Changes in Neuronal Communication Linked to Falls and Freezing of Gait in Parkinson’s, Study Finds

neuronal communication changes, Parkinson's motor symptoms

Parkinson’s disease-related falls and freezing of gait — when patients are unable to move their feet forward when trying to walk — are associated with changes in a specific type of neuronal communication in different brain regions, a study reports.

The study, “Cholinergic system changes of falls and freezing of gait in Parkinson disease,” was published in Annals of Neurology.

Many people with Parkinson’s disease will experience falling and freezing of gait, which tend to become more frequent as the disease progresses. In some cases, symptoms cannot be controlled with dopaminergic therapy, suggesting that non-dopamine mechanisms contribute to Parkinson’s disease motor symptoms.

Previous studies have shown that the brainstem (region that connects the brain to the spinal cord) and basal forebrain (important in the production of acetylcholine) regions with degenerated acetylcholine-releasing neurons projecting to the thalamus and cerebral cortex are associated with falls and slow gait speed in Parkinson’s patients.

Acetylcholine is a brain chemical (neurotransmitter) released by nerve cells to send signals to other cells (neurons, muscles, and glands). The thalamus is involved in several important processes, including consciousness, sleep, and sensory interpretation; the cerebral cortex plays a key role in memory, attention, perception, awareness, thought, language, and consciousness.

Scientists have also observed reduced dopaminergic nerve terminals in the striatum, reduced cholinergic (meaning “acetylcholine-releasing”) nerve terminals in the cortex, and more severe beta-amyloid accumulation in Parkinson’s disease “freezers” compared with “non-freezers.”

The striatum coordinates multiple aspects of cognition, including both motor and action planning; the cholinergic system contains nerve cells that use acetylcholine to propagate a nerve impulse, and has been associated with a number of cognitive functions, including memory, selective attention, and emotional processing.

University of Michigan researchers hypothesized that distinct patterns of cholinergic projection system changes in the brain are associated with freezing of gait and falls in Parkinson’s patients.

The team examined and performed [18F]FEOBV positron emission tomography (PET) scans on 94 Parkinson’s patients (72 men and 22 women) with a history of falling and “freezing.” Most subjects were taking dopamine agonists, carbidopa-levodopa or combinations of both.

[18F]FEOBV is a radioactive marker that selectively binds to the vesicular acetylcholine transporter (VACht) that loads acetylcholine into synaptic vesicles — sac-like structures in neurons that store chemical messengers before releasing them into the gap between nerve cells (synapse), enabling neuronal communication.

A PET scan is a non-invasive imaging technique to visualize metabolic processes in the body. Before the scan, [18F]FEOBV is administered via injection; doctors wait for the radiotracer to be distributed throughout the body, and then scan the patient to detect and quantify the patterns of its accumulation in the body.

Because the marker binds to VACht, scientists use it to quantify active cholinergic nerve terminals in the brain.

“Participants were asked about a history of falling. A fall was defined as an unexpected event during which a person falls to the ground. The presence or absence of (freezing of gait) was based on clinical examination and directly observed by the clinician examiner,” according to The Movement-Disorder Society Sponsored-Unified Parkinson’s Disease Rating Scale (MDSUPDRS), the researchers wrote.

They reported that 35 participants (37.2%) had a history of falls, and 15 (16%) had observed freezing of gait.

Compared with non-fallers, fallers had a significant decrease in VACht expression within the right thalamus, specifically in the lateral geniculate nucleus, which is the primary center for processing visual information. This suggests that the visual information processing required for walking around safely might be compromised in Parkinson’s patients with a history of falling.

On the other hand, patients with freezing of gait had significantly reduced VACht expression in the bilateral striatum and hippocampus — required for learning and memory — compared with non-freezers.

The team found that a history of falls was associated with cholinergic projection system changes that relay to the thalamus, while the neural signals behind freezing of gait transmit to the caudate nucleus — a brain region associated with motor processing.

They also found that Parkinson’s fallers had a lower density of thalamic cholinergic nerve terminals compared with non-fallers.

Freezing of gait was related to longer disease duration, more severe parkinsonian motor ratings, and higher levodopa levels.

These results suggest that changes in acetylcholine-mediated neuronal communication are linked to falls or freezing behavior, depending on the affected brain region.

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New Diagnostics for PD Might Allow Early Diagnosis, Prevention

Parkinson's diagnosis

A new way of diagnosing Parkinson’s disease based on manifestations that appear decades before motor symptoms — the current hallmarks for diagnosis — might allow early diagnosis and even prevention.

The study, “From Prodromal to Overt Parkinson’s Disease: Towards a New Definition in the Year 2040,” was published in the Journal of Parkinson’s Disease.

Parkinson’s disease is characterized by progressive loss of coordination and movement. Currently, a person is diagnosed when those symptoms appear. However, there are some risk factors and symptoms that precede motor manifestations and constitute the early stages of the disease (called prodromal).

“Brilliant work of many in different scientific fields has paved the way for the concept of prodromal  [Parkinson’s disease]; that is, a phase of years to decades in which non-motor and subtle motor symptoms may indicate spreading PD pathology, but do not meet the threshold for diagnosis according to the classic motor-based clinical criteria,” researchers said.

The development of new diagnostic criteria that allow the identification of prodromal Parkinson’s might help to better understand disease progression, lead to early diagnosis and treatment, and prevent classic motor symptoms.

Now, Parkinson’s experts Daniela Berg, MD, Christian-Albrechts-University of Kiel, Germany, and Ronald B. Postuma, MD, MSc, Montreal General Hospital, Canada, have developed a mathematical model that calculates a person’s risk of being in the prodromal phase of the disease. This model is based on three main premises relative to Parkinson’s prodromal phase:

  • The fact that the neurodegenerative process in Parkinson’s is slow and continuous, possibly starting in the gut or olfactory system, finally reaching the nervous system;

  •  The increased knowledge regarding risk factors and clinical symptoms that occur years or decades prior to motor manifestations. These can be correlated to imaging findings and tissue examinations;

  • Studies have found that people who manifest different combinations of risk and prodromal markers can many times progress to Parkinson’s disease.

Currently, however, the model has some limitations. For example, it does not consider age and sex factors, and cannot predict whether or when motor symptoms will appear.

“The prodromal PD criteria are meant to be research criteria and constitute a first step in what should be a continually updated process,” researchers stated.

New Parkinson’s biomarkers — substances present in the body that indicate the occurrence of a condition — are continually being discovered, providing new information that makes the model more reliable. In time, the hallmarks for diagnosis might be based on the presence of biomarkers instead of motor symptoms.

Wearable technology, such as mobile phones, also allows the continuous capture of movement in daily life, which will benefit “from new methods of data handling and analyses,” researchers said.

“With new data arising from objective movement measurements, the earlier detection of motor symptoms will become possible. Objectively measured markers … wearable-based markers of activity … indicate that we can expect to change our understanding of early motor PD,” researchers said.

The model will be available online, allowing doctors to calculate the risk for patients. Additionally, there will be a platform where experts can share information and discuss the new criteria for diagnosis.

With this collaborative model, researchers expect to incorporate the new criteria and have a functional model by 2040. This is expected to allow early diagnosis and treatment and, in time, prevention of clinical symptoms.

“Our review highlights the importance of making an earlier diagnosis of neurodegenerative diseases, and in particular PD, for now primarily to understand the disease better,” Berg and Postuma said in a press release. “However, in the future, once we have preventive therapy, it will become critical to find patients in the earliest stages of the disease so that we can prevent the disease from developing and affecting quality of life.”

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Medical Marijuana ‘Can Help Everyone,’ Says Director at Maryland Cannabis Facility

cannabis plant

Warning the reporter accompanying him not to take any pictures, veteran horticulturalist Michael Castleman punches an electronic code and unlocks the door to Room 209, nicknamed the “Mother Room.”

Photography is indeed forbidden inside this living vault, which contains 20 phenotypes of cannabis plants thriving under the glare of 25 ceramic metal halide lamps for 18 hours a day. The plants, arranged in groups of four and narrowed down from an original 1,000 seeds, bear colorful names like Oro Blanco, Bubblegum Diesel, and Sunshine Daydream.

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Marijuana plants of the Oro Blanco variety dry in Room 212 of the Kind Therapeutics cannabis cultivation facility in Hagerstown, Maryland. (Photos by Larry Luxner)

“This is the heartbeat of the whole facility,” Castleman told BioNews Services, publisher of this website. “We keep mothers 12 to 16 weeks before we replace them, and we take cuttings every day. If anything happens to these plants, we’re out of business.”

That business is Kind Therapeutics USA of Hagerstown, Maryland — which holds a license to produce cannabis products in Maryland under a management agreement with MariMed, a publicly traded company based in Massachusetts. The venture’s various offerings contain both cannabidiol(CBD) and tetrahydrocannabinol (THC), the main psychoactive compound in cannabis.

The company occupies a newly renovated 180,000-square-foot facility and a 10,000-square-foot processing lab that for 130 years housed the Statton furniture factory. Located across the street from a livestock auction house, the sophisticated operation now ranks among the East Coast’s largest suppliers of cannabis for the U.S. medical marijuana industry.

“Hagerstown is very depressed — one of the most economically depressed areas in the state — so we’re bringing life and jobs to this area,” said Abigail Diehl, Kind Therapeutics’ director of business development and sales. “We’re already Maryland’s largest indoor cannabis grower.”

Kind’s product lines include Kalm Fusion powdered tincture and chewable tablets in either mango lime coconut or green tea lemonade. There’s also Nature’s Heritage extracts, concentrates, and vape pens, as well as six types of LucidMood vape pens advertised online under the slogan “Elevate your mood without clouding your mind.”

Medical use legal in 33 states and D.C.

With other entrepreneurs, Diehl is betting that the expanding U.S. legalization of cannabis for medicinal use will boost sales of the company’s products to treat everything from skin cancer to multiple sclerosis (MS).

At the moment, 33 states and the District of Columbia have declared medical marijuana legal; in D.C. and 10 states — Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington — recreational use is also allowed, even though the federal government still considers marijuana in all its forms illegal.

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Boxes of “Healer” CBD/THC cannabis drops await distribution at the Kind Therapeutics.

Internationally, Canada is now the world’s largest legal marijuana market, having legalized its cultivation and sale in October 2018 through the Cannabis Act. Uruguay became the first country to fully legalize marijuana in 2013, with sales permitted in local pharmacies.

Last month, Israel became the third country — along with the Netherlands and Canada — to allow the export of medical cannabis. Tikun Olam, which has given MariMed exclusive rights to produce its cannabis products in Maryland, is among Israel’s top cannabis producers.

“The laws are constantly changing, so it’s difficult to get an accurate number. But this is going to be a $70 billion industry in coming years,” said Diehl, whose family has been a major Maryland fruit and vegetable distributor for nearly half a century. “When the state legalized cannabis in 2016, my friends said I needed to get into this business too, so I jumped in full throttle.”

The U.S. Food and Drug Administration (FDA) made history when, in June 2018, it approved a first marijuana-derived therapy to treat any disease. In this case, the cannabidiol was Epidiolex — developed by Britain’s GW Pharmaceuticals — to be given to patients with Dravet and Lennox-Gastaut syndromes, both severe forms of epilepsy.

“This FDA ruling speaks volumes,” Diehl said. “They’re saying, ‘guys, cannabis is not just for people who want to get high. This is a real medicine that can help everyone, including children.’”

Hype vs. data

A 2018 report, “Special Issue: Cannabis in Medicine,” found that cannabis-based productscan reduce spasticity — muscular stiffness or involuntary spasms — in MS patients.

Data from two trials, in Italy and the Czech Republic, support the idea that GW’s Sativex is effective in treating moderate to severe spasticity. The oromucosal spray is a formulated extract of the cannabis plant, and has been approved in Australia, Canada, Israel, and more than a dozen European countries.

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Michael Castleman examines baby marijuana plants.

For those with cystic fibrosis, cannabis — in its edible but not smoked form — improves appetite, a key consideration since CF patients are often undernourished. Marijuana’s anti-inflammatory properties may also help reduce inflammation in the lungs, although its overall effects on those with CF remain to be seen.

Cannabis use has also generated vast interest among people with Parkinson’s disease, prompting the Parkinson’s Foundation to plan its first conference on that subject in Denver (March 6-7).

A recent studyjointly conducted by the nonprofit group and Northwestern University found that 80 percent of Parkinson’s patients report using cannabis, and 95 percent of neurologists have been asked to prescribe medical marijuana. But only 23 percent of doctors have received formal education on the subject.

“Having worked as a clinician for the past decade in Colorado — a state at the forefront of medical marijuana use — it is clear that people with Parkinson’s and their families are intensely interested in the potential of marijuana and cannabinoids in helping manage symptoms and other aspects of the disease,” Benzi Kluger, MD, a professor at University of Colorado Hospitaland co-chair of the upcoming conference, said in a recent press release.

“To date, there is more hype than actual data to provide meaningful clinical information to patients with Parkinson’s.”

Legal and financial obstacles

This is an extremely regulated industry. In Hagerstown, the premises are under constant surveillance, all plants are accounted for, and all 61 employees had to pass a criminal background check before joining Kind Therapeutics.

Castleman, one of those employees, is happy to show off Room 205, which contains around 400 cannabis plants in living soil. Down the hall is Room 212 — the drying room — which contains upwards of 2,000 plants. Here they hang for exactly 21 days, at exactly 60 percent relative humidity.

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The entrance to the Hagerstown, Maryland, facility.

“We’re doing a slow cure on the flowers,” Castleman said. “A lot of companies do a ‘fast dry’ where they crank the temps up to 70 degrees and have everything dry in five days. But that degrades the integrity of the flower. Our system preserves the trichomes and increases the terpene profile.”

In partnership with Tikun Olam, Kind Therapeutics opened a seed-to-sale dispensary — known as First State Compassion — in Wilmington, Delaware, in 2015. MariMed also operates in Rhode Island, Massachusetts, Illinois and Nevada, and along with GenCanna produces hemp in Kentucky.

Because medical marijuana isn’t legal nationwide, Kind Therapeutics cannot do its banking with Wells Fargo, Bank of America, or any other multistate bank in the U.S. Instead, it’s turned to Severn Saving Bank, a local institution, for about 90 percent of its financial needs.

Medical regulation is another issue.

“In some states, if you have a prescription for opioids from your doctors, you can take it to any marijuana dispensary and get cannabis instead,” Diehl said. “Yet doctors are still pushing opioids, and a lot of them are scared to touch cannabis because of the federal ban.”

Looking to the future

Maryland, Diehl said, still needs to allow for cannabis in a variety of edible forms, like gummy bears or fruit chews, because many chronic disease patients don’t want to smoke. “So they’re making food on their own” like brownies and cookies, she added, and they don’t know the concentrations to do it right.

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Baby marijuana plants at the Kind Therapeutics cultivation facility.

Ryan Crandall, MariMed’s chief production officer and a veteran of the computer software industry, thinks it crucial that cannabis products be affordable as well as effective. For example, a 100 mg bottle of “Healer” tincture costs $32 and lasts one to two weeks.

“It’s a premium product at a very economical price point, because we want to get this medical product into patients’ hands economically,” he said.

Another product, known as Rick Simpson Oil (RSO), is named after the Canadian cannabis activist who developed it. RSO is notable because it’s a full-plant extract that contains higher levels of THC.

“The lion’s share of people using RSO are getting incredible medical benefits from it, and I’ve met two people in the last month alone who are on maintenance doses and have been cancer-free for years,” Crandall said. “One patient with stage 3 lung cancer was given six months or less to live. He was on chemo and his doctor recommended an RSO regime. He believes the thing that’s keeping him cancer-free is RSO.”

More than 83,000 patients are now registered with the Maryland Medical Cannabis Commission, which entitles them to buy cannabis products at an authorized dispensary. Yet Diehl said it’s been an uphill battle to persuade county authorities to approve new dispensaries around the state — though the landscape does appear to be changing as medical cannabis gains national acceptance.

“A lot of counties just treat us as a CVS now, which is how it should be,” Diehl said in a reference to the U.S. pharmacy chain store. “Some people are still completely opposed to it, and scared that it’s an illegal drug. They don’t want dispensaries in their back yard, but things change when it hits home, when someone they love gets sick and this is going to benefit them.”

Even so, she said, “I don’t want to have it come to that just to get them on board.”

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Loud, Startling Sounds Can Decrease Parkinson’s Muscle Stiffness, Study Suggests

loud sounds, muscle stiffness

Loud and alarming sounds can reduce muscle stiffness in Parkinson’s disease patients treated with subthalamic nucleus deep brain stimulation (STN-DBS), a study suggests.

The study, “Influence of alarming auditory cues on viscoelastic stiffness of skeletal muscles in patients with Parkinson’s disease,” was published in Clinical Biomechanics.

Almost 100 years ago, a French neurologist described a phenomenon called paradoxical kinesis (meaning “difficult to understand movement”) consisting of a dramatic but temporary reversal of Parkinson’s motor symptoms in the face of startling situations such as an oncoming car or loud sounds.

“The phenomenon of [paradoxical kinesis] suggests the existence of neural systems that can override parkinsonian impairment in certain conditions,” the researchers wrote in this study.

The association between paradoxical kinesis and muscular rigidity has never been described, probably due to the subjective, observer-dependent scoring methodology while performing clinical assessments of “rigidity during the transitory motor alterations” and also due to the “subjective nature of the examinations according to the Unified Parkinson’s Disease Rating Scale (UPDRS),” according to the researchers.

Increased rigidity has been linked to more viscoelastic stiffness of skeletal muscles. Muscles behave like springs, and while something that is elastic immediately returns to its original shape once a stress has been removed, a tissue that is viscous will deform permanently. Therefore, viscoelasticity refers to the muscle having properties of both, allowing it to slowly recover from being stretched or deformed.

Measurement of muscle tone using a myotonometer — a device that measures viscoelastic characteristics of soft tissues — has proved useful in quantifying the effect of therapeutic interventions on rigidity in Parkinson’s patients.

“Thus, evaluation of viscoelastic stiffness could potentially enable quick and reliable measurements of muscular rigidity during the enhancement of motor performance due to external cues in patients with [Parkinson’s disease],” the researchers wrote.

The team from the University of Tartu in Estonia assessed the effect of alarming auditory signals on viscoelastic stiffness of skeletal muscles in patients treated with STN-DBS — a surgical treatment for Parkinson’s disease that involves implanting a device to stimulate targeted regions of the brain with electrical impulses generated by a battery-operated neurostimulator. Patients can use a handheld controller to turn the DBS system on and off.

The team recruited 10 advanced stage Parkinson’s disease patients (three women and seven men) who had been treated with STN-DBS for approximately 4.5 years prior to the study.

Eight subjects had akinetic-rigid (i.e., slowness of movement accompanied by muscle stiffness), and two had the tremor-dominant subtype of Parkinson’s disease. Ten age- and gender-matched healthy individuals were also recruited to use as controls.

Using a myotonometer, the investigators measured the viscoelastic stiffness of the participants’ wrist skeletal muscles, or in other words, the muscle’s resistance to the force that changes its shape, after one night of Parkinson’s medication withdrawal.

Wrist examinations were performed by two different examiners, 10 times each. Measurements were repeated and compared during the DBS-on and DBS-off periods, with and without auditory alarming signals.

Compared with the DBS-off period, muscular stiffness was significantly reduced in the DBS-on phase, supporting the the effectiveness of the stimulation treatment in lessening one of Parkinson’s motor features.

In addition, wrist stiffness was also significantly decreased during the DBS-off period in the presence of alarming auditory signals.

“The mean values of stiffness during the DBS-on phase were lower than during the DBS-off with [alarming auditory] signals phase but the difference was not significant,” the researchers wrote.

Exposure to loud sounds did not change muscle stiffness in the control sample, suggesting that the paradoxical kinesis phenomenon is more pronounced in Parkinson’s patients.

“According to our data, the changes in muscular rigidity due to [alarming auditory] signals are an exclusive characteristic of the patients with [Parkinson’s disease],” the researchers said.

Further larger-scale research is necessary to confirm this study’s findings and assess the efficacy of auditory cueing in Parkinson’s disease.

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Treadmill Incline Training Improves Walking Speed of Parkinson’s Patients, Study Finds

treadmill incline training

Eight weeks of training on a treadmill with continuously varying surface inclines improved gait disturbances, particularly walking speed, in Parkinson’s disease patients, researchers report.

Their finding were published in the study, “Exploring gait adaptations to perturbed and conventional treadmill training in Parkinson’s disease: Time-course, sustainability, and transfer,” in the journal Human Movement Science.

As the disease progresses, Parkinson’s patients experience an increase in gait difficulties and balance problems, lowering their mobility and quality of life.

In addition, studies have shown that Parkinson’s patients take shorter and slower steps, and have high stride-to-stride variability.

Because some gait disturbances are drug-resistant, nonpharmacological treatment options are needed to improve these patients’ quality of life.

“Improved stride length and stride-to-stride variability have been demonstrated following several weeks of treadmill practice for both, overground and treadmill walking, respectively,” the authors wrote.

Researchers had recently demonstrated that eight weeks of treadmill therapy with additional postural perturbations (i.e., varying surface inclines) improved overground gait speed and dynamic balance control in Parkinson’s patients.

Now the same team at Friedrich-Alexander University Erlangen-Nürnberg has analyzed spatiotemporal gait adaptations to treadmill training — with and without an incline — both on and off the machine.

They used data from a randomized controlled Phase 1 trial (NCT01856244) aimed at investigating the effectiveness of a sensorimotor treadmill intervention to improve walking and balance abilities in people in the early stages of Parkinson’s disease.

Sensorimotor treadmill training was conducted on a special machine that challenged the participants through small oscillations, simulating walking on natural, uneven surfaces. This intervention was compared with conventional treadmill training without surface perturbations.

Thirty-eight Parkinson’s patients were randomly assigned to 40 minutes of treadmill training two times per week for eight weeks. Of these patients, 18 performed treadmill training with continuously varying surface inclines, while the other 20 walked on the treadmill without surface perturbations.

Patients were assessed every week during training protocol (prior to the training sessions), within one week after the intervention, and at a three-month follow-up.

Gait variability significantly decreased in both training groups. Nonetheless, longer stride length and time, stance time, and swing time were significantly improved only in the treadmill incline training group.

For reference, one gait cycle consists of two phases: stance, or the period of time that the foot is on the ground, and swing, meaning the period of time that the foot is off the ground moving forward.

Researchers then investigated the sustainability of gait changes over three months.

At the three-month follow-up, there were significant changes between the groups in stance and swing time, which were due to a much higher variability in the conventional treadmill training group. Statistical comparisons within the groups revealed no significant changes in the treadmill incline training group.

Additional statistical analysis also showed decreased step length asymmetry in the conventional treadmill training group.

The team then assessed the extent of transfer effects to overground gait in both training regimes.

“When considering the entire sample, significant changes in overground gait parameters at [week 8] were observed only for stance- and swing time, with a significantly decreased stance time … and a corresponding increase in swing time,” they wrote. However, these findings were statistically significant only in the treadmill incline training regime.

“[Parkinson’s disease] patients demonstrated marked gait adaptations to the eight-week treadmill intervention, which were partially retained after three months follow-up,” they noted.

Treadmill training with small oscillations seemed to reduce gait disturbances, but the transfer of such changes to overground walking was limited in most evaluated variables.

Further research is still necessary to corroborate these findings.

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Intimacy Can Be Challenging with Parkinson’s Disease

intimacy

Sherri Journeying Through

The other day, my husband told me he felt alone. Then he said he felt distanced. How could that be? We are together almost every day, 24/7. But being together and being together are very different, especially when it comes to having Parkinson’s disease.

This disease has many symptoms, of which tremor is the most prominent. Other symptoms are not often discussed, particularly depression. Another that I will discuss in this column is intimacy difficulty. 

Most people with Parkinson’s are aware that intimacy can be an issue for many reasons. One may be an unintentional lack of interest the person with PD may not even be aware of. Another may be pain or discomfort. Yet another may be the inability to “perform.” Any of these reasons can disrupt the relationship, sending messages of rejection or appearing to indicate the partner is undesirable and even unloved. 

First, let me say that, whether you’re the person with PD or the partner, you are not alone. I, too, struggle with this subject for many reasons. I can feel inadequate in many ways, but I didn’t realize I was inadvertently making my husband feel distanced and alone until the other day when we had a heart-to-heart talk.

According to the American Parkinson Disease Foundation, “From lack of sexual desire to low libido to difficulties with orgasmic functioning, this chronic, progressive, neurological disease can impair your sexuality in one way or the other.” The Michael J. Fox Foundation adds that “as many as 70 to 80 percent of those with PD experience sexual dysfunction.”

Dealing with bradykinesia, or slowness of movement, and rigidity can become an issue in a relationship. Symptoms such as tremors and dyskinesia also can contribute to dysfunction and leave one or both partners feeling inadequate.

This also plays out in everyday signs of affection such as hugging, kissing, or holding hands. The person with Parkinson’s can appear aloof to the need for affection and leave a partner feeling more distanced with each day. Before long, both are wondering why the other has stopped finding them attractive and don’t want to be with them sexually anymore. I can’t help but believe that the sad stories I have heard about spouses who have left their partners with Parkinson’s disease are more likely due to a lack of communication than just having the disease.

It’s hard to overcome feelings of inadequacy when they are kept bottled up and aren’t talked about. The first person to talk to about how you’re feeling is your partner or spouse. A frank and honest discussion about the effects of Parkinson’s on intimacy and how to overcome it in everyday life is critical. It might mean an intentional hug in the morning or time set aside only for conversation. (This does not include talking while watching the television.)

Speaking of television, the other day, I was watching a show and at the end, a man proposed to his girlfriend. Of course, she said yes — it was a Hallmark movie, after all. Then the guy said, “I hope the magic never fades.” 

None of us wants the magic to fade, especially if we have Parkinson’s. It’s taken so much already. We need to keep communicating with each other, no matter how hard it may be at times. It’s those times that bind us together more tightly, and the tighter we hold each other, the greater the magic will be. 

***

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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Monitoring with PKG System Helps Change Care in Nearly a Third of Parkinson’s Cases, Real-World Study Reports

PKG recording system

Continuous monitoring of movement symptoms using a wearable device called the Personal KinetiGraph (PKG) may help clinicians make more appropriate treatment choices for their patients with Parkinson’s disease, according to a real-world clinical study.

The study, “Qualitative Evaluation of the Personal KinetiGraphTM Movement Recording System in a Parkinson’s Clinic,” was published at the Journal of Parkinson’s Disease.

Parkinson’s is a progressive disease characterized by the degeneration of dopamine-producing neurons, causing several motor symptoms such as bradykinesia — slowness of movement — muscular rigidity, and tremor.

Although Parkinson’s can cause a range of non-motor symptoms, such as sleep problems, constipation, slurred speech, and mood disorders, management of the disease is mainly focused on reducing the burden of motor symptoms. To do so, clinicians must rely on patients’ reports and one-time clinical assessments to find the most appropriate treatment strategy as well as to make therapy adjustments.

The development of wearable sensors represents a new opportunity to help clinicians more accurately evaluate Parkinson’s patients’ movement patterns.

“New wearable sensors have the advantage of offering continuous objective measurement of patient movement during regular activities of daily living,” the researchers wrote. “[They] have the potential to provide important additional information in a more accurate way to augment day to day clinical care of Parkinson’s patients.”

The PKG system, developed by Global Kinetics Corporation, is a wristwatch-like device worn on the side of the body that is most affected by the disease and continuously collects patients’ movement data — such as tremor, slow or involuntary movements, motor-skills fluctuations, and immobility — providing information to the patient’s doctor.

The PKG system is now commercialized for clinical use in 17 countries, including the U.S. and several European countries. Global Kinetics recently announced that its PKG-Watch was recommended by two separate expert panels to improve clinical management of Parkinson’s disease.

Researchers at the Parkinson’s Institute and Clinical Center in California have now evaluated the impact of using continuous objective movement measurement with the PKG system in the routine clinical care of Parkinson’s patients. The Parkinson’s Institute began using the PKG system in December 2015 as an additional evaluation method on top of clinical visit history and examination.

“The wearable PKG technology provides objective measurements which allow us to further deliver the highly individualized care that a patient deserves,” Carrolee Barlow, MD, PhD, former CEO of the Parkinson’s Institute and Clinical Center and senior author of the study, said in a press release.

In routine care, physicians targeted PKG use to patients they believed could benefit from objective movement measurement — mainly those who were new to the clinic; were experiencing clear symptom fluctuations; were unable to clearly report their symptoms; and were considering or using deep brain stimulation or Duopa (carbidopa/levodopa, marketed by AbbVie).

Between December 2015 and July 2016, 89 patients with Parkinson’s disease were selected to use the PKG system as part of their routine clinical evaluation and follow-up, 81 of whom were included in the final analysis. Forty-five patients had one PKG, and 44 had two PKGs, 10 of whom went on to have three PKGs completed.

Physicians provided their collective views on the impact of the system on patient care in a total of 112 surveys. Of these, 41% indicated that the PKG provided additional information to the physician. However, 59% reported that the system failed to provide additional information.

Of the surveys reporting that the PKG did provide additional information, 78% indicated the data provided by the PKG system resulted in changes in patient care, while 22% revealed “the PKG provided additional information but that no alteration in patient care occurred based on this information,” according to the researchers.

The personalized monitoring system was found to provide new and precise information on daily off time — the period when medication is not working efficiently —  in 50% of the cases.

“Physicians … adjusted treatment nearly a third of the time based on the real-time clinical status captured during objective continuous monitoring outside the clinic setting,” the researchers wrote.

“These results demonstrate the real-world clinical benefits that PKG can provide to patients and clinicians in their continuing effort to optimize Parkinson’s therapy, and manage symptoms effectively,” said John Schellhorn, CEO of Global Kinetics Corporation. “The results of this study support the use of PKG as an important tool for individualizing therapy to best meet each patient’s unique needs.”

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Parkinson Voice Project to Host Lecture on Making the Most of Exercise Routines

PVP exercise lecture

The Parkinson Voice Project (PVP) is hosting a complimentary educational lecture that will focus on optimizing exercise strategies for Parkinson’s disease patients and caregivers.

The presentation “Packing Some ‘Punch’ Into Your Parkinson’s Exercise Routine” will take place at 10:30 a.m. CST Feb. 9 at PVP, in Richardson, Texas. It will be live-streamed on the PVP website and on Facebook. A video of the lecture will be posted online by Feb. 15. (Those who wish to attend in-person may register here, or call (469) 375-6500 for more information.)

The session will address the importance of exercise for those with Parkinson’s in managing symptoms and maximizing function, as well as cutting-edge concepts in exercise strategies. The hope is that participants will better understand how to apply specific training to address specific impairments. The lecture also will explore why boxing training has become a popular way for patients to fight symptom progression.

By lecture’s end, it is hoped participants will be able to describe physical motor challenges associated with Parkinson’s disease, list three physical therapy exercises specifically developed to treat Parkinson’s, and describe three benefits of non-contact boxing for those diagnosed with the disease.

The lecture will be presented by Michael Braitsch — also known as “Dr. Mike”  — a board-licensed doctor of physical therapy, a former amateur boxer, a kinesiology professor, and an internationally certified fight referee. In addition to treating individual patients, Braitsch leads group exercise programs to help people with chronic conditions move and feel better. 

A board member of the Adaptive Martial Arts Association and the University of Texas Southwestern Medical Center Adaptive Sports Expo, he’s also actively researching the effects of non-contact boxing training on Parkinson’s-associated impairments. In addition, Braitsch offers Tai chi and South Paws boxing classes for Parkinson’s patients.

According to PVP’s website, Braitsch hopes to foster community wellness by changing the way physical therapy is structured for people with chronic and progressive conditions.

Held at PVP’s Clark and Brigid Lund Parkinson’s Education Center, the presentation is part of the Parkinson’s Lecture Series featuring disease experts. On Jan. 12, PVP hosted a lecture that emphasized nutritional health and disease management. More lectures this year will include “New and Emerging Therapies in Parkinson’s,” “Dance for Parkinson’s,” and “The Power of Perseverance for Living with Parkinson’s.” Visit this site for a complete listing.

The non-profit PVP aims to preserve the voices of those with Parkinson’s and other neurological diseases through intensive speech therapy, continued support, research, education and community awareness. It hopes to team up with other speech language pathologists to reproduce its SPEAK OUT! and LOUD Crowd therapy programs globally. By marrying speech, voice and cognitive exercises, the programs seek to lessen speech problems related to Parkinson’s.

In a related Parkinson’s News Today story, experts contend that exercise that motivates Parkinson’s patients to push limits can offer a range of benefits. 

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Gene Therapy Preserves Nerve Fibers in Mouse Model of Severe Neurodegeneration

Gene therapy

An investigational gene therapy was able to preserve nerve axons — long projections that connect nerve cells and transport information — in a mouse model of severe axonal degeneration.

Because axon degeneration precedes the death of neurons in several neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the findings support this therapy’s potential as an effective treatment.

The study, “Gene therapy targeting SARM1 blocks pathological axon degeneration in mice,” was published in the Journal of Experimental Medicine.

Axons, or nerve fibers, are the long projections of a nerve cell, which conduct electrical impulses away from the cell body to other nerve cells, muscles, and glands. There is currently no treatment that effectively inhibits axon degeneration.

When an axon is injured, a protein called SARM1 becomes activated and triggers axons to self-destruct. In healthy nerve cells, this protein is switched off. Deleting the gene that codes for this protein, the SARM1 gene, has been shown to have a protective effect against axonal degeneration after injury in both a fruit fly model and a mouse model.

SARM1 acts as an enzyme that destroys metabolic factors needed for axons to work properly. It works by rapidly degrading a metabolite, called NAD+, causing a metabolic failure in neurons that trigger axonal degeneration. When this protein is mutated, it prevents rapid energy loss and subsequent destruction of axons.

SARM1’s multiple components must bind together for the protein to work properly. If one of these components is changed, the protein’s assemblage is faulty and unable to function. As such, scientists only have to alter or mutate a part of the protein to inhibit its function.

Researchers at St. Louis’ Washington University School of Medicine have developed a gene therapy to block the activity of SARM1.

The team introduced single mutations, affecting only one nucleotide — the building blocks of DNA — in the SARM1 gene, which resulted in the production of a faulty SARM1 protein. Similar to neurons without the SARM1 gene, when this gene therapy was inserted into nerve cells grown in the laboratory, no axonal degeneration was observed.

Accordingly, in injured neurons with a normal SARM1 protein, NAD+ levels were reduced. However, upon treatment with the gene therapy, they remained constant.

Researchers then treated neurons with vincristine, a chemotherapy agent, to simulate nerve cell damage. Two days later, the treatment resulted in axonal fragmentation. However, neurons that received the gene therapy remained intact and had normal metabolic activity — proof of how the therapy was able to inhibit SARM1 function.

To test the gene therapy in living organisms, the team used an inactive virus — adeno-associated virus (AAV) — as a vehicle to deliver the therapy into nerve cells of a mouse model of severe axonal degeneration. Researchers had induced a severe nerve injury in the sciatic nerve to trigger axonal degeneration.

Within five weeks, the viral vector containing the altered SARM1 gene was present in several of the affected nerves, including peripheral nerves and spinal cord nerve cells.

In animals treated with the gene therapy, their axons remained intact up to 10 days after nerve injury, and neurons preserved their normal conformation, architecture and myelin — a protective coating around nerve fibers — thickness.

In control (untreated) mice, there was almost a complete (99%) loss of axons at sites of nerve injury.

“With our viral gene therapy, we delivered a mutated form of SARM1 that is not only inactive itself but also blocks normal SARM1 proteins that have become activated in mice with nerve injuries,” senior author Jeffrey D. Milbrandt, MD, PhD, said in a university news release. “For a long time, viral gene therapy was a pipe dream, but there are now a number of ongoing clinical trials in other disorders that suggest we are on a promising track.”

“This has the potential to be transformative because it cuts across so many diseases,” said co-senior author Aaron DiAntonio, MD, PhD. “Rather than addressing a single disease, it is potentially a treatment for a disease process that is shared among many different neurodegenerative disorders.”

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FDA Declines to Approve APL-130277 for Treating ‘Off’ Periods; More Information Requested

APL-130277.

The U.S. Food and Drug Administration (FDA) has told Sunovion Pharmaceuticals that it is unable to approve APL-130277 (apomorphine sublingual film) in its present form for the treatment of Parkinson’s disease “off”  periods.

Sunovion submitted new drug application for APL-130277 in April 2018. Now the FDA has now issued a “complete response letter” in which it requests additional information, but no new clinical trials.

Off periods in Parkinson’s are characterized by the reappearance or worsening of symptoms — such as tremors and dyskinesia (involuntary movements) — due to a gradual decline in levodopa’s effectiveness as a therapy. About half of all patients on levodopa experience off episodes, which, although frequent in the morning after awakening, may occur multiple times throughout the day. These episodes become more frequent and severe as the disease progresses.

Noting the frequency and scarce treatment options for off periods, Antony Loebel, MD, Sunovion’s executive vice president and chief medical officer, said in a press release that “Sunovion remains committed to working with the FDA to address its requests so that we can bring apomorphine sublingual film (APL-130277) to patients as expeditiously as possible.”

Currently, Parkinson’s patients in the U.S. have only apomorphine — brand name Apokyn (apomorphine hydrochloride, US WorldMeds), as an approved medicine for off periods. Apomorphine is able to enter the brain quickly and, similar to levodopa, stimulate dopamine receptors to provide short-term relief. However, Apokyn’s subcutaneous (under-the-skin) delivery may cause pain and injection-site reactions.

In turn, APL-130277 is a sublingual (under the tongue) formulation of apomorphine, intended to provide on-demand and fast-acting lessening of all types of off episodes, meaning those that are unpredictable, and those that occur at the end-of-dose or after awakening in the morning. It was designed  to be taken up to five times a day, no sooner than two hours from the prior dose.

APL-130277 contains a two-layer film, one with apomorphine and the other including an acid neutralizer to improve absorption and reduce oral irritation. Compared to Apokyn, APL-130277 is less likely to induce nausea due to a more gradual absorption, said Loebel, who is also the head of global clinical development for Japan-based Sumitomo Dainippon Pharma Group (which owns Sunovion) in an October 2018 interview with Parkinson’s News Today.

The FDA new drug application for APL-130277 was supported by a 12-week, double-blind Phase 3 trial (NCT02469090). The results showed that, within 30 minutes of dosing, the treatment enabled a clinically meaningful reduction in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 3 score, a measure of Parkinson’s motor symptoms, in comparison to placebo.

The benefits were seen as early as 15 minutes post-dose and were maintained for 90 minutes, when the last analysis was conducted. Similar improvements were seen at weeks four, eight and 12. A higher percentage of patients achieving a full-on response — or control of motor symptoms — within 30 minutes with APL-130277 also was observed.

The therapy was well-tolerated, with most treatment-related side effects being mild to moderate and reversible.

Most patients took the treatment two or three times each day, though no minimum dose was required. “So that indicates they’re getting a benefit and … it’s not given on a prescribed schedule — they chose to use it two or three times a day,” David Blum MD, Sunovion’s global head of neurology clinical research, said.

The company is still recruiting for a 24-week, open-label extension study (NCT02542696) at multiple locations. A total of 226 participants are expected to use APL-130277 at 10-35 mg. Outcomes focus on the safety and tolerability of longer-term use, including patient response without Tigan (trimethobenzamide), an antiemetic (a medicine against vomiting and nausea) required as pretreatment to Apokyn.

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