimulation (D1) or suppression (D2).

The researchers noted that standardized tests to evaluate the type and severity of ICDs are still lacking. Also, consistent use of international criteria for Parkinson’s diagnosis and prospective studies with larger samples are still needed to more accurately determine risk factors for ICDs among these patients.

“A better assessment of the behavioral disorders of [Parkinson’s] may be useful in the rehabilitative intervention for increasing the quality of life,” researchers concluded.

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Preparing for a Parkinson’s Hospital Stay

hospital stays

Sherri Journeying Through

Sooner or later, nearly all of us make a trip to the hospital for one reason or another. Just because you are placed in the hands of a capable physician doesn’t necessarily mean you will get the best care, especially if you have Parkinson’s disease. Following are some pointers to keep in mind for that emergency (or scheduled) trip to the hospital.

  • Keep an updated list of medications with you or make sure a caregiver knows where to find the information. Be sure the dosages are listed.
  • Bring someone who knows you well so they can communicate effectively with the staff on your behalf in case you’re unable.
  • Have a list of medications to avoid due to Parkinson’s disease.

Many patients are unaware that some common medications used for conditions such as headaches or gastrointestinal issues may block dopamine. Such medications have been associated with parkinsonism and the worsening of Parkinson’s disease.

Neuroleptics are used to manage symptoms of many psychiatric disorders. That can be a good thing if you need antipsychotic medication. However, for a person with Parkinson’s disease, their use can be life-threatening. 

Among the medications to be avoided are Compazine (prochlorperazine), Phenergan (promethazine), and Reglan (metoclopramide). Other meds, such as reserpine and tetrabenazine, may worsen Parkinson’s disease and should be avoided in most cases.

Having a list of forbidden meds could prove to be as valuable as your list of Parkinson’s meds. 

  • If you had deep brain stimulation surgery and have a rechargeable battery, it is important to bring your battery pack with you to be safe.

Hospital stays for Parkinson’s patients aren’t really all that different than for those without Parkinson’s. However, it’s important to remember that neglecting to discuss your drug regimen could be problematic. If you don’t neglect to do those two things, as a Parkinson’s patient, you’ve done what you can do to have the best stay possible. Enjoy that scrumptious green Jell-O!

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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Genes Controlling Molecular Pathway Increase Risk For Parkinson’s Disease, Study Finds

endocytic membrane-trafficking pathway, PD risk

Genes that control a molecular pathway responsible for moving biological cargo into cells contribute to the risk of developing Parkinson’s disease, researchers report.

The study, “The Endocytic Membrane Trafficking Pathway Plays a Major Role in the Risk of Parkinson’s Disease,” was published in Movement Disorders.

The movement of molecules into and out of cells is important for cellular communication. Scientists call the process of movement into cells “the endocytic membrane-trafficking pathway,” and it can be used for nutrient uptake, and directing toxic cargo for degradation.

Most cases of Parkinson’s disease are sporadic, meaning that they occur randomly and do not have a specific environmental or genetic cause. Although hereditary cases of Parkinson’s are rare, there’s evidence that some genes do not cause the disease outright, but increase the risk of developing it.

“Aligned with the genetic discoveries, a big effort has been made to identify how those genes interact within biological pathways to elucidate the cellular and molecular processes that could explain the neurodegenerative mechanism,” the researchers wrote.

Previous studies suggest that dysfunction in the endocytic membrane-trafficking pathway contributes to Parkinson’s disease, and several pathway-related genes (VPS35, DNAJC6, RAB7L1, SH3GL2, GAK, CHMP2B, LRRK2 and PLA2G6) have been proposed to play a part in the process.

Therefore, researchers from the National Institutes of Health (NIH) sought to investigate how 252 endosomal membrane-trafficking-related genes influence the risk of developing Parkinson’s disease.

The investigators used data from genome-wide association studies of the International Parkinson’s Disease Genomics Consortium (IPDGC), which involved 18,869 patients and 22,452 healthy controls, all of European ancestry. A genome-wide association study searches the genome (the complete set of genes present in an organism) for small variations that occur more frequently in people with, for instance, Parkinson’s than in people without the disease. This helps the scientific community identify genes that may increase the risk of developing a particular disease.

The study revealed that 2.14% of the observed genetic variation was related to the endocytic membrane-trafficking pathway, explaining roughly 9.34% of the overall heritability of Parkinson’s disease. Heritability refers to differences in the appearance of a trait across several people that can be explained by differences in their genes. It is not a measure of what causes a trait or, in other words, of “how genetic” or heritable a trait is.

However, scientists only focused on genes that would produce an RNA molecule and later generate a protein. Therefore, their estimates did not include adjacent regulatory genomic regions that may somehow affect the risk of developing Parkinson’s disease.

Taking these regions into consideration, changes in the endocytic membrane-trafficking pathway increased the risk 1.25 times for developing Parkinson’s disease.

For an unbiased analysis of causal effects, researchers then used a technique called Mendelian randomization to pinpoint genes that influenced Parkinson’s disease risk, and identified several endocytic membrane-trafficking pathway genes.

Increased blood expression of VAMP4, ARL8B, and GAK was associated with a reduced Parkinson’s risk, while RABGEF1, VAMP8, CLTCL1, and ITSN1 levels were associated with an increased risk.

Furthermore, increased gene expression of SH3GL2 and GAK within the brain was causally linked to Parkinson’s risk, whereas ARL8B expression was negatively associated.

The addition of a methyl group (a chemical group containing one carbon and three hydrogen atoms) to a DNA molecule modifies gene function and affects gene expression. The process is known as DNA methylation and has been associated with Parkinson’s disease.

Accordingly, researchers reported that higher methylation rates of GAK and HSPA1B were positively associated with Parkinson’s disease risk, whereas PLEKHM1 and VPS39 were negatively correlated with disease risk.

Of the 252 analyzed genes, 151 were found to be expressed in dopamine-releasing neurons in adult mouse brains.

The NIH team stated that its methodology could be used to study other important molecular pathways in Parkinson’s, and provide additional understanding about disease-related genetic risk factors.

“Unravelling the genetics underlying (Parkinson’s disease) will provide therapeutic options for drug discovery and ultimately could lead to the development of effective interventions,” the researchers said.

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My PD Frustration Consists of More Than Only Symptoms and Treatments

frustration

You don’t have to be positive all the time. It’s perfectly okay to feel sad, angry, annoyed, frustrated, scared and anxious. Having feelings doesn’t make you a ‘negative person.’ It makes you human.” –Lori Deschene

As many people with Parkinson’s will attest, both Parkinson’s disease (PD) symptoms and finding the right treatment to alleviate them can be extremely frustrating.

The perception

Just as frustrating for me is that everyone thinks I am fine. Since I have no tremors, there are no obvious symptoms. Most well-meaning, healthy people either tell me I look great or that they have the same issues as me — cognitive decline, balance, poor fine motor skills, slowness of movement, and fatigue.

The truth

I struggle to maintain balance and must consciously avoid walking into furniture. My body, especially on the left side, does not always listen to me when I tell it to do something. Trying to maintain focus to do this is draining in itself. I also feel weak inside and I am always extremely fatigued. It is an exhaustion that no amount of sleep or rest can diminish.

A glimpse into my frustration

To help my fine motor skills, I have taken up ukulele lessons. I never played any instrument in my life, so I have no muscle memory to call on. The left hand and fingers play a huge role in learning how to use this instrument.

Recently, I had a meltdown in one of my lessons. My left fingers were not listening to me while trying to play some chords. The instructor was very patient, but I don’t think he understood the extent of my struggles. I was trying to play a G chord, which requires positioning three fingers from my left hand on various frets. These fingers would not cooperate and they just froze. With all the energy I expended trying to get my fingers positioned, I worked up a sweat.

Finally, so full of despair and frustration over what I have lost, I just broke down in tears. I can no longer control my body.

Empathy

The frustration continues on many fronts for me: the symptoms themselves, trying to find something to help treat my symptoms, and well-intentioned people not comprehending what I struggle with daily. Many years before I was affected by this disease, a friend of mine was diagnosed with PD. I could never understand why it was so hard for her to put on a seat belt.

Now I know.

I have a form of Parkinson’s disease, which I don’t like. My legs don’t move when my brain tells them to. It’s very frustrating.” –George H. W. Bush

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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Dopaminergic Therapy Improves Cognitive Motivation in Parkinson’s Patients, Study Reports

dopamine, cognitive motivation

Dopaminergic treatment normalizes cognitive motivation in patients with Parkinson’s disease, making them more likely to choose a higher reward option in a computer-based task, a study reports.

The study, “Dopamine restores cognitive motivation in Parkinson’s disease,” was published in the journal Brain.

Approximately 40 percent of Parkinson’s patients experience a decrease in motivation, including cognitive apathy, which may manifest as needing assistance to start a mental activity or speech.

Dopamine plays a key role in motivating individuals to invest physical effort in return for a reward. Although lower levels of dopamine associated with Parkinson’s disease are believed to play a key role in cognitive apathy, scientists still need conclusive evidence.

The two current explanations for the link between dopamine and cognitive motivation include promoting cognitive effort and boosting working memory, a form of short-term memory important for reasoning and decision-making.

Recent studies of human motivation have used neuroeconomic approaches, which require participants to decide how much effort they are willing to make in exchange for a given reward. This strategy is valuable in the context of Parkinson’s, as the subjective value a person places on something is represented in the striatum — an area of the brain with reduced dopamine levels in Parkinson’s patients — and may be an objective marker of individual apathy.

Now, a team of Australian researchers have evaluated whether dopamine is key to decision-making based on cognitive effort. The investigators used a new task, in which 20 participants with idiopathic (of unknown cause) Parkinson’s (mean age of 67.1 years, 12 men) had to choose between a low-effort/low-reward option and a high-effort/high-reward offer in each trial. Of the participants, 12 were determined to be apathetic based on the Dimensional Apathy Scale (DAS).

To account for the effects of the disease and treatment, patients were tested on levodopa and/or dopamine agonists and off (following overnight withdrawal) dopaminergic treatment, and choices were compared with those of 20 healthy individuals used as controls.

Each session had two phases. In the initial reinforcement phase, participants were taught to perform each level of cognitive effort to a ceiling performance, “to ensure that they could be positively reinforced on every trial at every effort level,” according to the researchers.

Cognitive effort was assessed as the number of rapid serial visual streams (one to six) that participants had to monitor for a target stimulus (the letter “T”) over 10 seconds. Each trial, for a total of 60 trials, consisted of 24 stimuli. Stimuli were presented on a laptop monitor, positioned about 60 cm from the participants.

The participants had to press a button to indicate the appearance of the target letter. At the end of each trial, the participants were awarded one point if they were able to complete the trial above a threshold level, or zero if not.

The initial reinforcement phase was followed by the choice phase, where participants had to indicate their preference between a baseline low-effort/low-reward and a variable high-effort/high-reward offer (10-point maximum). They were told their decisions were hypothetical and did not affect their compensation.

Results revealed that patients off medication were significantly less motivated, perceived the task to be more mentally demanding, and chose the more valuable offer less frequently than controls. This was particularly evident at high levels of effort and intermediate levels of reward.

Dopaminergic treatment lessened the perception of mental demand and made patients more willing to accept the more valuable offer independent of the likelihood of success, revealing no differences from controls.

Computational models then showed that dopamine reduced the variability in choice behavior. The data further showed that choices correlated with the executive subscale of the DAS, which specifically assesses cognitive motivation. According to the scientists, this suggests a close relationship between their measure of cognitive effort and subjective reports of day-to-day cognitive apathy.

“Here, we present the first evidence that dopamine causally modulates cognitive motivation,” the researchers wrote. “From a clinical perspective, these data emphasize the importance of optimizing dopaminergic therapy, not only to improve the motor symptoms and physical motivation in patients with Parkinson’s, but also to improve their willingness to engage in cognitively demanding behaviour.”

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Levodopa Shows No Disease-modifying Effects in Parkinson’s, Study Finds

levodopa study

Levodopa/carbidopa treatment is effective in managing Parkinson’s motor symptoms, but does not protect against disease progression among patients with early disease, a study shows.

The research, “Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease” was published in The New England Journal of Medicine.

Levodopa is the main treatment for Parkinson’s disease. However, neurologists might delay prescribing levodopa for different reasons, including concern about the development of levodopa-induced dyskinesias (abnormal, uncontrolled, involuntary movements), which is one of the most common dose-limiting side effects of this treatment approach.

However, almost all patients eventually receive levodopa to control their motor symptoms.

In an earlier clinical trial, called ELLDOPA , 361 patients with early Parkinson’s disease received levodopa or placebo for 40 weeks. Two weeks after that, clinical examination showed that the participants who had received levodopa had a slower disease progression than those on placebo. However, brain imaging studies revealed that levodopa had either accelerated the death of dopaminergic neurons, or it had modified the protein responsible for the transport of dopamine in brain nerve cells.

“Therefore, whether levodopa has an effect on the progression of Parkinson’s disease beyond its immediate benefit with respect to symptoms remains unknown,” scientists wrote.

Now, researchers from the University of Amsterdam designed a multicenter, randomized, placebo-controlled, delayed-start trial to assess levodopa’s effect on patients with early Parkinson’s disease who had insufficient disability to receive anti-Parkinson medication: the Levodopa in Early Parkinson’s Disease (LEAP) study (ISRCTN30518857).

Patients who had received their diagnosis within the previous two years were randomly assigned to an early-start group (207 subjects): levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks; or to a delayed-start group (210 participants): placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks.

During Phase 1 (the first 40 weeks of the trial), patients received levodopa or placebo. During Phase 2 (the second 40 weeks) patients in both trial groups received levodopa. Assessments were made at baseline (trial initiation) and at weeks 4, 22, 40, 44, 56, 68, and 80.

The study’s primary endpoint (goal) was the difference in the mean change, from trial initiation to week 80, in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). That tool assesses both motor and non-motor symptoms associated with Parkinson’s disease (higher scores indicate more severe disease).

Secondary outcomes included the progression of symptoms between weeks 4 and 40 and between weeks 44 and 80, as measured by the category scores on the UPDRS; disability; cognitive impairment; depression; and disease-related quality of life.

At week 80, there was no significant difference between the early-start and delayed-start group regarding motor and non-motor symptoms, as measured by the UPDRS, indicating that levodopa had no disease-modifying effect.

To test if early treatment initiation was prognostically better than a delayed one or vice-versa, scientists compared symptoms’ progression rate in week 4-40 and week 44-80. Once again, no significant changes were observed between groups in either study period.

No significant changes in therapy-related motor fluctuations, including dyskinesias, were found between groups. During the first 40 weeks, patients on the early-start group complained more of nausea (23%), compared to the participants on the delayed-start group (14.3%).

Also, no significant differences were observed regarding disability, cognitive impairment, depression and disease-related quality of life between the groups.

“We conclude that treatment with levodopa at a dose of 100 mg three times per day in combination with carbidopa at a dose of 25 mg three times per day had no disease-modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks. Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson’s disease warrants evaluation in future trials,” researchers concluded.

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In US, Parkinson’s Diagnosis Linked to Higher Healthcare Use, Spending, Study Shows

healthcare costs, use

A diagnosis of Parkinson’s disease is associated with greater Medicare costs and out-of-pocket spending, according to a population-based study in the U.S.

These findings also revealed substantial geographic variation in prevalence and health service use and spending among Medicare beneficiaries.

The study, “State-level prevalence, health service use, and spending vary widely among Medicare beneficiaries with Parkinson disease,” appeared in the journal npj Parkinson’s Disease.

State-level variations in clinical outcomes, disease prevalence and healthcare use, quality and spending among Medicare beneficiaries have influenced healthcare planning at both federal and state levels. In the U.S., healthcare and reimbursement are being governed at the state level more and more.

“Medicare is a federally administered program providing health insurance to individuals over the age of 65, while Medicaid, which provides coverage to individuals below the poverty line, is funded by individual states,” the researchers wrote in the study.

Parkinson’s patients on Medicare often qualify for Medicaid due to having to spend more on healthcare and/or long-term care associated with the disease. However, Medicare remains the main payer for office visits, hospitalizations, home care, and nursing facility assistance for individuals older than 65 who are considered dual-eligible, meaning they are covered by both Medicare and Medicaid.

Data on how Parkinson’s care and spending vary across the U.S. are lacking. This information would help guide health policy and planning in a time when the prevalence of Parkinson’s is increasing with the aging population, as shown by the Parkinson’s Foundation’s Parkinson’s Prevalence Project, which estimates that 1.2 million people will be living with the disease by 2030.

To address this lack of information, the current Parkinson’s Foundation study looked at differences among states in disease prevalence, patient characteristics, spending, out-of-pocket costs, and health service use for 27.5 million Medicare beneficiaries in 2014.

“This study highlights the growing importance of optimizing care and treatment for people with the disease today,” John L. Lehr, the foundation’s CEO, said in a press release.

The analysis found 392,214 individuals diagnosed with Parkinson’s nationwide. New York, Connecticut, Florida, District of Columbia, and Rhode Island had the highest prevalence, encompassing 20.7% of all Parkinson’s patients on Medicare.

Among the potential reasons for the higher prevalence in these states, the researchers cite a possible “larger proportion of high-risk factor patient groups, a higher concentration of providers who recognize and document [Parkinson’s], increased public awareness of [Parkinson’s] symptoms, or increased health care seeking behaviors.”

Women represented 45.8% of the total number of Parkinson’s patients on Medicare. West Virginia, Kentucky, Mississippi, Louisiana and Arkansas had the largest proportions of women, each with more than 48.5%.

“Although women diagnosed with [Parkinson’s] are a sizable portion of the patient population, they are highly underrepresented in [Parkinson’s] research and clinical trials,” said Allison W. Willis, MD, the study’s senior author. Willis, a professor at the Perelman School of Medicine at the University of Pennsylvania, added that more attention needs to be paid to women, who have less access to specialized care, to improve disease outcomes.

In addition, the data showed that 26.1% of the patients were 85 years or older. Connecticut (33.2%), Pennsylvania (31.2%), Hawaii (31.2%), and Rhode Island (31.1%) were the states with the highest proportions of this age group.

Dual-eligible patients made up less than 10% of the total patients in North Dakota, Minnesota, New Hampshire, Arizona, Wisconsin and Utah, but more than 25% in Connecticut, Maine, Mississippi, California, and the District of Columbia.

Throughout 2014, Parkinson’s patients on Medicare had 219,049 hospitalizations, 37,839 readmissions, 3,699,767 outpatient doctor’s office visits, 34,159 hospice stays, 113,027 skilled nursing facility stays, 466,160 emergency room visits, 1,308,934 durable medical equipment events, 6,676,119 laboratory tests, 2,435,654 imaging assessments, and 4,879,538 home health visits.

Hospitalization rates were highest in New York, Michigan, Illinois, West Virginia and Florida, and lowest in Hawaii, Alaska, Utah, North Dakota, and Idaho. Readmission rates were highest in Florida, though with less variation by state.

Medicare paid nearly $7.9 billion for healthcare services for people with Parkinson’s. Inpatient care ($2.1 billion), skilled nursing facility care ($1.4 billion), hospital outpatient care ($881 million) and home health ($776.5 million) were the costliest services. For all services, Medicare and out-of-pocket spending were higher for beneficiaries with Parkinson’s than those without this disease.

Nevada, Texas, Massachusetts, Florida and New York were the top five states in spending, all greater than $22,000 per beneficiary with Parkinson’s. The highest out-of-pocket costs were found in the Great Lakes, Northeast, and South Central regions.

“Our study provides initial evidence that there is substantial geographic variation in health service use and spending for [Parkinson’s],” the researchers wrote.

“This state-level analysis will help inform policymakers on the societal costs of [Parkinson’s] and target areas where [Parkinson’s] patients may have more needs,” said James Beck, PhD, the Parkinson’s Foundation’s chief scientific officer. “We must realign our national priorities to support increased funding for research and care for people living with [Parkinson’s].”

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Study Explores Parkinson’s Effect on How Brain Represents Tool Embodiment

Tool embodiment

A new way to understand and study how the brain represents tool embodiment — the physical actions for using tools — was proposed in a new research article.

The study recommends methods for understanding Parkinson’s disease signs and symptoms relating to the brain’s ability to represent motor output, which can aid in the diagnosis, treatment, and monitoring of neurological conditions.

The research article, “Defective Tool Embodiment in Body Representation of Individuals Affected by Parkinson’s Disease: A Preliminary Study,” was published in Frontiers in Psychology.

People have the capacity to use tools for acting in the environment. For example, they can use a rod because something is out of reach; the tool helps them get an object that would otherwise be unreachable. To do so, the human brain takes the object into account as if it were part of the body; when using a rod, the brain represents the hand as if it were the tip of the rod — the brain “embodies” the tool.

This ever-changing representation of the body, derived from all sensory input around the body that the brain uses to plan and execute actions, has been termed the “body schema.” Although there is increasing research on understanding the body schema and tool embodiment in healthy individuals, the body schema is thought to be affected in several pathological conditions. These include people with neurological diseases affecting motor control or spinal cord injury, as well as amputees who use a prosthesis. Yet there is little known about the body schema and tool embodiment in Parkinson’s disease, a neurological disease characterized by sensory and motor symptoms affecting motor action.

To understand how the body schema is affected by neurological disease, researchers from the Istituto Auxologico Italiano and the University of Turin, Italy, studied tool embodiment in Parkinson’s disease patients.

The study included 14 people affected by Parkinson’s disease and 18 healthy controls. The researchers had the participants use a rod to point toward a far target and studied the accuracy and how long it took for the patients to point toward the target before and after they had spent time training with the rod.

They also investigated changes in the brain’s estimation of arm length through a test called the Tactile Estimation Task. In this task, participants estimated the distance between two tactile stimuli presented simultaneously on the arm. If the rod is correctly embodied, the arm should be represented from its base to the tip of the rod, and, consequently, the distance between the two might be perceived larger than the actual gap.

All patients were tested when their symptoms were efficiently managed by Parkinson’s medicine, or “on” state of medication.

After tool-use training, control participants’ behaviors completely changed: they were slower to perform movements after training to try to hit the target. More specifically, after training, healthy individuals reported a higher value of deceleration — when individuals are nearest to the target after having achieved peak of velocity of movement. However, such differences did not emerge in the Parkinson’s participants. Researchers did not observe any differences in estimation of arm length before and after the tool-use training in either Parkinson’s or control participants.

These results suggest possible difficulties in the tool embodiment process for Parkinson’s patients. The lack of changes in these participants before and after training possibly reflects the absence of effective tool embodiment into the body schema. This study proposes a new way to understand Parkinson’s signs and symptoms in terms of how they affect a patient’s body schema.

“This study suggests a novel way to conceive Parkinson’s sensory motor signs and symptoms: the disease might affect the tool embodiment in cognitive body representation, as a possible secondary effect of altered plasticity of body schema, since the sensory and motor symptoms, or altered multisensory integration process due to the degeneration of dopaminergic neurons in the basal ganglia,” researchers stated.

“Tool embodiment in body representation can extend the potentiality of individual’s action; however, if deficient, it might have remarkable consequences and implications on motor behavior, specifically in those clinical conditions like Parkinson’s, in which the body and action are primarily affected by symptoms,” they said.

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