Welcome to Dr. C’s Journey with Rigid Parkinson’s Disease

Journey, Different approach to Parkinson's

Before I delve into the diverse range of topics I plan to write about, let me introduce myself.

I was diagnosed with a type of rigid Parkinson’s disease (PD) in my early 60s. It is an idiopathic form, and hard for others to see. I experience the symptoms of rigidity, inaccurate muscle aiming, and slowing of movement, along with some non-motor symptoms and quite a bit of pain.

I have a good response to Sinemet (carbidopa-levodopa), but still see a slow progression in my symptoms. I see the effects every day of my life. I have been on a journey to make sense of what is happening and to attain a high quality of life in the face of PD symptoms. This column will share my journey and the insights I’ve gained along the way.

I am also a researcher and writer (see: www.DrC.life).

After years of hearing, “You look fine, I don’t see the PD in you,” while having the worst of the symptoms under medication control, I thought it was time to put pen to paper. I have a unique background that combines clinical experience helping people with the ability to reframe things so that they may be viewed in a new light.

In this column, I will discuss new ideas and things you haven’t heard before. But mostly they will be ideas that are reframed. This is the result of my struggle to make meaning out of rigid Parkinson’s disease and what it is doing to my life. Hopefully, the information will help you to make sense of some experiences you might have in connection with PD.

The unique perspective that this column will bring to the topic of attaining quality of life with rigid Parkinson’s disease is one I believe will be of interest to the reader. I have a Ph.D. in rehabilitation counseling and I specialized in the treatment of cerebral-neurological disorders. I have helped people attain a higher quality of life after terrible things happened to their brains.

I am also a scientist, and during the past five years, I have conducted extensive research on the ideal rehabilitation plan for a person like me, with early signs of PD. I have put such a plan in place for my own life, although it’s not as perfect as I would like, and I am struggling with things like cutting back on ice cream.

I think that tackling the disease head-on with a vigorous rehabilitation plan makes as much of a difference in the quality of my life as medication does. (I’m not saying to replace the medication, but rather to enhance it.) My plan includes the following:

  • Five to 10 hours of light and hard exercise per week.
  • Fifteen to 20 hours of mental-stimulation activities per week.
  • An ADA house (one that meets standards set by the Americans with Disabilities Act) close enough to receive support from family.
  • Decreased stress, a healthy diet, and doing fun things.

Those are the basics of the plan, which is quite flexible. A lot of fine-tuning happens when the basic plan is applied specifically to the needs of a person, like you, the reader.

Any rehabilitation plan needs to consider where a person falls within the spectrum of Parkinson’s symptoms. In a treatise on PD by Stewart Factor and William Weiner, the authors speak to the importance of understanding the non-motor symptoms associated with PD and the necessity of early intervention.

“Dr. C’s Journey with PD” is personal, but it also will address these two points and various aspects of the PD spectrum. In each column, I will try to leave readers with something that might improve their quality of life with Parkinson’s.

Next week: Parkinson’s disease as a spectrum.

***

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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Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggests

pain management

Treatment with Xadago (safinamide) or cannabinoids and opioids may the best therapeutic options to effectively manage pain in patients with Parkinson’s disease, researchers suggest.

The study, “Comprehensive Examination of Therapies for Pain in Parkinson’s Disease: A Systematic Review and Meta-Analysis,” was published in the journal Neuroepidemiology.

Parkinson’s disease is known mostly for its motor symptoms such as muscle rigidity and tremors, but other non-motor symptoms are very common. About 68-95% of Parkinson’s patients suffer with pain, which can significantly affect their quality of life and promote both depression and anxiety.

There are several therapeutic strategies available for Parkinson’s disease, however their potential to manage disease-associated pain is not established.

Parkinson’s Clinic of Eastern Toronto researchers reviewed available data from 24 published reports to explore current treatments’ capacities for pain relief. The reports covered the results of 25 randomized clinical trials and a total of 1,744 patients undergoing therapeutic interventions and 1,610 patients undergoing a control intervention.

The mean age of study participants was 66 years and most were male (61% and 60% in treatment or control groups, respectively). Mean disease duration was of 7.9 in the treatment group, and 7.2 years in the control group.

The treatment with the biggest capacity to reduce pain severity was Xadago, followed by cannabinoids and opioids, multidisciplinary team care and COMT inhibitors, such as Comtan (entacapone) and Tasmar (tolcapone).

Electrical and Chinese therapies also had some capacity to reduce pain, although results between studies were very heterogeneous.

Treatment with the investigative pardoprunox (SLV-308) and surgery had only moderate effect on reducing pain severity, while the weakest effects were in dopaminergic agonists and miscellaneous therapies.

Collectively these findings revealed that Xadago “is an important adjunct to the standard parkinsonian medications for alleviating pain” in Parkinson’s, while analgesics in the form of opioids and cannabinoids can “be effective but not nearly to the same extent,” researchers wrote.

In addition, the team believes this study shows that adjusting levodopa levels with Comtan rather than with dopaminergic therapies may provide greater pain relief.

Still, additional trials focusing on pain management, as well as in its underlying mechanisms in Parkinson’s patients, are warranted to “form a consensus on the effectiveness of these therapies.”

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Study Reveals Mechanisms Underlying Pain Processing in Parkinson’s Disease

pain, subthalamic nucleus

A novel pain-sensing brain network links pain in Parkinson’s disease to a specific region of the brain, called the subthalamic nucleus, an animal study has found.

The findings illustrate why this specific brain region is a potential target for pain relief in Parkinson’s, as well as in Huntington’s disease, and other neurodegenerative disorders.

The study, “Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing,” was published in the journal eLIFE.

Pain is one of Parkinson’s non-motor symptoms and may manifest as burning, stabbing, aching, itching or tingling sensations. Scientists believe that these symptoms, which are not directly related to the pain caused by the disorder’s motor symptoms, result from dysfunction of the central nervous system.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), a brain area involved in motor function that is hyperactive in Parkinson’s patients, is an effective technique to ease motor dysfunction. This surgical treatment also has been shown to weaken pain intensity, but the mechanism underlying this benefit remains unclear.

Early studies have indicated that the STN could be part of a network involved in pain perception, but little is known about the type of sensory stimulus activating this brain area.

“We set out to determine whether the [STN] is involved in translating a harmful stimulus such as injury into pain, and whether this information transmission is altered in [Parkinson’s],” Arnaud Pautrat, the study’s lead author, said in a press release.

The research team from France and the U.K. conducted electrophysiology (electrical activity) experiments in rats subjected to a shock to the hind paw. This showed that neurons in the STN could be separated into three groups, depending on whether their electrical activity increased, decreased or was unchanged upon being shocked. Most of the responsive cells changed their activity specifically after pain stimulation and not other types of stimuli.

Then, the team explored if damage to the STN changed these responses. Results showed that rats with lesions in this brain area took much longer to manifest discomfort in comparison to controls.

Subsequent experiments in a rat model of Parkinson’s revealed that neurons in the STN had higher firing rate (greater activity) and exhibited bigger and longer responses to pain than healthy animals. According to researchers, these findings suggest that Parkinson’s-associated pain is caused by impaired pain processing in this brain area.

To understand where pain signals in the STN could come from, the team focused on the superior colliculus and the parabrachial nucleus, two brain areas that relay damage signal originating from the spinal cord.

Blocking the activity or damaging these regions changed the number of STN cells responding to pain, revealing the key role of both regions. Also, researchers found that the parabrachial nucleus and the STN are directly connected.

“We have found evidence that the [STN] is functionally linked to a pain-processing network and that these responses are affected in Parkinsonism,” said Veronique Coizet, PhD, the study’s senior author. Of note, Parkinsonism is a general term for neurological disorders that cause movement problems similar to those of Parkinson’s patients.

Overall, the team believes this network is possibly implicated in the pain relief achieved with DBS in Parkinson’s patients. Coizet noted that more work is necessary to fully characterize the effects of DBS on the STN in animal models.

“The STN-DBS technique can thus be considered in the future as a new target for the treatment of pain in pharmaco-resistant patients suffering from previously described neurodegenerative disease, but also, for example, in chronic pain disease or pharmaco-resistant patients with certain form of migraine,” researchers wrote.

“Further experiments are now needed to fully characterize the effects deep brain stimulation on this brain region in our experimental models, with a view to finding ways to optimize it as a treatment for pain caused by Parkinson’s and other neurological diseases,” Coizet added.

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DBS Effectively Reduces Tremor in Parkinson’s Patients, Regardless of Stimulated Brain Area, Study Shows

Parkinson's tremor

Deep brain stimulation (DBS) can effectively reduce tremor in people with Parkinson’s disease, regardless of the brain region stimulated, according to a recent review study.

The review, “STN vs. GPi deep brain stimulation for tremor suppression in Parkinson disease: A systematic review and meta-analysis,” was published in the journal Parkinsonism & Related Disorders.

Tremor is a main symptom of Parkinson’s disease, strongly affecting patients’ quality of life. It is estimated that 47-90% of Parkinson’s patients have an action tremor and 76-100% have a resting tremor.

Reduction of tremors is an important goal in Parkinson’s treatment, and could have a significant impact in patients’ well-being and everyday life. However, tremor is difficult to treat and often does not respond to anti-tremor medications.

Deep brain stimulation — electric stimulation in strategic brain areas through surgically implanted thin wires in the brain — is used to treat people with advanced Parkinson’s disease whose motor symptoms, such as tremors, are not reduced with medication.

Several studies have shown that DBS eases motor symptoms, reduces the necessary daily dose of medication, and improves patients’ quality of life.

Currently, the main approved targets for DBS in Parkinson disease are the subthalamic nucleus (STN) and the globus pallidus interna (GPi), areas of the brain involved in motor function.

While recent studies have found no significant differences between the therapeutic effects of the stimulation of both targets, many clinicians maintain an older preference for STN over GPi, due to a supposedly greater reduction in tremors and in medication.

However, evidence supporting STN-DBS superiority in tremor suppression is limited.

Researchers have conducted a systematic review of all randomized clinical studies comparing the therapeutic effects of STN-DBS and GPi-DBS on tremors in Parkinson’s patients, published before March 2017.

Their search identified five suitable longitudinal randomized control trials with five years follow-up data. The data included the two DBS targets, STN and GPi, and tremor sub-scores of the Unified Parkinson’s Disease Rating Scale (UPDRS) before and after DBS, and with or without dopaminergic medication.

Their analysis showed that deep brain stimulation significantly reduced tremor symptoms in Parkinson’s patients, and that these effects were observed regardless of medication status.

When looking at the two targets of deep brain stimulation, researchers found that both methods reduced tremor severity in Parkinson’s patients, with no significant differences between them. These results support that DBS of each target promotes similar long-term benefits on tremor.

However, analysis of therapeutic effects on tremor over the course of five years showed that STN-DBS was more effective to reduce tremors after two and five years than at the first six months. In turn, GPi-DBS showed a more stable degree of effectiveness on tremors over time.

“Although both targets were effective, practitioners should be aware that it is possible one target could appear superior in studies depending on the duration of follow-up,” researchers wrote.

They also noted that when Parkinson’s patients present with tremor as the primary complaint, or as an issue adversely affecting quality of life, selection of deep brain stimulation target should focus on the presence of other problems “such as cognitive impairment, speech difficulties, presence of mood disorders, and presence of impulse control disorders.”

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DBS Linked to Distinct Motor and Cognitive Pathways in Brain, Finding That May Improve Its Use

deep brain stimulation

The benefits of deep brain stimulation (DBS) on motor function in Parkinson’s patients are mediated by a different brain pathway than the one involved in the procedure’s unwanted cognitive effects, according to a new study.

This finding may help improve the effectiveness and safety of DBS use in patients with Parkinson’s disease.

The research, “Functional segregation of basal ganglia pathways in Parkinson’s disease,” was published in the journal Brain.

DBS is an efficient alternative surgical procedure to treat Parkinson’s motor symptoms, such as tremor, rigidity, stiffness and slowed movement, in patients with an inadequate response to medications.

The treatment targets the subthalamic nucleus (STN), a brain region that is hyperactive in Parkinson’s patients. Besides its role in motor control, the STN is also involved in cognitive processes such as decision-making.

Prior research has shown that the STN is part of a brain pathway linking the striatum — a key region in movement and cognition — to the thalamus, which relays motor and sensory signals. This pathway is affected by loss of the neurotransmitter dopamine in the striatum due to Parkinson’s.

The STN is also involved in a brain pathway connecting motor-related areas in the cerebral cortex with the globus pallidus, a major component of the basal ganglia, which is mainly implicated in the control of movement and posture. The STN has been proposed to act through this pathway to delay, and thereby optimize, behavioral responses.

Although researchers suggest that DBS may alter the activity of both these brain pathways, no study had assessed the treatment’s effects on cognition and movement control in an integrated perspective.

A research team from Charité – Universitätsmedizin Berlin, in Germany, combined behavioral experiments with clinical observations, brain mapping and computer-based modeling. The study involved 20 Parkinson’s patients (18 men, mean age 63) undergoing STN-DBS, and 20 controls given a tracking task that required normal (automatic) and controlled reach movements.

Improvements in motor function — such as in movement velocity — were independent from unwanted cognitive effects, such as premature actions taken in situations requiring deliberation and decision-making. These motor and cognitive effects were independently mediated by the striatum-thalamus and the cortex-globus pallidus pathways, respectively.

“Our findings integrate with previous reports regarding cognitive and clinical implications of distinct pathway effects in Parkinson’s,” the researchers wrote.

Besides a better understanding of the neuronal networks affected by Parkinson’s, the findings also shed light on the workings of DBS.

“Only an improved understanding of the treatment’s mechanism of action will allow us to make [DBS] more effective,” Wolf-Julian Neumann, MD, the study’s first author, said in a press release.

As such, the results “may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson’s,” the researchers wrote.

The team is now planning to use measurements of neural activity to differentiate patients and healthy individuals.

“This will allow us to adapt brain stimulation treatments according to the needs of the individual patient and in real time,” said Andrea A. Kühn, MD, the study’s senior author. “It is an important step on the way to developing an intelligent, personalized and demand-adapted treatment.”

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Accepting the Invitations You’re Afraid to Accept Can Be Worth It

Sherri Journeying Through

Several years ago, my youngest son discovered the camera, and through its lens, he discovered a whole new world.

On one particular day, I was feeling down and he asked why.

“I don’t know,” I replied. There was no real reason. Some days are just like that when you have Parkinson’s disease. It comes for free with the experience of having the disease.

“You wanna come with me to take pictures?” he asked. That was unusual, as he usually went alone to do his assignments for his photography class.

“No, I’ll stay here.” No one else was home and I wasn’t going to go with him and make him miserable.

“Are you sure?” Rarely did he ask someone to go. Even rarer was the second invitation. I was tempted but replied with the same answer.

“Come on. You’ll feel better,” he said with a slight grin and cocked his head in an attempt to cheer me up.

I smiled inside, my outside smile refusing to work. Thanks, Parkinson’s (sarcasm intended). “You go ahead. I’ll be fine,” I answered.

And so he went off to get a few things from his room and as he went out the front door, I went downstairs.

As I got to the bottom stair, I turned around and went back up as fast as I could. Yes, I did want to go. I did want to feel better. But most of all, I never wanted to regret turning down that rare invitation of spending time with my youngest son. I opened the door, hoping against hope that he was still there. The car was gone, but he was running up the driveway!

“Can I still come?” I asked.

“Yeah, I just forgot something.” I thanked God, put on my shoes, grabbed my camera and my coat, and got into the car.

That day, we took pictures of moss and birds, pictures in blues and greens, squawking geese and floating ducks. We saw thunderclouds, rusted cars, and nests hidden in the limbs of trees. We climbed over barbed wire fences and stepped in mud holes. We heard blaring guitars in the middle of nowhere and froze in the icy cold air of an Idaho winter. We chased a hawk as it teased us while soaring above in serpentine circles with the air currents over a meadow of frozen wheat stubble. And then, like the moss and the squawking geese and the iced stream, he spotted it.

With blues and grays, pinks and yellows dabbed with gold, there it was, the picture of the day. The sunset sang out to both of us at the same time. And as we both grabbed our cameras to capture the moment, we noticed the tree, framed before the sunset. It was a magnificent picture and moment. A glorious moment.

And I thanked God. I thanked Him for all things good and not so good. For moss on trees and squawking geese. For barbed wire fences and mud holes. For floating ducks and iced-over streams running through snow-covered meadows. For bird nests hidden in limbs of trees and little birds on bare treetops huddled together to keep warm. For the freezing cold and that silly, playful hawk. But most of all, I thanked God for my son and that he forgot something and ran back up the driveway.

“Come on,” he said, “You’ll feel better.” And he was right.

An invitation that wouldn’t quit. A glorious afternoon. Time spent with my son. Parkinson’s? Worth it.

***

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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High Cholesterol Levels May Protect Against Parkinson’s Disease, Study Suggests

cholesterol, Parkinson's risk

High levels of blood cholesterol may decrease the risk of men developing Parkinson’s disease, according to a large-scale clinical study.

The study, “Higher serum cholesterol and decreased Parkinson’s disease risk: A statin‐free cohort study,” was published in the journal Movement Disorders.

High blood cholesterol, in particular, low-density lipoprotein cholesterol (LDL-C), is a well-established risk factor for coronary disease and stroke. Human and animal studies suggest it may also play a role in the risk of Parkinson’s, although, so far, the data remains controversial.

To explore the association between high cholesterol levels over time and Parkinson’s risk, researchers reviewed the clinical records of 261,638 individuals collected from the medical databases of Maccabi Health Services, the second largest health maintenance organization in Israel.

The study covered all patients, ages 40 to 79, who had undergone at least two cholesterol evaluations between 1999 and 2012 (the study period) and who did not receive statins, which are cholesterol-lowering agents.

During the study period, 746 patients were diagnosed with Parkinson’s disease, 70% of which were definite cases. Disease incidence rates increased with age for both men and women, ranging from 0.06% in men and 0.04% in women at ages 40-44 to 4.8% in men and 3% in women at ages 75-79.

At the beginning of the study, total cholesterol and LDL-C levels were similar among men and women and were slightly higher than optimal standard values. In fact, one-third of the participants had LDL-C levels above 140 mg/dL, the level at which statin therapy is usually recommended, according to clinical guidelines.

Analysis of one-year lagged clinical data revealed that total cholesterol levels greater than 180 mg/dL and LDL-C higher than 110 mg/dL were associated with a reduced risk of Parkinson’s disease in statin-free middle-age men and elderly women.

In men ages 50 to 69, higher total cholesterol levels were associated with an 18-29% reduced risk of Parkinson’s, whereas high LDL-C levels were linked to a 20-28% reduced risk.

In women ages 70 to 74, a similar protective association was reported, but with lower impact. Higher total cholesterol levels were linked to a reduced risk of up to 7%, and high LDL-C levels correlated with a 2-12% reduced risk of Parkinson’s.

“Although our findings could not determine whether decreased cholesterol alone causes PD or whether cholesterol and Parkinson’s disease share a common cause, they strongly imply relevance for clinical practices and health policies,” the researchers wrote.

Additional long-term studies are necessary to “further elucidate the favorable range of cholesterol levels and its changes throughout life that could affect Parkinson’s disease,” they concluded.

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Parkinson’s Patients Show Elevated Levels of Specific Protein in Key Brain Area, Study Reports

GPNMB protein in Parkinson's

Alterations in certain types of fat in a brain area called the substantia nigra may result in elevated levels of the GPNMB protein and drive neurodegeneration in Parkinson’s disease patients, according to Harvard researchers.

The study, titled “The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson’s disease patients and increases after lysosomal stress,” appeared in the journal Neurobiology of Disease.

The GPNMB protein has a well-known role in driving tumor progression by suppressing immune responses. The protein is also thought to regulate inflammatory responses associated with neurodegenerative disorders, possibly exerting neuroprotective effects.

Variations in the GPNMB gene have been associated with Parkinson’s disease. Altered levels of GPNMB messenger RNA — which contains the information to generate proteins — have been described in Parkinson’s patients, specifically in the substantia nigra, a brain area which controls movement and typically shows progressive loss of dopamine-producing neurons in Parkinson’s disease.

Patients with lysosomal storage disorders (LSDs), characterized by an abnormal accumulation of toxic materials in cells — have higher than normal GPNMB protein levels, which correlates with disease severity and progression.

The link between LSDs and Parkinson’s disease has been increasingly evident, as shown by dysfunctional lysosomes during the development of the disease.

Lysosomes are cellular structures that act as the waste disposal system of the cell by digesting unwanted materials. Many genetic factors underlying familial Parkinson’s play a role in the autophagy-lysosomal cell pathway, responsible for degrading misfolded, or structurally altered, proteins within cells.

Lower activity of the lysosomal enzyme glucocerebrosidase (GCase) — implicated in Gaucher disease and responsible for breaking down a type of fat called glycosphingolipid — has been reported in the substantia nigra of patients with sporadic Parkinson’s and has been suggested to drive accumulation of the protein alpha-synuclein.

Alpha-synuclein is the main component of Lewy bodies that accumulate inside nerve cells and contribute to disease. Lysosomal dysfunction is also important in aging, which is the major risk factor for Parkinson’s disease.

To further explore the correlation between GPNMB and Parkinson’s, researchers focused on potential changes in GPNMB protein levels in the substantia nigra of post-mortem Parkinson’s patients’ brains that also exhibited age-dependent reduction in GCase activity and a corresponding elevation in glycosphingolipids.

Brains from 30 sporadic Parkinson’s patients and 25 unaffected patients were used. GPNMB protein levels were markedly higher in the substantia nigra of Parkinson’s patients, but not in other brain areas. These patients had lower GCase activity and an associated elevation of glycosphingolipids in this brain region.

Both Parkinson’s patients and healthy individuals showed a trend toward increased GPNMB levels with age. However, protein levels were not associated with age of onset, duration of disease, neuronal loss, disease severity, or extent of neurofibrillary tangles inside cells, which are all characteristic of Parkinson’s disease.

In mice that displayed alpha-synuclein buildup, no GPNMB elevations or altered GCase activity were observed. But inducing lysosomal dysfunction and the accumulation of glycosphingolipids using a GCase blocker in healthy mice led to similar changes in GPNMB brain levels as that seen in Parkinson’s patients.

These mice also showed increased protein levels in brain regions displaying activation of glia (non-neuronal cells of the nervous system) consistent with neuroinflammation.

The findings indicate that GPNMB levels do not depend on changes in alpha-synuclein, but instead relate to altered lysosomal function.

“It is plausible that changes in lipids is one driver of the pathophysiological elevations of GPNMB observed in the [substantia nigra] of [Parkinson’s] patient brains,” the scientists wrote. “This is the first demonstration of region-specific elevations of GPNMB protein in Parkinson’s.”

The investigators also said the findings indicate that GPNMB as a biomarker, in concert with genetic and other risk factors, may reveal “early and late pathology relevant to Parkinson’s disease prevention and treatment.”

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New Purification Method May Improve Stem Cell Replacement Therapy for Parkinson’s

Stem Cell Purification Method

A new process to select and purify stem cells that hold therapeutic potential to replace dopamine-producing neurons may hasten clinical development of this promising avenue to treat Parkinson’s disease.

Upon being transplanted, these cells promoted dopamine production and reduced the severity of disease-related motor symptoms in an animal model of Parkinson’s disease.

The pre-clinical study with that finding, “Discovery of Novel Cell Surface Markers for Purification of Embryonic Dopamine progenitors for Transplantation in Parkinson’s Disease Animal Models,” was published in Molecular & Cellular Proteomics.

Current standard therapies for Parkinson’s disease focus mainly on restoring dopamine signaling in the brain to reduce the severity of symptoms and improve patients’ quality of life. However, this strategy does not resolve the main mechanism that leads to dopamine reduction — the loss of a specific population of brain cells called dopaminergic neurons.

In recent years the transplant of stem cells (a type of cell that can give rise to almost any cell type in the body) that can replace dopamine-producing neurons has become an attractive therapeutic pathway. But its translation into the clinics has been delayed, in part, due to the difficulty to select and purify stem cells that hold therapeutic potential without contamination of unwanted progenitor cells that could lead to tumors  and other complications.

“Although robust methods have been introduced that produce enough modified cells, uncertainty remains for selecting the right cell types from human pluripotent cells for transplantation,” researchers wrote.

Researchers now have developed a new standardized method that can ease the selection and purification of stem cells that specifically differentiate into dopamine-producing nerve cells, which are those affected in Parkinson’s disease.

The team engineered human stem cells to produce a green florescent protein that could be detected easily, as well as the LMX1A protein, which is an important marker of dopaminergic progenitors during brain cell differentiation.

These stem cells were cultured for 12 days in the laboratory and transformed into the desired mature dopamine-producing neurons. In undifferentiated cells, the fluorescent reporter was not produced.

The team further isolated their cells of interest based on the presence of a surface protein, called contactin 2 (CNTN2), which also is a characteristic marker of dopaminergic brain cell progenitors.

To test their activity, researchers transplanted these purified cells into the brains of rats with Parkinson’s disease, and compared the animals’ outcomes with those transplanted with unpurified stem cell-derived cells, or those left untreated.

Both groups of treated rats showed significant symptom improvement after 10 weeks of receiving the cells. Still, the rats that received CNTN2-enriched cells — produced and isolated using the new method — had a faster motor recovery and better dopamine production.

Researchers believe these results demonstrate that “purity of transplanted cells might be a more critical parameter to achieve recovery of motor abilities compared to the number of transplanted cells.”

Given that, the newly established purification method can be an efficient approach to produce large numbers of human stem cell-derived “dopaminergic progenitors for therapeutic applications,” they added.

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Xeomin Eases Tremor Severity, Improves Hand Function in People with Essential Tremor, Phase 2 Trial Shows

essential tremor, Xeomin

Intramuscular treatment with Xeomin (incobotulinumtoxinA) decreases tremor severity and improves hand function in patients with essential tremor of the upper limbs, according to Phase 2 trial results.

Results of the trial, titled “Efficacy and safety of incobotulinumtoxinA for upper-limb essential tremor in a randomised, double-blind, placebo-controlled trial using kinematics-guided clinical decision support,” was presented at the recent 2018 World Congress on Parkinson’s Disease and Related Disorders in Lyon, France.

Essential tremor — often misdiagnosed as Parkinson’s disease — is a progressive movement disorder, found in more people ages 40 and older. It mainly affects the hands and arms, but head, voice, and leg tremors may also occur.

Unlike Parkinson’s, which is associated with motor symptoms such as slow movement and muscle stiffness, essential tremor does not cause other health problems, although unsteady gait may be observed. Also, while patients with Parkinson’s typically experience tremors when their hands are at rest, those with essential tremor have them when using their hands.

Researchers conducted a randomized, double-blind Phase 2 clinical trial (NCT02207946) — sponsored by Merz Pharma, Xeomin’s developer — to evaluate the effectiveness and safety of a single, kinematics (motion)-guided intramuscular injection of Xeomin in adults with moderate to marked essential tremor in their upper limbs. The trial was conducted in the U.S. and Canada.

A total of 30 patients were included — 19 of whom were randomized to receive Xeomin, at a total dose of up to 195 Units, and 11 received a placebo. The participants all got an injection in the wrist, with optional injections into the shoulder and/or elbow. Muscle selection was based on each patient’s patterns of tremor, while doses per muscle were based on a kinematics-guided TremorTek analysis, which uses a combination of wearable movement sensors and computer software.

Differences between Xeomin and placebo were assessed at weeks four and eight for maximum wrist-tremor amplitude and motor performance, measured by the Fahn-Tolosa-Marin (FTM) Part B score. Analyses of tremor severity, with the FTM tremor scale, and grip strength were conducted over 24 weeks.

Treatment with Xeomin induced a trend toward decreased wrist-tremor amplitude, compared with placebo, at week four, and showed a significant improvement at week eight. Persistent anti-tremor effects were seen by motion measurements up to 24 weeks after a single injection of Xeomin.

The data further demonstrated that Xeomin significantly improved motor performance at both the fourth and eighth weeks. Maximum grip strength in the treated arm decreased by 20%, with no notable change in those on placebo. Although two patients receiving Xeomin reported localized finger-muscle weakness, none of the participants discontinued treatment due to muscle weakness.

“Kinematics-guided incobotulinumtoxinA (Xeomin) administration significantly decreased tremor severity and improved hand motor function versus placebo in patients with ET of the upper limb,” the researchers wrote.

Xeomin was recently approved by the U.S. Food and Drug Administration to treat adults with chronic sialorrhea, or excessive drooling, a common condition in Parkinson’s patients. It has also been approved for the treatment of adults with abnormal head position and neck pain due to involuntary contraction of neck muscles, abnormal spasm of the eyelids (blepharospasm) in patients previously treated with Botox (onabotulinumtoxinA), and to reduce muscle stiffness of the upper limbs.

The post Xeomin Eases Tremor Severity, Improves Hand Function in People with Essential Tremor, Phase 2 Trial Shows appeared first on Parkinson’s News Today.

Source: Parkinson's News Today