Explaining, Not Complaining: A New Approach to Pain

new approach

Pain visits me all the time now. There are multiple days when high pain levels make me nauseated. I am sick and tired of having to say how sick and tired I feel. I’m experimenting with a new approach: responding to the pain in a dispassionate way, making observations, and providing explanations.

Neo (my neocortex, mentioned in a previous column) snickers, “Who are you kidding? You can’t sit with five days of high pain without the Grouch showing up and leaving behind a trail of consequences.” Neo tends to be a bit of a naysayer, much like Eeyore in the books about Winnie-the-Pooh, by A.A. Milne.

“Not true,” I quickly retort. “For the last two five-day stretches of bad pain, I did not let the Grouch speak in public. My partner shared her sincere gratitude on this accomplishment. It makes it easier on her and makes the home less stressful, decreasing my total pain level.”

Neo replies, “I’m not talking about just zipping the lip. I’m talking about that inner dialog, the way you speak about the high levels of pain to yourself. What happened the other night after five days with high pain?”

I let out a deep sigh. “That was a difficult night, following a difficult week. It seemed like so many events were crashing around me. I tried to quiet my thoughts, but the pain was too loud, overpowering. Eventually, it consumed me.”

Neo challenges my perception. “Did you hear how you talked to yourself about this high-pain experience?”

Reflecting, I admit, “Yep. With every pain surge, I complained about how miserable I felt. There wasn’t an external Grouch for others to see, but he showed up in my thoughts — a lot!”

“Exactly!” Neo exclaims. “It is the Grouch you have to change if you seek improved well-being. It’s easy to complain, and you have plenty of company on social media. But finding a different path, implementing healthy solutions — that’s where the hard work happens.”

I’ve seen glimmers of a different inner dialog. Rather than reacting to the high pain, I should be sitting in the “pause between” and observing it with as little emotion as possible; analyzing the pain and reporting back to Neo like a journalist covering a story. A new inner dialog needs to develop to keep the Grouch at bay. It’s a dialog about being caressed by calmness, about knowing this is possible at any time and making calmness the focus of my attention.

“Nice idealism,” Neo says, waving his brain neurons at me. “You know you haven’t been fully successful at this yet.”

I sigh, “True, I haven’t achieved a perfect day. Maybe I never will. But I am trying to improve every day.” Taking a deep breath to calm the emotions Neo has stirred by pointing out my failings, I continue, “I also find that seeking quietude in the pause between helps me. I’m facing one day at a time while doing all I can to implement a new pattern of thought and behavior. I’m just taking small, incremental steps right now, but I’m happy with the progress.”

Neo reminds me in that Eeyore tone, “You know how hard this is to accomplish.”

I stand, move to the windows and look out on the perennial gardens. The summer colors are starting to diminish, but the plants still have plenty of blooms. “You know, Neo,” I say calmly, “Life is like gardening in many ways. Take a shovelful of dirt, arrange plants by complementary colors, and lay a broad, level path to walk, pause, and enjoy. Showing up and accomplishing those baby steps every day eventually brings forth a garden of wonder and delight.”

Neo and I are quiet together while we walk the garden path.

***

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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Phase 3 Trial to Test Continuous Pump Delivery of Levodopa in Treating Motor Fluctuations

Phase 3 trial opening

A new Phase 3 clinical trial, called the “BouNDless study,” will soon compare continuous administration of ND0612 to oral immediate-release carbidopa/levodopa (CD/LD) in people with Parkinson’s disease who are experiencing motor fluctuations, Mitsubishi Tanabe Pharma America (MTPA) announced.

Both of the above-mentioned treatments work by increasing the level of the neurotransmitter dopamine in the brain — their key distinction is delivery. Unlike the conventional oral medication, ND0612 is given in continuous injections via a subcutaneous (under the skin) pump, not unlike how insulin might be delivered to people with diabetes.

“While oral CD/LD is the established standard for treating motor symptoms in Parkinson’s disease, many patients experience a decline in benefit as their disease advances, requiring them to take multiple doses throughout the day in an effort to control symptoms, often with unpredictable results,” Atsushi Fujimoto, the president of MTPA, said in a press release.

“We look forward to researching the potential efficacy and safety of continuous subcutaneous treatment with ND0612 on managing motor fluctuations and other complications of Parkinson’s disease, through the BouNDless study.”

The Phase 3 trial (NCT04006210), now getting underway, will compare ND0612 to immediate release CD/LD treatment in people with Parkinson’s whose symptoms are not being controlled by conventional treatments, defined as an average of 2.5 hours (or more) of motor fluctuation each day, with at least two hours per day during which motor symptoms are not under control (off time) while the person is awake.

Following a screening period, all participants will go through an open-label oral immediate release CD/LD adjustment period, followed by an open-label ND0612 conversion period. They will then be randomly assigned to either ND0612 or its matching placebo, plus immediate release CD/LD. After this 12-week main study, all have the option to continue in open-label extension period for one year.

The study’s main goal is to determine the effect of ND0612 on daily “good” on time, defined as time without dyskinesia (involuntary movement) or with non-troublesome dyskinesia.

BouNDless is set to soon start enrolling about 300 people at some 120 different sites around the globe. More information is available here.

The study is being funded by the pharmaceutical company NeuroDerm, which is developing ND0612; if the treatment is approved, MTPA will be the company selling it in North America. Both NeuroDerm and MTPA are owned by Mitsubishi Tanabe Pharma Corporation.

“Given the limitations of current therapeutic options for Parkinson’s disease, we recognized the importance of developing a potential non-surgical continuous treatment that may stabilize CD/LD plasma levels and alleviate the disabling motor fluctuations that are often exacerbated with disease progression,” said Sheila Oren, MD, MBA, chief medical officer at NeuroDerm. “We are excited that the Phase 3 study of ND0612 is underway, and we may be one step closer to potentially bringing a much-needed treatment option to patients.”

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Phase 2 Trial of Parkinson’s Psychosis Therapy Enrolling Across U.S.

Parkinson's psychosis

A Phase 2 clinical trial of SEP-363856, an oral treatment candidate for patients with Parkinson’s psychosis, is recruiting participants throughout the U.S.

The Sunovion-funded SEP361-203 study (NCT02969369) will be conducted at 24 U.S. sites and will include approximately 36 participants, 24 on SEP-363856 and 12 on placebo.

Trial locations and their contacts can be found here.

Eligible patients are at least 55 years old, received a Parkinson’s diagnosis at least one year prior to the study and have been experiencing symptoms such as visual hallucinations (to see, hear or feel things that do not exist) and/or delusions, which refers to holding false and typically paranoid beliefs.

Women may be eligible if they are postmenopausal. All participants need to have a caregiver able to attend all study visits. Full details on inclusion and exclusion criteria are given here.

Following a screening/washout period lasting up to two weeks, Sunovion’s SEP361-203 will be given in oral capsules at 25, 50, or 75 mg once daily for six weeks, followed by 12 weeks of an open-label extension phase and one week of follow-up.

The study will test the safety, tolerability and effectiveness of SEP-363856, via changes in the Scale for Assessment of Positive Symptoms – Parkinson’s Disease (SAPS-PD) total score, which addresses hallucinations and delusions.

Other assessments include the Clinical Global Impression-Severity of Illness (a measure of disease severity), the Neuropsychiatric Inventory (composed of an interview of the caregiver), and the Mini Mental State Evaluation of cognitive function, which measures memory, orientation, concentration, and language. Blood and urine tests also will be performed.

All study visits, tests and trial-related medication will be provided at no cost. Participants also may be reimbursed for travel and other expenses. The study is expected to be completed by May 2020.

Parkinson’s psychosis is one the non-motor symptoms of the disease. Its most common manifestations are hallucinations and delusions, but illusions (misinterpreting existing things), panic attacks, and vivid dreams also may occur.

Currently, Nuplazid (pimavanserin), developed by Acadia, is the only U.S. Food and Drug Administration (FDA)approved medication for treating hallucinations and delusions associated with Parkinson’s disease.

Suncoast Neuroscience Associates in St. Petersburg, Florida is one of the locations enrolling participants for the SEP361-203 study. Patient care there is led by Alberto Vasquez, MD, a neurologist and lead principal investigator at Suncoast. To contact the researchers at Suncoast, click here.

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Nourianz Approved in US as Add-on Therapy to Carbidopa/Levodopa to Treat Off Periods in Parkinson’s

Nourianz FDA approval

The U.S Food and Drug Administration (FDA) has approved Kyowa Kirin’s Nourianz (istradefylline) tablets as an add-on therapy to treat off periods in Parkinson’s disease patients on a carbidopa/levodopa regimen.

Off periods — when the effects of a medication wear off before a new dose can be taken — are characterized by the re-emergence of Parkinson’s motor symptoms and are typically more common as the disease progresses.

Nourianz blocks a receptor, known as the adenosine A2A receptor, found at high levels in the basal ganglia, a region of the brain that controls movement. By blocking this receptor, Nourianz can alter the release of neurotransmitters — chemical substances produced in response to nerve signals that allow nerve cells to communicate — in the basal ganglia, in this way modulating motor activity.

FDA approval comes after the agency first rejected the therapy in 2008 due to concerns about its efficacy and asking for more data. Nourianz has been sold in Japan since 2013 under the brand name Nouriast.

“[This] approval is the culmination of decades of perseverance in exploring the science and clinical effects of istradefylline and inhibition of adenosine A2A receptor signaling in people with Parkinson’s disease,” Jeffrey S. Humphrey, MD, chief development officer of Kyowa Kirin Pharmaceutical Development, said in a press release. “We are grateful for the FDA approval and for the many dedicated scientists and  patients whose participation in our research programs has resulted in a new treatment option for Parkinson’s disease.”

The decision was based on data from four 12-week, placebo-controlled Phase 2 and 3 clinical trials (NCT00955526, NCT00455507, NCT01968031, and NCT00250393) that assessed the safety and efficiency of two doses (20 mg and 40 mg) of Nourianz to reduce the mean total hours of awake time per day spent in the off state and also lessen motor symptoms.

These trials enrolled a total 1,143 participants who were being treated with levodopa/carbidopa, levodopa/benserazide, or levodopa and any other dopa-decarboxylase inhibitor. Treatment with Nourianz significantly decreased daily off time when compared with patients on a placebo.

However, in 2016, data from one of the Phase 3 trials (NCT01968031), which evaluated the efficacy of Nourianz administered orally as a 20 mg or 40 mg once-daily treatment for 12 weeks, revealed a trend toward a greater reduction in the daily off-time compared with placebo, but this difference did not reach statistical significance.

New data from an interim analysis (which included 476 patients) of a post-marketing surveillance study conducted in Japan and submitted in October 2018 revealed that Nourianz was effective in 61.3% of patients, as assessed by the physician’s global assessment. Motor function improved, as observed by a decrease of 33.7 (after treatment) to 30.3 (from the beginning of the study) in the Unified PD Rating Scale (UPDRS) Part III (motor assessment) scores.

This new analysis also showed that off time was reduced in 38.2% of patients, and off-time symptoms improved in 44.7% of patients. Additionally, motor dysfunction was lessened in 48.5% of patients.

The most common side effects of Nourianz included involuntary muscle movement (dyskinesia), detected in 1% of the patients on Nourianz, dizziness, constipation, nausea, hallucinations, and insomnia. The FDA has requested that patients prescribed Nourianz are monitored for dyskinesia.

“Parkinson’s disease is a debilitating condition that profoundly impacts patients’ lives,” Eric Bastings, the acting director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research, said in an FDA press release. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

Kyowa Kirin also has another adenosine A2A receptor antagonist, KW-6356, which is now undergoing testing in Phase 2 trials for Parkinson’s disease.

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Fox Foundation Awards $5M to Support Genetic Studies of Parkinson’s in Africa, Asia and India

Fox Foundation grant

With the overarching goal of helping scientists develop and test targeted therapies in Parkinson’s (PD), The Michael J. Fox Foundation (MJFF) is awarding $5 million in grants to three teams conducting genetic studies in African, East Asian and Indian populations.

The funding seeks to broaden these studies in order to better understand the role of genetics in PD onset and progression, and to expand treatment options for patients globally. Historically, the majority of research has focused on people of European descent. The grants will enable genetic testing of samples from more than 30,000 people.

“While the field has made significant strides in genetic research, we know we have more to learn about the changes in DNA that lead to Parkinson’s disease and impact its progression,” Brian Fiske, PhD, MJFF senior vice president of research programs, said a news release. “This is an all-star initiative with world-class geneticists, clinic networks and study volunteers coming together to paint a global picture of Parkinson’s and work toward cures for everyone.”

Since researchers discovered the first genetic mutation linked to PD in 1997, more than 80 others have been identified. Scientists are studying the cellular impact of these mutations, associated with about 15 percent of PD cases, in order to better understand Parkinson’s and possible ways of treating it.

Potential therapies aimed at proteins including LRRK2, one of the most commonly known genetic causes of Parkinson’s, are in clinical trials. Work like this is what the global Parkinson’s genetics program hopes to build upon. The non-profit foundation has long backed genetic studies, and diversity and inclusivity in clinical investigations.

Grants under this global program — with support from the Edmond J. Safra Foundation, a long-time partner of the Fox Foundation — will go to the following projects:

“Parkinson’s is a global issue, and we are grateful to The Michael J. Fox Foundation for fostering representation in research,” said Njideka Okubadejo, a professor of research at the University of Lagos in Nigeria. “We hope this partnership results in greater understanding of disease causes and contributors, and leads to new treatments for people living in Africa and beyond.”

Parkinson’s is the second most common age-related neurodegenerative disorder (after Alzheimer’s), and estimated to affect 7 to 10 million people worldwide.

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What Changed After DBS Surgery No. 1

DBS surgery

Deep brain stimulation (DBS) can affect both cognitive and motor symptoms in Parkinson’s patients who undergo the surgery. The procedure gives hope to those who are substantially inhibited by tremors and dyskinesia — people like my dad. After doctors determined he’d make a good candidate for the surgery, Dad had his first operation almost two weeks ago. The surgeon placed electrodes in his head and zipped him back up.

Since his first surgery, Dad has observed his physical changes with curiosity. Experts allude to a “honeymoon phase” that often lasts for days or even weeks after the first DBS procedure. For whatever reason, the initial phase seems to spark changes within the body even though the electrodes aren’t yet powered by their battery.

An instruction pamphlet from the University of California, Davis, states: “Sometimes there is a ‘honeymoon’ period following electrode implantation but before the battery is activated – during this period, some of your symptoms may be much better even though the DBS has not been connected or turned on yet. This will fade away and you can expect to return back to your previous level of functioning.“

What has that experience been like for my dad? Let me tell you.

Dyskinesia after DBS

The main reason Dad wanted to undergo DBS was to manage his dyskinesia. As you can imagine, losing control over the way your body moves is physically and mentally taxing. Dad’s medications help him maintain independence, but when they’re leaving his system for the night, dyskinesia hits. Since the completion of his first surgery, Dad says that his dyskinesia is either entirely gone or barely noticeable.

Additional changes

Dad has also observed symptoms that are worse than or the same as they were before the surgery: “My right hand seems to be worse than normal but not by much. I suspect this is because my drugs are not working. And I’m freezing about the same as I was before I had the surgery.” Knowing that this window of change isn’t permanent, Dad observes the shifts but looks to the future for long-term effects.

What can we learn from the honeymoon phase?

Although Dad is experiencing the honeymoon phase, the idea that his body is responding to the electrode placement is fascinating. Why has there been a change in the way his body reacts to Parkinson’s? What causes the honeymoon effect? And why does it affect individual patients in different ways?

What we do know is that when the honeymoon period ends, Parkinson’s symptoms return to their original state. And once you start DBS, it generally takes several months to experience the full effects, since you and your neurologist have to program the electrodes to operate according to your unique symptoms.

DBS phase 2

Tomorrow, Dad will enter the operating room for the second time. This time, his surgeons will connect the electrodes in his brain to the battery in his chest. This surgery is more invasive and may be more painful. The recovery period will likely be longer. It’s easy to worry, pointing to the potential surgical complications.

But despite his current and upcoming challenges, Dad’s attitude remains positive. Just yesterday, he was making jokes about being able to communicate with radio stations due to his new hardware. Imagine what he’ll be able to do when the electrodes are connected to their battery! We remain hopeful, looking to the future with curiosity.

***

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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When Silence Is Golden

silence

There is a story of a little girl who was late coming home from school one day. Her mother was beside herself with worry. When the girl finally came through the door, her mother’s concern quickly turned to frustration.

“Where have you been?” she asked her daughter. “I’ve been worried sick about you!”

“I was walking home from school with the new girl in class,” the little girl said. “She dropped all her homework papers and they blew into a puddle. She was so upset that she sat down on the curb and cried. I didn’t know what else to do, so I just sat down and cried with her.”

When a loved one is hurting, sad, and overwhelmed by life, there’s not much we can do to help them. Sometimes the only thing we can do is listen. Listen while they pour their heart out. Listen in silence. 

What I mean by that, is this …

Words are not always needed. Sometimes, we need only to sit next to the one who is suffering and allow the tears to fall.

I just finished reading a book in which one of the characters was reluctant to speak. He wasn’t comfortable talking to people if he didn’t know them well. He was content without having to fill the silence around him. Because of him, the main character soon discovered how much could be said without the use of words. By just sitting beside someone, not feeling the need to talk, he was able to offer silent support and comfort. 

With Parkinson’s, it becomes more difficult and frustrating to talk. The words are harder to get out. Sometimes they don’t make much sense, unless you are listening well. Even then, a person with Parkinson’s may be hard to hear because they talk softer than they once did.

People often say, “I know what you are going through,” or “I understand.” But unless they have experienced exactly what you are going through, they cannot understand.

That’s when it’s time to sit down on the curb — when no words are needed and silence really can be golden — and just listen.

***

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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Rescuing Activity of Specific Neurons Improved Motor Function in Parkinson’s Mice

neurons

Rescuing the activity of neurons in the subthalamic nucleus — part of a brain region that controls movement — lessens motor dysfunction in a mouse model of Parkinson’s disease (PD), according to a recent study.

The “study argues that the loss of this intrinsic activity promotes abnormal synchronization and motor dysfunction in Parkinson’s disease,” Mark Bevan, PhD, the study’s senior study author, said in a press release. Bevan is a professor of physiology at Feinberg School of Medicine, Northwestern University.

The study, “Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons” was published in the journal Cell Reports.

The glutamatergic subthalamic nucleus (STN) is part of the basal ganglia, a brain region that controls movement and impulse control, and one of the key sites affected in Parkinson’s disease. Composed mainly by glutamate-producing neurons, in Parkinson’s models the firing of these neurons is decreased.

Of note, glutamate is a key excitatory neurotransmitter — chemicals that nerve cells use to send signals to other cells. Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire.

Loss of dopamine-producing neurons, a hallmark of Parkinson’s disease, causes neurons within the STN to develop abnormal, synchronized activity, which results in impaired motor function.

Researchers at Northwestern University used a mouse model of Parkinson’s disease to investigate the mechanisms that lead to the abnormal activity of neurons within the STN.

“We first determined the mechanisms that cause STN neurons to adapt to the loss of dopamine by slowing their autonomous pacemaking activity,” said Eileen McIver, PhD, the study’s first author.

They found that loss of dopaminergic neurons resulted in lower activity “in the motor territory of the STN.” They then found that the cause for this abnormal activity was an increased activity of neurons in the basal ganglia carrying the D2 receptor. (The D2 receptor has the capacity to regulate the levels of dopamine by inhibiting the release of this neurotransmitter.)

This trigger increased the activity of an ‘indirect’ pathway” of the basal ganglia leading to additional chemical changes — activation of NMDA glutamate receptor and ATP-sensitive potassium channels — that ultimately reduced the firing of STN neurons.

Rescuing the activity of STN neurons using designer receptors exclusively activated by designer drugs (DREADDs) rapidly improved motor function in Parkinson’s mice. DREADDs are a class of engineered proteins that allow the targeted delivery of a receptor protein to specific cells.

“Within ten minutes of injecting the designer drug to activate DREADDs in the STN, we saw a symptomatic improvement,” McIver explained. Overall, these findings “provide proof-of-concept for the use of tools like DREADDs as a therapeutic approach in Parkinson’s disease,” he said.

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Depression Is Risk Factor for Impulse Control Disorders in Parkinson’s Patients, Study Finds

depression

Patients with Parkinson’s are at a greater risk of developing impulse control disorders (ICDs) if they are depressed, according to results from an international study.

The findings also revealed that treatment with dopamine agonists increases this susceptibility, and caution is advised when prescribing such therapies to depressed Parkinson’s patients.

The study, “Depression as a risk factor for impulse control disorders in Parkinson’s disease,” was published recently in the journal Annals of Neurology.

Depression and ICDs are two of the most common non-motor symptoms of Parkinson’s disease. However, while depression often precedes the onset of motor problems, ICDs are related to Parkinson’s treatment, especially to dopamine agonists. “This association with [dopamine agonists] makes ICDs a potentially avoidable disorder,” the researchers wrote.

Prior studies have shown that depression and ICDs often coexist in people with Parkinson’s, but were not able to assess whether depression increases the susceptibility for ICDs.

A team of Spanish researchers used data from the Parkinson’s Progression Markers Initiative, a multi-center clinical trial to identify biomarkers of Parkinson’s progression, to address this gap. A total of 354 patients were included, mostly from specialized university hospitals in the U.S. and Europe. None had ICD at baseline, as assessed with the Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease.

ICD and medication use were evaluated at follow-up evaluations every three months initially, and every six months after visit four. The researchers also evaluated anxiety with the State-Trait Anxiety Inventory, apathy with the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), and sleep impairments via the REM sleep behavior disorder screening questionnaire.

At baseline, 54.8% of patients were aged between 60 and 75 years and 61.3% were men. The results showed that 68 participants (mean age 60.8 years, 13.3 months since diagnosis) had either depressive symptoms or were diagnosed with depression and taking antidepressants.

The prevalence of depression was higher in women than in men (27.78% vs 15.93%) and depressed patients did not receive dopamine agonists more frequently than non-depressed patients either at baseline or during follow-up.

Also, anxiety and apathy scores were higher in patients with depression (aged 61.6 years, 182 men, 12.7 months since diagnosis).

Over a median follow-up of approximately four years, the patients with depression at baseline showed a nearly two-fold greater risk of developing ICDs, as reflected in an incidence rate of 19.4 cases per 100 patient-years — a measure obtained by multiplying the number of persons at risk over time — compared to 10.3 cases in those without depression.

As shown previously, using dopamine agonists also increased the risk for ICDs. In fact, patients with depression had an ever greater risk of developing ICDs if taking these treatments. Controlling for multiple potential confounding factors — such as age, sex, apathy and anxiety — did not alter these findings.

“Our results show depression acts as a risk factor for the development of ICDs in [Parkinson’s] patients,” the scientists wrote.

“Notably, our results [also] show that the use of [dopamine agonists] in patients with depression is linked to a higher ICD risk,” they added. As such, dopamine should be used with caution in this patient population, the researchers commented.

Importantly, depression should be routinely monitored “to optimize medical decisions regarding the risk of developing ICDs.”

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PPMI RNA-Sequencing, the Largest Dataset of Gene Activity in Parkinson’s, Now Available to Researchers

PPMI RNA-Sequencing

The largest dataset ever compiled on Parkinson’s disease research — equivalent to 47.5 billion single-spaced typed pages — is now available to scientists, and can be used to investigate genetic changes over time in people with the neurodegenerative disorder.

Funded by the Michael J. Fox Foundation, the “Parkinson’s Progression Markers Initiative (PPMI) RNA-Sequencing Project” can help researchers assess how genetic changes observed in Parkinson’s impact disease progression or response to medication.

The study was led by Kendall Van Keuren-Jensen, PhD, at the Translational Genomics Research Institute (TGen), and David W. Craig, PhD, at the University of Southern California (USC).

A team of researchers analyzed samples obtained exclusively from the MJFF-sponsored Parkinson’s Progression Markers Initiative (PPMI), the most comprehensive study on PD until now. The PPMI study included more than 4,750 anonymous samples from 1,589 people with clinical and genetic PD risk factors and healthy control volunteers.

“PPMI has built the most robust Parkinson’s data set to date, collecting clinical, imaging and biological information from volunteers over at least five years to better understand disease onset and progression. The PPMI RNA-Sequencing Project significantly increases the study’s value and moves us closer to its goals to better define, measure and treat Parkinson’s disease,” Todd Sherer, PhD, the Foundation’s CEO, said in a press release.

Using a technique called RNA sequencing, researchers were able to analyze the entire RNA content of the PPMI samples. Analyzing the data — containing more than 108 terabytes of raw and processed sequencing data — took 480,000 hours of processing time, the researchers said.

All genetic information contained within genes, known as DNA, is ultimately translated into proteins. However, several complex steps exist before a protein can be produced. DNA is first transformed into RNA, after which a process called translation begins. That process gives rise to proteins.

By comparing the RNA levels of people with PD and controls, researchers can get a deeper understating of the key genes that play a role in the disease — and how their activity changes over time.

“Mutations in genes can affect proteins in ways that contribute to Parkinson’s disease, but that’s only part of the picture. To understand all the causes of the disease, we need reliable data on as many molecular measurements as we can: DNA, RNA and resulting proteins,” said Van Keuren-Jensen, co-director of the Center for Noninvasive Diagnostics at TGen, an affiliate of City of Hope.

“RNAs function as messengers from genes to create proteins, and many types of RNA have additional roles in cells that we are just beginning to understand. We sequenced these samples to capture as many types as possible, including protein-coding genes, lncRNAs and circular RNAs,” Keuren-Jensen added.

The RNA-sequencing data from the PPMI project is accessible to all researchers, who first need to apply for access through the PPMI website.

“Through PPMI, the Fox Foundation has created an unprecedented resource for the research community. And this RNA sequencing project is bringing another layer of information to explore and compare toward greater understanding of the disease and how to stop it,” said Craig, professor of translational genomics and co-director of the Institute of Translational Genomics at Keck School of Medicine of USC.

Data from the new study can be used to explore genetic changes associated with Parkinson’s and the impact of gene expression on factors including age, disease progression, and even medication use. Analysis of these data could help researchers better understand Parkinson’s, its variability, and ways to measure and treat it, the MJFF said.

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