Specific Dopamine-producing Neurons Crucial to Adaptive Movement, Early Study Finds

motor skills and Parkinson's

Dopaminergic neurons — nerve cells gradually lost to Parkinson’s progression — that contain an enzyme called aldehyde dehydrogenase 1A1 are essential for acquiring the motor skills needed for proper movement in given situations, a mouse study reports.

The research, “Distinct connectivity and functionality of aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons in motor learning,” was published in Cell Reports. The work was developed by the Intramural Research Program of the National Institute on Aging (IRP-NIA).

Parkinson’s disease severely affects dopaminergic neurons, those that produce dopamine, a neurotransmitter (cell-signaling molecule) that relays information between nerve cells and between the brain and the rest of the body.  These neurons are found in two specific brain regions involved in motor control: the striatum and the substantia nigra.

Nerve cells may or not contain aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that is involved in cellular detoxification. Parkinson’s seems to mostly damage ALDH1A1-positive dopaminergic neurons, suggesting the enzyme may be a key player in this neurodegenerative disorder.

Both ALDH1A1-positive and ALDH1A1-negative dopaminergic nerve cells contribute to voluntary motor behavior. But the degree to which ALDH1A1-positive neurons are crucial to acquiring motor skills remains to be understood.

Using a mouse model of Parkinson’s, scientists targeted  dopaminergic neurons positive for ALDH1A1, and produced a detailed connectivity map of these specific neuronal networks in the mouse brain.

ALDH1A1-positive neurons were found to be in constant communication with other brain structures there. Importantly, researchers found that those dopamine-producing neurons of the striatum and substantia nigra that received the greatest percentage of molecular information (input) were located in the caudate-putamen nuclei, a brain region involved in movement control.

Researchers then selectively removed ALDH1A1-positive neurons to mimic the degeneration pattern observed in late-stage Parkinson’s disease. The animals’ ability to show new motor skills — new ways of voluntary movement, like foot position for maintaining balance while walking on a moving surface — was assessed using the rotarod test. In this test, mice must learn to balance while walking on a constantly rotating rod much like a treadmill.

Mice without ALDH1A1-positive neurons displayed a distinctly poorer ability to learn new motor skills, and slower walking speeds compared to control animals.

“Compared with a modest reduction in high-speed walking, the ALDH1A1+ nDAN-ablated mice showed a more severe impairment in rotarod motor skill leaning,” the researchers wrote. “Unlike control animals … [these] mice essentially failed to improve their performance during the course of rotarod tests.” (nDANs are nigrostriatal dopaminergic neurons.)

These animals were then treated with dopamine replacement therapy, either levodopa or a dopamine receptor agonist, one hour before a new motor skills assessment. Dopamine replacement therapy is standard treatment for the motor symptoms associated with Parkinson’s.

Levodopa (L-DOPA) treatment allowed the animals without ALDH1A1-positive neurons to travel longer distances, and to walk more frequently at higher speeds during a session. But it failed to improve their ability to acquire new motor skills during repeated tests. Treatment with a dopamine receptor agonist was also ineffective.

“When the ALDH1A1+ nDANs were ablated after the mice had reached maximal performance, the ablation no longer affected the test results, supporting an essential function of ALDH1A1+ nDANs in the acquisition of skilled movements. These findings are in line with the theory that nigrostriatal dopamine serves as the key feedback cue for reinforcement learning,” the researchers wrote.

These results provide “a comprehensive whole-brain connectivity map,” they concluded, and reveal a key role of ALDH1A1-positive neurons in newly learned motor skills, suggesting that motor learning processes require these neurons to receive a multitude of information from other nerve cells and to supply dopamine with “dynamic precision.”

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Bacteria in Gut Can Promote Parkinson’s by Altering Brain’s Immune Reactions, Study Says

'gut-brain axis' in disease

Bacterial infections in the intestines may trigger Parkinson’s progression by altering the immune system and damaging dopaminergic neurons, according to an early study supporting a “gut-brain” connection in this disease.

The findings, “Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice,” were published as a letter in Nature. A letter is a short report of original research that is of interest to investigators in other fields.

Strong evidence suggests mutations in the PINK1 gene, which codes for an enzyme that protects mitochondria — the cell’s energy-producing powerhouse — during periods of cellular stress are linked to early onset hereditary Parkinson’s. When mutated, tangles of the PINK1 protein build inside mitochondria in brain cells and damage them.

“Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles,” the researchers noted.

PINK1 is thought to participate in the clearance of damaged mitochondria, but studies do not consistently support the protein’s exact role in the cellular cleaning process.

Although mutations in PINK1 in Parkinson’s patients are known to promote disease progression, mice without the PINK1 gene are generally healthy. In fact, the animals display little, if any, Parkinson’s-related motor symptoms, suggesting the neurodegenerative disorder may be triggered by factors other than the loss of this protein’s function.

Based on their previous work, scientists at the Université de Montréal hypothesized that infection with a specific type of bacteria — called Gram-negative bacteria — could activate the immune system and “order it” to produce mitochondria-specific autoreactive CD8+ T-cells. Often called cytotoxic T-lymphocytes, CD8+ T-cells are very important for immune defense against intracellular pathogens (infectious agents).

Scientists first tested their theory in a lab dish. They infected mouse cells with several bacteria, including Gram-positive and Gram-negative ones, and observed that only the Gram-negative bacteria induced the activation of an immune response, with the highest levels obtained when the intestinal bacteria Escherichia coli (EPEC) and Novosphingobium aromaticivorans were used.

To determine whether Citrobacter — a Gram-negative mouse intestinal pathogen that is used as a model of human EPEC infection — triggered an immune activation, researchers then infected wild-type (normal) mice and animals engineered to lack the PINK1 protein. The bacteria were administered directly into the animals’ stomach by a tube (oral gavage).

In mice lacking the PINK1 protein, intestinal infection with this Gram-negative bacteria was found to activate immune mechanisms necessary for CD8+ T-cells to travel to peripheral tissues and the brain, compromising cell function.

Neurons within the animals’ striatum — a brain center crucial for motor control that’s severely damaged in Parkinson’s — were significantly degenerated, and as such, these mice exhibited Parkinson’s-like symptoms, the research team reported. The animals’ motor difficulties, which included limited back leg activity and slower movement four months post-infection,  were treated with  levodopa.

Microorganisms in the gut are known to communicate with the central nervous system through nervous, endocrine, and immune signaling pathways. Notably, studies suggest that harmful proteins related to Parkinson’s may start in the gut and later spread to the brain.

“These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease,” the researchers concluded.

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Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

gene therapy study

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to reverse signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

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AV-101 Reduces Parkinson’s Dyskinesia Without Amantadine Side Effects, Preclinical Study Suggests

AV-101 results

VistaGen Therapeutics’ candidate, AV-101, reduced levodopa-induced dyskinesia (abnormal involuntary movements) while maintaining levodopa activity in a non-human primate model of Parkinson’s disease.

Importantly, AV-101 treatment did not cause the adverse side effects observed with amantadine, a therapy that works similar to AV-101 to ease Parkinson’s symptoms.

Hallmark motor symptoms of Parkinson’s disease include tremor, slowness of movement (bradykinesia), stiffness (rigidity), jerky movements (dyskinesia) and poor balance. As the disease progresses, patients typically need to gradually increase treatment dose for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s. These sudden, involuntary movements can be treated with amantadine, which acts on a specific part of NMDA receptors — molecular structures involved in neuronal communication — in the brain.

Amantadine’s exact mechanism of action is not fully understood, but studies indicate it inhibits NMDA receptors and reduces the levels of a chemical messenger called acetylcholine, which increases dopamine activity and provides anti-parkinsonian effects.

Nonetheless, the dose of amantadine needed to treat dyskinesia is often associated with side effects such as depression and cognitive impairment.

AV-101, developed by VistaGen, is an oral NMDA receptor antagonist that, unlike amantadine, acts on a different part of the receptor.

Researchers compared AV-101’s effectiveness to lower levodopa-induced dyskinesia to that of amantadine.

AV-101 was given to non-human primates that had been treated previously with MPTP, a neurotoxin that induces death of dopamine-producing neurons and mimics Parkinson’s symptoms.

AV-101 significantly reduced the abnormal, involuntary movements without affecting the timing, extent, or duration of the therapeutic benefits of levodopa.

“The antidyskinetic activity of AV-101 that we measured compares favorably with our observation with amantadine in parkinsonian monkeys,” Thérèse Di Paolo, PhD, one of the study’s authors, said in a press release.Di Paolo is on the faculty of pharmacy at Laval University in Quebec, Canada. Di Paolo is amongst the world’s leading researchers focused on Parkinson’s disease and levodopa-induced dyskinesia.

Importantly, the experimental therapy did not raise any safety concerns. “Better than amantadine, with its known side effects (in humans with Parkinson’s disease and in parkinsonian monkeys), we observed no adverse effects with AV-101,” Di Paolo said.

“We believe these preclinical data and AV-101’s positive safety profile in all clinical studies to date support AV-101’s potential to treat LID [levodopa-induced dyskinesia], while both maintaining the antiparkinsonian benefits of levodopa and without causing hallucinations or other serious side effects that may be associated with current amantadine-based therapy for LID,” noted H. Ralph Snodgrass, PhD, VistaGen’s chief scientific officer.

Scientists plan to present the preclinical results at an upcoming conference.

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Accordion Pill May Help Reduce Motor Fluctuations in Parkinson’s Disease, Phase 2 Trial Shows

Accordian Pill, Parkinson's

The Accordion Pill Carbidopa/Levodopa (AP-CD/LD) administered three times a day reduced the variability of blood plasma levels of levodopa in Parkinson’s disease patients, which suggests that the treatment may help to ease motor fluctuations, a Phase 2 trial shows.

Warren Olanow, MD, professor at Mount Sinai School of Medicine, New York, and the study’s lead author shared these results in a scientific poster, titled “Pharmacokinetics of multiple doses of Accordion Pill Carbidopa/Levodopa in patients with Parkinson’s disease,” at the 2019 IAPRD World Congress, June 16–19 in Montreal, Canada.

Levodopa is the most widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that ensures levodopa is safely delivered to the brain, where it is processed to generate dopamine. Low levels of dopamine in Parkinson’s patients lead to the characteristic motor impairments associated with the disease.

However, patients with advanced disease who are being treated with levodopa often develop motor fluctuations, which result from “off” periods (when symptoms return) between levodopa doses due to its short-term effects.

This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.

Intec Pharma’s AP-CD/LD was designed to address this problem. The pill has a specific gastric retention and release system containing carbidopa and levodopa which allows the therapy to be released in both immediate and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over eight to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

The Phase 2 study (NCT03576638) evaluated the pharmacokinetic (PK) profile (a compound’s processing inside the body) of AP-CD/LD compared to Sinemet (an approved combination of immediate-release carbidopa-levodopa, marketed by Merck) in 12 Parkinson’s patients.

Participants received either an AP-CD/LD capsule — containing 50 mg of carbidopa with 500 mg of levodopa — three times a day, or they were given an immediate-release Sinemet tablet — consisting of 37.5 mg of carbidopa and 150 mg of levodopa — five times a day.

Blood samples were collected pre-dose, and then at 30-minute intervals post-dose over 16 hours and again at 24 hours post-dose.

The study’s main objective was to assess the variability in the blood concentration of levopoda between four and 16 hours after dosing.

The results showed that patients treated with AP-CD/LD three times a day had less variability in the concentration of levopoda in their blood compared with those given Sinemet given five times a day. Treatment with AP-CD/LD was found to be safe as there were no reports of adverse events.

As decreasing the fluctuations in blood levopoda levels is linked with reduced motor complications, “these preliminary results suggest that treatment with AP-CD/LD may reduce motor complications compared with standard [immediate-release]-CD/LD treatment in advanced [Parkinson’s disease] patients,” the researchers wrote.

“These PK results are important as they confirm our expectations that AP-CD/LD 50/500 [three times per day] reduces levodopa variability in [Parkinson’s disease] patients, which we expect will translate to a reduction in motor fluctuations in these patients,” Jeffrey A. Meckler, vice chairman and CEO of Intec Pharma said in a press release.

Intec Pharma is also conducting a Phase 3 trial, named ACCORDANCE (NCT02605434), to compare the safety and efficacy of AP-CD/LD and Sinemet in hundreds of adults with advanced Parkinson’s.

“We are eagerly awaiting the top-line results from our Phase 3 ACCORDANCE trial in the July/August time frame and these positive PK data support our belief that AP-CD/LD treatment could provide Parkinson’s disease patients with a better baseline [levodopa] therapy to reduce motor complications,” Meckler added.

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Report Showcases Benefits of Creativity Induced by Levodopa


A new report describes two Indian men with Parkinson’s disease who experienced “creative awakenings” after they started being treated with levodopa.

Appropriately titled, “A tale of two patients: Levodopa and creative awakening in Parkinson’s disease – A qualitative report,” the study was published in the Asian Journal of Psychiatry.

Levodopa is one of the mainstays of Parkinson’s treatment, and there have been scattered reports of people treated with it developing increased artistic creativity. The new study details the cases of two men, both from India, where levodopa-induced creativity has not been previously reported.

The first man, Mr. A, is a 68-year-old shopkeeper. He developed symptoms of Parkinson’s in 2010, and began treatment with levodopa in 2017.

Six months after he started on levodopa, Mr. A noticed some coconut shells lying in his yard and was struck by the urge to make something out of them. “It just happened, I just had these ideas,” he is quoted in the study as saying.

Mr. A began making various things out of the coconuts — pen holders, paperweights, cups, and more. He kept doing it, and now makes five to 10 such items per day.

Although he claims he was “not an artistic kind of person before all this,” Mr. A now sells his crafts at various shops. Although it’s not a full-fledged business, he says it does help him with his finances.

The second man, Mr. R, is a 63-year-old farmer who was diagnosed with Parkinson’s in 2011. He began levodopa treatment in 2015, and shortly thereafter, upon seeing his grandchild coloring, decided to start painting.

“I draw or paint all the time. I just can’t stop,” he said. “I’ve been doing it for nearly three years now.”

Mr. R, who regularly paints two or three pictures a day, has turned this newfound passion into a career. “Now it is a major source of income for me,” he said. “What gives me greater happiness is that I use the money I generate to support other people who need financial assistance for their medical needs.”

Both Mr. A and Mr. R are, on the whole, quite satisfied with the unexpected turns their lives have taken.

“I feel it’s given me a purpose in life,” said Mr. R. “If Parkinson’s disease was the only way I could have done all this, I won’t complain, honestly.”

“‘I am really happy. I don’t know what else to say,” said Mr. A.

It’s not clear exactly why levodopa treatment leads to creative awakenings in some patients. Several mechanisms have been proposed, such as:

  • “Creativity is a result of hyperactivity and behavioral disinhibition;”
  • “Creativity is a result of stimulation by dopamine agonists;”
  • “Creativity might be the emergence of innate skills in some predisposed Parkinson’s patients on dopaminergic therapy.”

However, in this report, researchers wanted to emphasize how this creative expression could be beneficial to patients.

“All in all, it would seem reasonable to assume that [making art] helped [Mr. A and Mr. R] cope positively with [Parkinson’s] and its deficits,” the researchers said. “Such artistic expression is therapeutic; it’s a form of art therapy, and we call for this usefulness to be further explored in routine clinical practice.”

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Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

Zonisamide, Parkinson's

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depression and aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.

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‘Framing OFF Through Art’ Exhibit on View at World Parkinson Congress

Artworks focus on off periods

More than 1 in every 3 — some 40 percent — of Parkinson’s patients have “off periods,” the return of motor and non-motor symptoms as the effectiveness of a  treatment’s dose wears off. Artworks created in collaboration with patients, part of an Acorda Therapeutics program, are helping to express what these periods are like and focus attention on them.

Called Framing OFF Through Art, the six-piece exhibition was recently featured at the 5th World Parkinson Congress in Kyoto, Japan, attended by more than 3,000 people from at least 60 countries. The initiative is the centerpiece of Acorda’s Live Well. Do Tell program, launched last year.

Off periods are characterized by the re-emergence of Parkinson’s symptoms, such as sadness and anxiety, when the effects of levodopa/carbidopa wear off. Such episodes are typically more common as the disease progresses, and vary from person to person.

Because off periods can be difficult to discuss or even identify, the artwork is intended to visualize feelings associated with them. The hope is that the art will spur other patients to recognize their “off” symptoms, and discuss them with their care team. The artists who created the pieces have been touched in some way by Parkinson’s.

”Research has consistently shown that off periods are among the most common issues for people living with Parkinson’s disease,” Ron Cohen, MD, Acorda president and chief executive officer, said in a news release.

“We believe that people with Parkinson’s will be able to see aspects of their own experiences with Parkinson’s and off periods in these works of art.”

The artwork ranges from acrylic sculptures to oil paintings. Each artist was paired with two patients and their caregivers. The exhibition debuted in October at a New York event where the artists, patients and caregivers were guests. The need to better understand off periods, as well as how to discuss them, is highlighted in the Live Well. Do Tell statement of need.

As part of a rotating series, a piece called “Rooted Resilience” is featured on the Live Well. Do Tell website. Created by abstract impressionist and colorist Tim Kinney, who has several friends with Parkinson’s, the multi-color painting of a tree depicts the way Gustavo Pavon, diagnosed in 2006, described his off periods.

The painting’s transition from dark roots to the brightness of the leaves and sky is meant to illustrate emergence from an off time.

Marcela Del Bosque, Pavon’s wife and caregiver, is mentioned in a narrative accompanying the painting as describing the transition in this way:

“When Marcela saw the painting, she immediately picked up on this and noted that when Gustavo is in a dark place — in an off period — he’s quiet and doesn’t smile. Then, Gustavo’s bright smile that she loves reappears and he returns.”

The work’s branches and colors also symbolize Pavon’s growth — his “branching out” —  to embrace community support and speak more openly about his experience. For nearly a decade, Pavon had only told a few people about his condition and off symptoms that include shivering and stiffness.

Go here to learn more about off periods and for additional resources.

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Blink Rate May Help Predict Blood Levodopa Levels in Parkinson’s Patients, Study Suggests

blink rate levodopa

Measuring how often a person spontaneously blinks could help predict motor changes in people with Parkinson’s disease being treated with levodopa, a study suggests.

The study, “Using Spontaneous Eye-blink Rates to Predict the Motor Status of Patients with Parkinson’s Disease,” was published in the journal Internal Medicine.

Levodopa is used as standard therapy for Parkinson’s disease, which is characterized by loss of dopamine-producing brain cells. The therapeutic formulation can cross the blood-brain barrier and enter the brain, where it is converted into dopamine. This dopamine then activates dopamine receptors and improves the function of movement control centers in the brain.

Especially in advanced disease, during which the body is making less of its own dopamine, maintaining just the right levels of levodopa in the blood is critical. The level of levodopa needs to be high enough to sustain a therapeutic effect, but if it gets too high, the patient may experience undesirable dyskinesia (uncontrolled body movements).

However, getting the level just right can be a fickle process. Levodopa is processed quite rapidly in the body, remaining actively stable inside the body for less than two hours, and its precise absorption pattern is governed by a complex set of interacting factors.

Thus, the level of levodopa has to be measured at multiple times in a patient to ensure that it is kept within more efficient levels. But this monitoring process requires taking multiple blood samples, which can be impractical and invasive. Therefore, researchers are investigating other strategies to assess levodopa levels without requiring blood samples. Previous research has demonstrated a connection between levels of dopamine in the brain and the rate at which a person spontaneously blinks.

Supported by these findings, Japanese researchers hypothesized that blinking rate could be correlated with levels of levodopa in the blood, and as such, blinking rates might be able to act as a more feasibly measurable proxy to assess levodopa levels.

To test this, the team gave a device that measures blinking to three people with Parkinson’s disease. The Jins Meme device is shaped like ordinary eyeglasses and is wirelessly connected to a computer, which processes the wearer’s data to calculate a “Blink Index.”

The researchers also collected blood samples every 15 minutes for the hour before the patients took levodopa, and then every half hour to one hour thereafter.

The blinking rate of the three patients varied widely over time. The researchers noted that blinking rates at the beginning of the study were quite high, which they believed could be due to the patients adjusting to the device. Despite this, blink rates did correlate with levodopa levels in the blood.

All the patients tended to have higher blinking rates when their levodopa levels were high, and vice versa. “This finding suggests that [blink rate] can be used as a substitute for plasma levodopa levels,” the researchers wrote. Therefore, “the continuous monitoring of [blink rate] may be useful for predicting the motor status in patients” with Parkinson’s.

Larger studies are needed to further validate and test the diagnostic potential of blink rates, the researchers said. Still, this study does serve as a proof-of-concept for using blinking rate as a proxy for levodopa levels in the blood of people with Parkinson’s.

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Gocovri Leads to Steady ‘On’ States in Parkinson’s Patients, Phase 3 Pooled Data Suggest


Gocovri (amantadine) can effectively reduce the number and duration of “off” periods and dyskinesia (uncontrolled movement) episodes in Parkinson’s patients under long-term levodopa treatment, leading to a good steady “on” state, pooled Phase 3 clinical data show.

These findings were reported in a study, “Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials,” that was published in the Journal of Parkinson’s Disease.

Levodopa is a precursor of dopamine and one of the gold-standard treatments to manage the motor symptoms of Parkinson’s disease. However, patients who take it over extended periods develop off-episodes, moments in which the therapy losses its effect and involuntary movements (dyskinesia) reappear.

Some adjustments and alternative treatments, such as Gocovri (marketed by Adamas Pharmaceuticals), can help control these off-episodes and dyskinesia. But it is not clear how these treatments act as a whole.

Therefore, the researchers reviewed the effects of Gocovri from data collected during two Phase 3 placebo-controlled trials, called EASE LID (NCT02136914) and EASE LID 3 (NCT02274766).

The analysis included data from 162 Parkinson’s patients who participated in these trials, of whom 77 received Gocovri and 85 received a placebo for 12 weeks. The patients had a mean age of 64.5 years, had been diagnosed with Parkinson’s disease for 9.9 years, and had been taking levodopa for about 7.6 years.

During the trials, patients kept diaries in which they were asked to detail their daily on- and off-periods, and events of dyskinesia. Patients divided their awake time into 30-minute intervals and reported the state they were in at each interval.

Three main states were considered: “on” without troublesome dyskinesia (good “on”), “on” with troublesome dyskinesia (troublesome dyskinesia), and off-periods. Troublesome dyskinesia referred to involuntary movements that impaired, at least partially, the performance of daily functions.

Most patients (67%) reported waking up in an off-state, which decreased to 13% of patients during the first two awake hours. Thereafter, the number of patients in each state remained constant throughout the day.

A lower number of patients (5%) woke up experiencing troublesome dyskinesia, which in contrast increased up to 24% within the two hours after being awake, then fluctuated between 20% and 44% through the rest of the waking day.

Patients were found to experience a mean of 3.0 episodes of troublesome dyskinesia and about 2.2 off-episodes during the day. The mean duration of each episode was approximately two hours for dyskinesia and 1.1 hours for an off-episode.

After taking Gocovri for 12 weeks, the proportion of patients reporting no episodes of “on” with troublesome dyskinesia was 57.1%, compared with 24.7% in the placebo group. The treatment also reduced the mean duration of the episodes and the mean number of transitions between states during the day, leading to a steadier good “on” state during the day.

In general, the treatment was found to be safe, with less than 10% of patients experiencing adverse events. The most common adverse events were dizziness, constipation, hallucinations, dry mouth, edema, swelling of the extremities, and urinary infections.

“Our results demonstrated a treatment effect of Gocovri for dyskinesia and OFF [states] throughout the waking day,” the researchers wrote.

“In the future, wearable sensors and other types of monitors may provide continuous monitoring through the day and allow more sensitive assessment of mild motor fluctuations and dyskinesia,” they said.

Of note, most of the researchers received compensation from or are employees of Adamas Pharmaceuticals.

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