In Small Study, Parkinson's Disease Patients with LRRK2 Mutation Have Elevated Risk for Different Cancers

By Jamie Talan

September 19, 2019

A multicenter team of scientists have identified an almost five to 10-fold increased risk of leukemia, and a 2.3-fold increased risk of colon cancer in patients with Parkinson's disease (PD) who carry the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (from two separate analyses).

They also found an almost two-fold higher risk of skin cancer in LRRK2-PD patients compared with those with idiopathic PD and age-matched controls. The findings were published online July 26 in Movement Disorders.

The discovery of a link between cancer and Parkinson's disease is not new, but the findings from several epidemiological studies have been mixed, and they were generally too small in number to make clear cut recommendations.

This study includes assessments from information gathered on 2,365 Parkinson's patients, however, and the implications are this: People with the LRRK2 G2019S mutation do have a substantially higher risk for certain cancers and neurologists should take this into account when managing their patient's medical needs.

“We might consider that if someone is a carrier of the LRRK2 G2019S mutation they should be closely monitored for Parkinson's and for certain cancers,” said Ilir Agalliu, MD, PhD, associate professor in the department of epidemiology and population health at Albert Einstein College of Medicine, which collaborated with other medical centers in New York, California, Israel, Spain, and Germany.

Dr. Agalliu, a cancer epidemiologist, said that previous studies have identified a relationship between PD and cancer, and the findings have generally pointed to a decreased cancer risk in smoking-related cancers and other cancers, with the exception of a higher risk for melanoma.

But the numbers didn't seem to add up for people with the LRRK2 mutations, and a small number of studies were suggesting a higher signal for non-skin cancers and breast cancers.

Dr. Agalliu and senior author Rachel Saunders-Pullman, MD, MPH, the Bachmann-Strauss professor and associate professor of neurology at the Icahn School of Medicine at Mount Sinai and chief of movement disorders at Mount Sinai Beth Israel, and their colleagues were funded by the Michael J Fox Foundation to collaborate with other MJFF LRRK2 consortium sites to look further into this association.

Their previous work included a meta-analysis of 1,549 patients, in which 11.4 percent were LRRK2 G2019S carriers. They found a 62 percent increased risk of nonskin cancer and a two- to three-fold higher risk for hormone-related cancers, mostly breast cancer, compared with patients with idiopathic PD. That association made them wonder how these numbers would compare with people without PD and without the G2019S mutation.

“The association between skin cancer and the LRRK2 mutation in Parkinson's highlights one of the most consistent cancer associations in Parkinson's,” said Dr. Saunders-Pullman.

“Parkinson's disease patients, whether they have a LRRK2 mutation or not, have generally been shown to have a higher rate of skin cancer, especially melanoma. Because skin cancer may be treatable if captured early, it is very important to counsel patients on the need for yearly, or possibly more frequent, skin examinations, and the need to seek medical attention for any suspicious moles,” she said.

Study Methods, Findings

The scientists looked at cancer outcomes via questionnaires in 257 PD patients with the LRRK2 mutation, 712 idiopathic PD patients, and 218 controls recruited from seven LRRK2 consortium centers.

They sent out a detailed health questionnaire that included information on demographics, lifestyle, and reproductive factors; self-reported cancer history; personal health-related histories; and family histories of PD and cancer. Everyone was tested for LRRK2-G2019S mutations. (Two centers in Germany and Spain also tested for other LRRK2 mutations: R1441G/C and I2020T, but this analysis only included the G2019S carriers.)

Overall, cancer prevalence was similar in all groups, including controls: LRRK2-PD patients (32.3 percent), idiopathic PD patients (27.5 percent), and controls (27.5 percent). But patients with LRRK2-PD had a 4.55 greater risk of leukemia and a 1.61 increased risk for skin cancer.

When compared with idiopathic PD patients and controls, the LRRK2-PD patients also reported a higher proportion of multiple cancers: 8.6 percent compared with 6.6 percent in idiopathic PD patients and 3.7 percent in controls.

The scientists pooled the current data with previous findings from a 2015 JAMANeurology study, and they examined cancer risk in 401 LRRK2-PD and 1946 idiopathic PD patients. When the numbers increased in the pooled analysis, they found an even greater risk of leukemia in LRRK2-PD patients: almost ten times higher.

The researchers noted however that there were only five cases of leukemia in the LRRK2-PD patient group compared with no cases in the idiopathic PD group or controls. They also reported a 2.34 higher risk of colon cancer. These studies represent the largest cohort of PD patients with genetic screening for LRRK2 mutations.

The researchers also looked at whether the association between the cancer risks in the LRRK2 G2019S mutation varied by ethnicity. About 75 percent of the study participants were of Ashkenazi Jewish ancestry and the results were similar among different ethnicities, they said.

The authors said that one of the study limitations is that these were self-reported cancers and their answers were not validated with cancer registries or medical records in all participating centers. They also did not have information on the stage or severity of the cancers.

“This very large multisite and multinational study supports an association between certain rare cancers and LRRK2 mutation Parkinson disease, in particular, blood related cancers,” said Dr. Saunders-Pullman. “It is hoped that, in the future, potential shared mechanisms may be elucidated, and that if low side effect therapeutics are available for one, they might be applicable for the other.

“We did not replicate an association with hormonal cancers, which was seen in our earlier study, and also reported by others,” Dr. Saunders-Pullman continued. “This underscores that the frequency of different cancers was different across specific sites, and while we were able to assess across a wider range of participants, there will be not only individual but ethnic and region specific differences.”

So why would the LRRK2 G2019S mutation lead to an increase in certain cancers?

“The biological mechanism is not fully understood,” said Dr. Agalliu. He said he suspects that “the LRRK2 gene has a lot of domains and some regulate the MAP kinase pathway that is usually activated in cancer. The LRRK2 mutations could also activate several other cancer pathways.”

The implications of the findings, he added, is that “we might consider closely monitoring people with this LRRK2 mutation for PD and for certain cancers.”

He and his colleagues are interested in looking at other mutations along the LRRK2 gene to see if there are other cancer risks. “In epidemiology, we like when we see consistency of patterns, and yes, we saw something. It is important to validate these studies,” he added.

Expert Commentary

There are multiple intriguing links between PD and cancer, particularly for melanoma, said Clemens R. Scherzer, MD, professor of neurology at Harvard Medical School, director of the Advanced Center for Parkinson's Disease Research, and director of the precision neurology program at Brigham & Women's Hospital.

“This study claims a potential associations between PD patients carrying the G2019S LRRK2 mutation and leukemia. Subset analyses point at possible signals for associations also with nonmelanoma skin cancer and colon cancer. This is intriguing and will inspire further work.”

“To identify and characterize LRRK2-positive patients around the globe is a huge endeavor. However, the main findings are preliminary, based on just five LRRK2-PD patients who reported leukemia,” Dr. Scherzer said.

“The risk for cancer in patients with LRRK2-PD will need evaluation in larger, prospective, and population-based cohorts before clinical recommendations can be made. The study is limited in sample size and vulnerable to false positives due to the multiple testing, confounders, and potential threats from recruitment and ascertainment bias.”

“This is another study from a group of investigators with a strong track record in LRRK2 and cancer. The results are overall consistent with their previous findings that LRRK2 is associated with certain cancers,” said Xiqun Chen, MD, PhD, assistant professor of neurology at Massachusetts General Hospital.

“It is important to further investigate whether LRRK2 is a causal contributor to these cancers. Biologically, LRRK2 can activate MEK-ERK-MAPK and AKT-4E-BP1, which mediate cell survival and proliferation. And structurally, the LRRK2 kinase domain shares similarity with the oncogene BRAF. Some cancers harbor somatic LRRK2 mutations. Better understanding of the biology would provide valuable insight into specific cellular contexts in determining cells' final fate in response to a common pathogenic factor (LRRK2 G2019S).”

“The study provides evidence to inform a personalized medicine approach to screen LRRK2 mutation carriers for early detection for cancer,” she added. Dr. Chen became interested in the association between Parkinson's and cancer about five years ago, and her lab is now focusing on studying why these connections occur. She recently organized a meeting in Boston to bring together neurologists and cancer specialists to begin a discussion and educate specialists in both fields.

Disclosures

Drs. Agalliu and Chen had no conflicts of interest. Dr. Scherzer has collaborated with Pfizer, OPKO, Proteome Sciences, Sanofi, and Berg Health; has consulted for Sanofi; has served as advisor to the Michael J. Fox Foundation, NIH, Department of Defense; is on the scientific advisory board of the American Parkinson Disease Association; has received funding from the NIH, the US Department of Defense, the Harvard NeuroDiscovery Center, the Michael J. Fox Foundation, and American Parkinson Disease Association

https://journals.lww.com/neurotodayonline/Fulltext/2019/09190/In_Small_Study,_Parkinson_s_Disease_Patients_with.1.aspx

Guest Opinion: Concussions and youth

Sep 18, 2019   By Dr. Alice Cha 

Stay current on traumatic brain injury for children and teens 

 Dr. Alice Cha

A lot of parents and coaches are familiar with that sudden "thump" when their child or player hits their head. 

Whether it occurs when a child falls on the playground unexpectedly or when the ball inadvertently hits a player's head, the injury can be significant. Unlike medical professionals, athletic trainers and parents are really the first responders in this situation. 

While severe head injury becomes readily apparent, mild traumatic brain injury -- or concussion -- can be difficult to identify and treat. Becoming familiar with this topic becomes crucial to working with medical professionals for the care of the injury and to making joint decisions on returning the child or player back to activity. 

Traumatic brain injury is defined as a blunt-force injury that disrupts the normal function of the brain or any injury that causes the head and brain to move quickly back and forth. In 2014, Centers for Disease Control and Prevention (CDC) found that there are approximately 2.87 million traumatic brain-injury-related emergency room visits and 56,800 deaths related to traumatic brain injury, including 2529 cases that were children. 

Unlike adults, children and adolescents up to 18 years old are particularly vulnerable because of their incompletely developed brain. Female athletes are 1.4 times more susceptible to mild traumatic brain injury than male athletes. 

In addition to the well-known consequences of impairments in thinking, memory, movement and sensation, head injury may even lead to personality changes or depression. Some cases have increased risk for degenerative brain diseases, such as Parkinson's disease or Alzheimer's disease. 

Most daunting may be the unpredictable onset of these effects, which may occur weeks or months later. This speaks to the importance of close and persistent monitoring at home and school by parents and coaches alike. 

When head injury happens, the child or adolescent should be immediately removed from sports or play until cleared by a medical professional. 

"Removal from play" for at least seven days for youths in youth sport organizations has been a California state law since January 2017. It's based on the fact any repeat concussion while the brain is healing from the first injury may be fatal. 

When medical professionals evaluate an injured child, they use a symptom scale that is stratified by their age group. They look for symptoms that are largely divided into four categories: physical, emotional, cognitive and sleep abnormalities. They will refer the patient to specialists if further neurocognitive testing is indicated. 

Unlike years ago, when "resting" was the foundation of treatment, long recovery time in a dark room is discouraged in CDC's first published pediatric guideline on mild traumatic brain injury, in 2018.

It advises a gradual return to low-impact activities after two to three days of rest. Then, with tolerance, the child should gradually start light aerobic activity, continuing to moderate activity, and, finally, regular activity. 

It should be pointed out that the CDC identifies children with lower cognitive ability, neurological or psychological disorders, learning disability and even social stressors to be at greater risk for delayed recovery. Parents and coaches should pay special attention to these groups and enroll them in active rehabilitation as needed.

The bottom line is that traumatic brain injury not only requires medical professional evaluation and removal from play, but symptom-monitoring and a return-to-play plan should be an intimate collaboration between parents, coaches, and healthcare providers. CDC's "HEADS UP" campaign provides great resources on how to approach this. 

It's the law

California's new law requires an athlete who is suspected of sustaining a concussion or other head injury in an athletic activity to be immediately removed from the athletic activity for the remainder of the day, and the athlete shall not be permitted to return to any athletic activity until he or she is evaluated by a licensed healthcare provider. 

The athlete shall not be permitted to return to athletic activity until he or she receives written clearance to do so from a licensed health-care provider. If the licensed healthcare provider determines that the athlete sustained a concussion or other head injury, the athlete shall also complete a graduated return-to-play protocol of no less than seven days in duration under the supervision of a licensed healthcare provider. 

Editor's note: Dr. Alice Cha is a hospitalist at Stanford Health Care-ValleyCare and a clinical assistant professor of medicine at Stanford University. She is also the co-director for Stanford ValleyCare Clinical Academy, a two-week summer program for high school students interested in medicine as a career. Learn more from the ValleyCare Charitable Foundation at vccharitable@stanfordhealthcare.org or 373-4560.

https://www.pleasantonweekly.com/news/2019/09/18/guest-opinion-concussions-and-youth

Hope Is Good Medicine When Fighting Parkinson’s Disease

 SEPTEMBER 18, 2019    BY "SHERRI WOODBRIDGE"

I thought I knew what to expect. But I was hoping that the first opinion was incorrect — that they had missed something or seen something that wasn’t there. 

I drove on, the second opinion soon to come.

Entering through the sliding glass doors, I made a right turn and pushed the elevator button. I ascended two floors, stepped out, made a left to the neurology department, and checked in. New patient paperwork filled out, I took a seat among others who sat waiting. 

The wait was unusually short. When my name was called, I stood and followed the nurse back to the room that I would occupy for the next two hours.

White. All white. 

The walls, the trash cans, the sheet of paper that covered the exam tables — everything was sterile white. Cold and uninviting. But then what is “friendly” about a doctor’s office? I would soon find out.

The nurse ran through the paperwork and repeated the questions that I had already answered with a pen. After taking my vitals, she stood, and as she turned to leave the room, she said, “The doctor will be right with you.”

“Yeah,” I thought. “Right with me.” At least I didn’t have to wait in the lobby. But before my thoughts had time to flourish, the door opened. 

The doctor’s smile was wide as he stretched out his hand. He was dressed in slacks and sweater, his dark, curly hair pulled back into a neat ponytail and topped with a knit beret. After the introductions, he began “testing.”

Testing for Parkinson’s disease is different than for most other conditions. There are no blood or urine tests, or scans — at least, there weren’t then, nearly 20 years ago. These “tests” began with the following:

•  Close your eyes. 
•  Start at 60 and count backward with your eyes closed. 
•  Arms out in front, palms up, palms down, tap thumbs and second fingers together, etc., etc.

He made notes for the next 20 minutes. Then he put his pen down, sat up straight, and with both feet on the floor, rolled his chair closer to me. Looking right at me, he put his hand on my knee. “I have to agree with Dr. So-and-So’s diagnosis. You have Parkinson’s disease. In fact, I think after reading through your records that they misdiagnosed you 12 years ago.” 

That diagnosis, 12 years earlier, was lupus. I could have flushed all that Plaquenil(hydroxychloroquine) down the sink instead of swallowing it. But, Parkinson’s disease? I was only 43 — isn’t it an older person’s disease?

I have since learned that Parkinson’s disease doesn’t discriminate. It doesn’t matter what age, nationality, or gender you are. I thought that I knew what to expect when I drove 30 miles for that second opinion, but looking back, I know that I wanted to hear something else, such as, “Well, I’m not sure what Dr. So-and-So was thinking, but you’re the healthiest person I’ve ever met.”

Hope springs eternal. 

Ah, hope

At a conference I attended on Parkinson’s disease, one of the speakers stated that the best medicine that we have when fighting any disease is hope. Hope for a better day, a breakthrough in research, a cure.

It’s easy to feel like giving in or giving up when you’re confronted with a challenge over which you seem to have no control — except your response to it. 

After the appointment, I went outside into the rainy afternoon. I walked across the wet pavement, unsuccessfully sidestepped the puddles, got into my car, and closed the door. I shivered, and then cried. 

My doctor didn’t tell me that I was the healthiest person he had ever met in all his years in medicine. He didn’t tell me that Dr. So-and-So was wrong or that I would get better. But he said that he’d be there with me to the end. 

Hope is good medicine

Now, I know that you can’t hold a doctor to a promise like that, but the feeling that he cared gave me hope. The knowledge that I had someone who understood what I was going through, who would be on my side through my journey made me feel less alone. 

Hope brings purpose back into view. It shuts out the “what-ifs” and turns down the dial of doubt. It disables the feelings of despair, enables you to have a confident expectation of a cure, finds the blessings in the curse, and faith for a brighter future.

I started the car, and as snow began to fall, a sense of peace came over me. All was well. I felt reassured that though I couldn’t choose to give back this disease, I could decide how I would face this challenge. 

I chose hope.

***

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.

https://parkinsonsnewstoday.com/2019/09/18/hope-good-medicine-second-opinion/

CRISPR/Cas9’s Potential in Better Understanding and Treating Parkinson’s Focus of Review Study

 SEPTEMBER 18, 2019   BY PATRICIA INACIO, PHD IN NEWS.

In a recent review, scientists highlight the potential of gene editing technologies like CRISPR/Cas9 to not only understand the molecular mechanisms behind Parkinson’s disease, but also identify new targets for treatment.

The review study, “Interrogating Parkinson’s disease associated redox targets: Potential application of CRISPR editing,” was published in the journal Free Radical Biology and Medicine. 

One of the hallmarks of PD is the loss of dopamine-producing neurons in the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in PD. This occurs due to the clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies inside neurons.

Parkinson’s is complex and multifactorial disease, with both genetic and environmental factors playing a role in either triggering or exacerbating the disease.

Genetic causes can explain 10% of all cases of PD —  called familial PD –, meaning that in the majority of the cases (sporadic PD) there is an interplay between genetics and environmental risk factors.

Researchers at Sechenov University in Russia and the University of Pittsburgh reviewed the role of metabolic pathways, especially problems with mitochondria — cells’ powerhouses — and iron accumulation, as well as mechanisms in cell death (called apoptosis and ferroptosis) in the development and progression of Parkinson’s disease.

These processes were discussed in the context of genome editing technologies, namely CRISPR/Cas9 — a technique that allows scientists to edit genomes, inserting or deleting DNA sequences, with precision, efficiency and flexibility.

“Empirical research has established many potential metabolic abnormalities that may represent the specific key mechanisms of PD pathogenesis. However, the diversity of these findings and the lack in understanding the connections between them slow down the progress in the development of specific treatments,” the researchers wrote. These abnormalities may be “[a]mong [the] many potentially important targets for CRISPR/Cas9 based research.”

“CRISPR is a promising technology, a strategy to find new effective treatments to neurodegenerative diseases,” Margarita Artyukhova, a student at the Institute for Regenerative Medicine at Sechenov and the study first author, said in a press release.

Mitochondria don’t work as they should in people with PD, resulting in shortages of cellular energy that cause neurons to fail and ultimately die, particularly dopamine-producing neurons. Faulty mitochondria are also linked to the abnormal production of reactive oxygen species, leading to oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them— that also damages cells over time.  

Because mitochondrial dysfunction is harmful, damaged mitochondria are usually eliminated (literally, consumed and expelled) in a process called mitophagy — an important cleansing process in which two genes, called PINK1 and PRKN, play crucial roles. Harmful changes in mitophagy regulation is linked with neurodegeneration in Parkinson’s.

Previous studies with animal models carrying mutations in the PINK1 and PRKN genes showed that these animals developed typical features of PD – mitochondrial dysfunction, muscle degeneration, and a marked loss of dopamine-producing neurons.

PINK1 codes for an enzyme that protects brain cells against oxidative stress, while PRKN codes for a protein called parkin. Both are essential for proper mitochondrial function and recycling by mitophagy. Mutations in both the PINK1 and PRKN gene have been linked with early-onset PD.

However, new research suggests that the role of PINK1 and PRKN in Parkinson’s could be more complex and involve other genes — like PARK7  (DJ-1), SNCA (alpha-synuclein) and FBXO7  — as well as a fat molecule called cardiolipin.

CRISPR/Cas9 genome editing technology may be used to help assess the role of different genetic players in Parkinson’s disease, and to look for unknown genes associated with disease progression and development. Moreover, this technology can help generate animal and cellular models that might help scientists decipher the role of certain proteins in Parkinson’s and discover potential new treatment targets.

Iron is another important metabolic cue in Parkinson’s. While it’s essential for normal physiological functions, excessive levels of iron can be toxic and lead to the death of dopamine-producing neurons in the substantia nigra.

Iron may also interact with dopamine, promoting the production of toxic molecules that damage mitochondria and cause alpha-synuclein buildup within neurons.

CRISPR/Cas9 technology can be used to help dissect the role of proteins involved in iron transport inside neurons, which in turn may aid in designing therapies to restore iron levels to normal in the context of Parkinson’s disease.

Finally, researchers summarized evidence related to the role of two cell death pathways — ferroptosis and apoptosis — in PD. Ferroptosis is an iron-dependent cell death mechanism by which iron changes fat (lipid) molecules, turning them toxic to neurons. This process has been implicated in cell death associated with degenerative diseases like Parkinson’s, and drugs that work to inhibit ferroptosis have shown an ability to halt neurodegeneration in animal models of the disease.

Apoptosis refers to a “programmed” cell death mechanism, as opposed to cell death caused by injury. Both apoptosis and ferroptosis speed the death of dopaminergic neurons.

CRISPR/Cas9 may help to pinpoint the key players in cell death that promote the loss of  dopaminergic neurons in Parkinson’s disease, while understanding the array of proteins that are involved in these processes.

“These insights into the mechanisms of PD pathology [disease mechanisms] may be used for the identification of new targets for therapeutic interventions and innovative approaches to genome editing, including CRISPR/Cas9,” the researchers wrote.

Genome editing technology is currently being used in clinical trials to treat patients with late-stage cancers and inherited blood disorders, Artyukhova notes in the release.

These “studies allow us to see vast potential of genome editing as a therapeutic strategy. It’s hard not to be thrilled and excited when you understand that progress of genome editing technologies can completely change our understanding of treatment of Parkinson’s disease and other neurodegenerative disorders,” she adds.

https://parkinsonsnewstoday.com/2019/09/18/crispr-cas9-potential-better-parkinsons-understanding-treatment-focus-review-study/

Antiparkinsonian Medication Improves Learned Movement Production by Boosting Neuronal Connectivity, Study Finds

SEPTEMBER 18, 2019   BY CATARINA SILVA, MSC 

Dopaminergic therapy may ease difficulties with gesturing and using tools in people with Parkinson’s disease by improving brain connectivity between the cognitive and motor regions, a study has found.

The study results, “Dopaminergic modulation of the praxis network in Parkinson’s disease,” were published in NeuroImage: Clinical.

Parkinson’s patients often have trouble performing skilled or learned movements that are crucial for daily living. Praxis is what scientists call this kind of cognitively directed motor action, while apraxia, generally speaking, refers to the difficulty itself, i.e., any disorder of learned movement.

“Although the neuronal basis of praxis functions has been comprehensively investigated in healthy individuals, functional imaging studies targeting these abilities including their impairments in clinical samples are still rare,” the researchers wrote.

Medical University of Vienna researchers studied the functional connectivity of the praxis network in individuals with mild-to-moderate Parkinson’s and at an increased risk for apraxia. They also investigated the influence of dopaminergic therapy on praxis function-related brain network.

For this purpose, a total of 13 Parkinson’s patients (seven men and six women, mean age of 60.23 years) and 13 healthy controls (seven men and 6 women; mean age of 56.77 years) underwent functional magnetic resonance imaging (MRI) and apraxia assessments.

Functional MRI measures the small changes in blood flow that occur with brain activity in response to stimuli or actions.

In the Parkinson’s group, all tests were performed twice: once with individually optimized dopaminergic medication (“on” state) and once without (“off” state).

None of the participants had trouble imitating gestures upon demonstration of object use, and none of the Parkinson’s patients showed apraxia-like symptoms. However, patients in the off period (without optimized symptom control by medication) performed significantly poorer in praxis assessments than controls.

Regarding functioning of the praxis-related brain network, patients in both states (on and off) displayed higher global efficiency than healthy individuals. Further analysis revealed that most of the communication within the network relayed to the bilateral supramarginal gyri, a portion of the brain that is thought to be involved in language perception and processing.

In addition, patients with optimized dopaminergic medication showed higher connectivity between praxis and motor areas, particularly between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas, in comparison to subjects in the “off” state.

This improved communication “might facilitate the propagation of long-term representations of object-related actions to motor execution areas,” thus enabling the correct execution of the wanted movement.

The praxis network was confined to the left-brain hemisphere in the control sample, while in patients “off” therapy, but not in “on” individuals, the  network expanded to the right hemisphere.

Importantly, antiparkinsonian treatment seemed to normalize patients’ learned movement skills and related network connectivity, suggesting such therapy may support higher-order cognitive motor functions, at least in early stages of this neurodegenerative disorder.

https://parkinsonsnewstoday.com/2019/09/18/antiparkinsonian-medication-improves-learned-movement/

Rekha Basu: Businesswoman works to raise awareness of disturbing side effects of Parkinson's treatment

September 18, 2019     By REKHA BASU

On a Monday evening last November, a dedicated group of shoppers sipped wine and pored over hundreds of unique rings, bracelets and necklaces at a downtown Des Moines eatery. The festive vintage jewelry sale was organized by friends of Shirley Burke who owned the jewelry, but was relinquishing it to raise money to attend a World Parkinson Congress in Japan.

How the graceful, creative, world-savvy professional got a Parkinson's diagnosis at the age of 37 remains an inexplicable part of the neurological disease once associated with people in their final chapter of life. But an even less known part of the disease is its link to how she came to own all those jewels. She is sharing her story, ashamed as it makes her, to let other patients and their families know potential side effects of a Parkinson's treatment she took

You may know about Parkinson's impact on motor functions  the muscle stiffness and rigidity; the decrease in voluntary movements and increase in tremors. Burke's speech was one of the first things to be impacted in 2013. When she started getting "dyskinesia," involuntary tremors in her fingers, she stopped eating in public. Her hands cramp up and the toes on her right foot curl painfully.

But Parkinson's can also wreak havoc on the psyche, bringing cognitive problems, depression and even psychosis. And when you add a "dopamine agonist," which mimics the effect of the brain chemical dopamine to reduce involuntary spasms, you may be gambling (literally) with fate.

Burke believes the drug caused her to hallucinate, blurred her vision and drove her to compulsive behaviors including shopping and gambling. The shopping was online and at estate sales. The gambling was online and in casinos. When she attended the Fourth World Conference on Parkinson's, she also heard patients talk of having compulsive sex. "Little did I know," she said. None of those had been a problem for Burke before her illness. But she says they nearly ruined her life, and led to her "darkest chapter."

The website of the Michael J. Fox Foundation, named after the popular actor who suffers from Parkinson's Disease, warns that dopamine agonists can cause hallucination and "In some people, these drugs can lead to impulse control disorders, such as compulsive gambling, hypersexuality ... and excessive shopping."

"The outcomes can range from a mere nuisance to disastrous consequences for family and social relationships, finances and careers," it says.

A 2014 study published in the Journal of the American Medical Association called for better warnings about dopamine agonists. "This relationship has been known for many years but clinicians may have failed to grasp its magnitude and possible implications," observed the Fox Foundation website, calling on the U.S. Food and Drug Administration to issue an "black box" warning to doctors about side effects.

"The medical community does not appreciate how common these problems are and how serious they may be," Dr. Howard D. Weiss, director of the Parkinson's Disease and Movement Disorder Programs at the LifeBridge Health Brain & Spine Institute in Baltimore, wrote.

Burke eventually went off the drug, and says within a week, the compulsions were gone. But she still has a tough road to walk. "The disease completely changed me to a different person," says the now 42-year-old. "On the surface everything looks OK but inside, it's an emotional and mental struggle."

There is fear and denial where before, there was only drive and determination. "Before the diagnosis (in 2016) I was very bubbly and social. These days I have to force myself. Crowds make me really anxious," she says.

Born in China, she moved to Ames, Iowa with her mother in the early 1990s to join her father, who was getting his doctorate at Iowa State University. She earned her master's in business and was employed by Principal Financial Group in a variety of capacities until her illness made it impossible to work. She had educated the executives and sales force in Chinese cultural and business etiquette, engaged and strengthened partnerships with international businesses, and led an employee resource group for Asian employees. "She is absolutely one of the most driven, amazing women," said her friend and former colleague Deb Tezak. "There was nothing holding her back."

Currently she's on three medications, one of which is made in Japan and has only recently been approved in the United States but is not yet in production here. So she travels there twice a year. There are bright spots in her life, including her supportive family and the larger community of friends and doctors. Also, two years ago, Burke's parents opened the Heavenly Asian Cuisine and Lounge in Valley Junction. She picked much of the elegant, tranquil decor, and has acquired the trust that owns it.

Taking over daily management, interacting with patrons and employees have brought new purpose and passion to her life and help cover her travel expenses. Though she doesn't drink alcohol, she has developed a passion for mixology. And under her, every Tuesday, 20% of net sale proceeds are donated to a charity.

There is still no cure for Parkinson's, whose cause remains unclear. It is believed to be primarily genetic, but triggered by environmental exposures, such as to pesticides. So Burke shares her darkest times and vulnerabilities, hoping the more people know, the more motivation there will be  by doctors, drug companies, federal and private researchers and regulators  to end the scourge and ensure treatments are safe.

https://www.chicagotribune.com/sns-tns-bc-basu-column-20190918-story.html