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Possible Link Found Between Vitamin B12 Levels and Dementia in Parkinson’s

vitamin B12 and dementia

People who have higher levels of vitamin B12 in their blood when they’re diagnosed with Parkinson’s disease may be less likely to develop dementia, a study suggests.

The study, “Higher vitamin B12 level at Parkinson’s disease diagnosis is associated with lower risk of future dementia,” was published in Parkinsonism & Related Disorders.

Dementia describes a group of symptoms in which memory and cognitive abilities become impaired enough to affect daily life. Dementia can be part of the non-motor symptoms associated with Parkinson’s disease; it is most common among people who are older and/or have had Parkinson’s symptoms for longer.

Vitamin B12 is a cobalt-containing molecule present in some foods. It is necessary for bodily processes, including red blood cell function and DNA synthesis.

Previous research found that, among people with Parkinson’s, those with cognitive impairment, such as dementia, had significantly lower levels of vitamin B12 in their blood. This suggests the possibility that low vitamin B12 levels predispose certain individuals to dementia.

Researchers decided to further investigate this idea by testing whether vitamin B12 levels at diagnosis were associated with dementia risk later on. To do this, they analyzed clinical data for people with Parkinson’s whose data had been collected as part of the Rochester Epidemiology Project.

They found 25 people with Parkinson’s (17 males, eight females) whose data also included a measurement of blood B12 levels within either one year before or three months after their diagnosis.

“This duration range was chosen to limit the impact of levodopa treatment, which has been associated with increased homocysteine levels and lower vitamin B12 levels,” the researchers wrote.

The median age of the group at diagnosis was 74 years. Of the 25 people included, 15 (60%) were later diagnosed with dementia, at a median age of 79.4 years.

On average, individuals who did not develop dementia had significantly higher vitamin B12 levels when they were diagnosed than those who did (648.5 vs. 452 ng/L).

With additional statistical modeling, the researchers found that a cutoff of 587 ng/L could separate those who did or did not develop dementia, with an overall sensitivity (true-positive rate) of 87% and a specificity (true-negative rate) of 70%.

The researchers further calculated that for every 100 ng/L increase in vitamin B12 levels at diagnosis, there was a statistically significant decrease in dementia risk, such that “a vitamin B12 level of 500 ng/L was associated with a 69% reduced risk of dementia compared with 400 ng/L,” they said.

These data suggest that vitamin B12 levels at Parkinson’s diagnosis are predictive of future dementia risk.

“The association between higher serum B12 levels and decreased dementia risk may provide prognostic information for clinicians as they counsel patients on the disease course of PD and raises further questions regarding the potential importance of vitamin B12 in these patients,” the researchers wrote.

It should be stressed that this was a small, retrospective study, so further research is needed to validate these findings. Additionally, the findings do not directly suggest that taking vitamin B12 supplements would lower the dementia risk — though this may be an avenue for future investigations to explore.

“Prospective evaluation of vitamin B12 status in PD is needed, and consideration of interventional B vitamin supplementation trials should be pursued,” the researchers wrote.

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Parkinson’s Foundation Q&A Provides Guidance From Experts on COVID-19

COVID-19 and Parkinson's

While there’s no evidence that people with Parkinson’s disease are more susceptible to contracting illness, COVID-19 tends to be more severe in the elderly and those with chronic diseases. Because of this, patients should take extra precautions to avoid contracting the disease, experts say.

In response to the COVID-19 pandemic, the Parkinson’s Foundation (PF) recently presented a live online question-and-answer event featuring Michael S. Okun, MD, the nonprofit’s medical director, and Fred Southwick, MD, an author and infectious disease expert. Both physicians are from the University of Florida Health, a PF Center of Excellence.

A video of the discussion may be viewed here.

In an overview of COVID-19, the experts emphasized that the highly infectious novel virus should be taken very seriously, particularly since most Parkinson’s patients are middle age at diagnosis.

“I’ve been studying infectious diseases for over 40 years, and I have to tell you this is by far the most dangerous virus that I’ve encountered and the worst epidemic in my career,” Southwick said during the discussion.

Still, it’s vital for Parkinson’s patients of all ages to remain calm during the outbreak and take preventive measures.

“You can’t panic,” he said. “You should respect this virus and you should follow the infection control protocol.”

According to the foundation, key steps include frequent hand washing, staying home and practicing social distancing, rescheduling non-urgent doctor appointments, obtaining three-months’ worth of medication supplies, talking with healthcare providers before bringing home a family member from a nursing facility, avoiding flights and travel, and getting pneumonia and flu vaccines.

To minimize “cabin fever” during prolonged periods at home, patients are encouraged to call or do video chats with family and friends often, and take walks. Those who do get sick should alert their doctor’s office before a visit so staffers are prepared to protect the patient and others.

According to Okun, in general, the Parkinson’s immune system is similar to that of individuals who don’t have Parkinson’s.

“Some of the cells that are part of the immune response in Parkinson are a little different … and we’re using that to understand Parkinson and engineer therapies,” he said. “But the immune system functions in a relatively normal way.”

One problem, however, is that Parkinson’s patients are more susceptible to lung infections that can make it hard to take deep breaths. Because COVID-19 attacks the respiratory system, individuals with Parkinson’s are at a higher risk.

“The danger is in the respiratory tract, and unfortunately, the muscles and the gag reflex and cough reflex in Parkinson’s patients can be impaired,” Southwick said. “So if they get this infection, because of the physical constraints, they are at higher risk. If you can’t take deep breaths, it’s harder to oxygenate.”

Furthermore, the experts said most over-the-counter cold and flu medications are generally safe to use with Sinemet (levodopa-carbidopa), an approved Parkinson’s therapy that increases dopamine levels in the brain to help with motor function. They cautioned, though, that monoamine oxidase-B inhibitors — molecules that modify metabolic pathways that lead to the breakdown of dopamine — should not be mixed with dextromethhorphan, common in many cough syrups. Patients who have hypertension should avoid medications that contain the decongestant pseudoephedrine.

In general, Parkinson’s and medicines used to treat it lower blood pressure. Patients who may have been exposed to the coronavirus should watch out for fainting or dizziness when standing or otherwise changing position. In any case, it’s important to establish the cause before beginning treatment.

Despite widespread reports, Okun and Southwick said there is no evidence that ibuprofen worsens COVID-19, but that if patients have concerns, they may consider Tylenol or another alternative.

They also suggest that, in lieu of in-person exercise classes and support groups, patients exercise safely at home, and use online resources such as the PF YouTube channel and PD Conversations.

For further questions about COVID-19 and Parkinson’s, call the Parkinson’s Foundation’s helpline specialists at 800-4PD-INFO. Go here for the PF’s latest information on the coronavirus.

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Gene Therapy Trial Patients, in Death, Helping Show What Did and Didn’t Work

gene therapy

Delivering a gene therapy directly to the substantia nigra, an area of the brain affected by Parkinson’s disease, led to sustained protein production for up to eight years, a post-mortem of analysis of two patients revealed.

The therapy’s use failed to show significant benefits in its clinical trials, but these evaluations — covering the longest number of years for such an analysis in gene therapy trial participants — are likely to help researchers working to improve the effectiveness of this approach. 

The study, “Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson’s disease,” was published in the journal Brain.

Parkinson’s is caused by the dysfunction or death of nerve cells that produce dopamine (dopaminergic neurons). A neurotransmitter, dopamine is produced in the substantia nigra, a part of the brain the controls balance and movement.

CERE-120, an investigative gene therapy first developed Ceregene, now part of Sangamo Therapeutics, is designed to protect these neurons. It works to deliver a gene called NRTN directly to the substantia nigra and surrounding area known as the putamen. This gene carries the instructions for a protein known as neurturin (NRTN) — a neurotrophic factor — which supports the growth and survival of neurons. 

In animal models, the human NRTN gene carried on a harmless virus known as adeno-associated virus serotype 2 (the CERE-120 therapy), and surgically implanted, was seen to protect dopaminergic neurons and led to an increase in dopamine production. 

An early open-label Phase 1 clinical trial (NCT00252850) in Parkinson’s patients showed CERE-120 was safe and well-tolerated, with some patients reporting benefits. However, a double-blind Phase 2 trial (NCT00400634), in which CERE-120 was surgically delivered to the putamen, failed to show significant improvement compared to those given a sham surgery.

Post-mortem studies of those treated showed persistent but limited NRTN protein production in the putamen. These levels were not sufficient to provide significant benefits. 

A second trial (NCT00985517) was designed to enhance NRTN production by delivering a higher dose to a larger area of the putamen as well as directly to the substantia nigra. Again, CERE-120 failed to show improvement beyond sham surgery in this new group of Parkinson’s patients.

To better understand the reasons for this failure, researchers at the Rush University Medical Center in Chicago conducted post-mortem assessments on two Parkinson’s patients who participated in the CERE-120 gene therapy clinical trials. 

One was from the first Phase 2 trial (putamen only) and survived for 10 years after surgery, while the other was enrolled in the second Phase 2 trial (putamen plus substantia nigra) and lived for another eight years. 

As a comparison, the team also evaluated the brains of two age-matched Parkinson’s patients who were not given gene therapy, and those of two age-matched people who neither had Parkinson’s nor other psychiatric or neurological illnesses at the time of their death.

In both treated patients, there was a persistent but limited production of NRTN in the putamen, and an associated increase in levels of an enzyme known as tyrosine hydroxylase (TH) — a key enzyme in the production of dopamine. TH levels were substantially higher in the case with combined putamen plus substantia nigra delivery compared to putamen delivery alone. 

The NRTN protein was found in up to 19% of remaining dopaminergic neurons in the substantia nigra of the patient who received CERE-120 delivered to the putamen only. In the patient with CERE-120 delivered to both the putamen and substantia nigra, NRTN was detected in up to 39% of the remaining neurons.

This protein was not detected in samples from patients not treated with gene therapy, or people without Parkinson’s. 

NRTN signaling works through a multi-component system, including a receptor known as RET. Consistently, RET expression levels were higher in the patient with combined CERE-120 delivery than in the patient with putaminal CERE120 delivery only.

In Parkinson’s patients, dopaminergic neurons are damaged by the buildup of the alpha-synuclein protein, which forms clumps called Lewy bodies. Studies have suggested that alpha-synuclein can reduce the expression of the RET receptor,  limiting NRTN production. 

Alpha-synuclein clumps were found in neurons that also showed NRTN, RET, and TH. No differences were seen in the numbers of Lewy bodies between the two treated and untreated Parkinson’s patients. 

Finally, low levels of the viral AAV vector were detected in both the putamen and the substantia nigra of patients compared to animal models, but its presence did not cause inflammation. 

“In summary we demonstrate that gene delivery of NRTN can induce long-standing transgene [artificially introduced gene] expression in Parkinson’s disease subjects lasting for at least 8–10 years with prominent upregulation of TH in focal areas of the putamen and substantia nigra that express NRTN,” the researchers wrote.

“If gene therapy is ever to be considered as a treatment for Parkinson’s disease, we will have to find a way to meaningfully increase TH-positive terminals in the striatum [brain area that includes the putamen], as motor benefits are primarily dependent on TH expression in the putamen,” they added.

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IRL752 Can Safely Manage Treatment-resistant Symptoms in Parkinson’s Dementia, Trial Shows

IRL752, Parkinson's dementia

Treatment with IRLAB Therapeutics‘ small molecule IRL752 is safe and well-tolerated by Parkinson’s disease patients with dementia, and may help manage symptoms that are unresponsive to levodopa, results from a Phase 2a trial show.

In particular, the treatment was found to reduce apathy, improve balance, and decrease the risk of falls. Planning and executive function also seem to improve with IRL752. Notably, no severe adverse events related to treatment were reported.

The study, “A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson’s Disease Dementia,” was published in Movement Disorders.

IRL752 is a small molecule that has the ability to enhance communications between nerve cells in the frontal cortex, a major brain area that controls cognitive functions. It does so by increasing the availability of two important chemical messengers (neurotransmitters) — norepinephrine and dopamine — and by activating specific genes involved in nerve cell communication.

Both of these chemical messengers are needed for cells to communicate properly but their levels are reduced in those with Parkinson’s disease, leading to the motor and cognitive deficits characteristic of the condition.

After showing that IRL752 is safe and well-tolerated in a group of 40 healthy volunteers included in a Phase 1 trial, with no cardiovascular effects reported, IRLAB designed a Phase 2a trial (2017-001673-17) to evaluate the treatment’s safety, tolerability, and preliminary signs of efficacy in people with Parkinson’s and dementia taking their normal antiparkinsonian medications.

“The aim with IRL752 is to improve balance and reduce the risk of falls in patients with Parkinson’s disease, which is the current top priority within the treatment of Parkinson’s disease,” Joakim Tedroff, MD, PhD, chief medical officer of IRLAB, said in a press release.

The trial included 32 patients, median age of 72 years, from Sweden and Finland who were randomly assigned IRL752 or a placebo. The treatment’s dose was adjusted for each patient during the first 14 days, after which dosing was kept stable for an additional 14 days of treatment. The average dose achieved in the stable dose phase was 600 mg daily.

The trial’s main goal was to determine the safety and efficacy of repeat IRL752 dosing in these patients. Secondary efficacy measures included IRL752’s effects on Parkinson’s symptoms, postural control and walking speed, freezing of gait, cognitive function, neuropsychiatric symptoms, and global function.

During the four-week treatment period, 72% of patients reported at least one treatment-emergent adverse event, 58% of which were possibly related to treatment. Most adverse events were mild, affected the central nervous system, and occurred predominantly in the first two weeks, when the dose was still being adjusted for each patient.

The most common adverse events related to IRL752 included abdominal pain, headache, tremor, increase in liver enzymes (indicating possible liver damage), and cognitive disorder.

Two patients reported severe adverse events during the study, but none were deemed related to treatment. Also, no patient experienced changes in vital signs or in cardiovascular parameters.

Regarding efficacy, patients taking IRL752 showed significant lessening of axial motor symptoms such as postural instability and falls, as well as reductions in apathy and cognitive impairment. These symptoms are known to be largely unresponsive to levodopa treatment.

Notably, “the possible effect of adjunct IRL752 treatment on postural dysfunction seemed not to be a result of a general effect on parkinsonism because none of the other classical hallmark symptoms of Parkinson’s disease were affected by the treatment,” the researchers wrote.

Instead, they believe that an increase in norepinephrine likely explains the improvements, as symptoms such as poor balance and apathy have been associated with lower levels of this neurotransmitter.

The researchers also showed that IRL752 reached concentrations in the blood believed to have a therapeutic effect, suggesting that “IRL752 may be dosed at potentially clinically effective dosing in this patient population.”

The company is now planning a Phase 2b clinical trial to continue evaluating the effects of IRL752 on the frequency of falls in Parkinson’s patients.

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Video Game May Help Detect Early Gait Impairment in Parkinson’s Patients

Goalkeeper video game

The Goalkeeper Game, a video game in which people assume the role of a goalkeeper in a soccer penalty shootout, may be a novel tool to detect early decline in gait performance in Parkinson’s disease patients, helping them receive treatment sooner, a study suggests.

The test is designed to non-invasively assess the gait of Parkinson’s disease patients under complex conditions — such as climbing stairs or walking over an obstacle — and was better at predicting a decline in gait performance in those situations than the well-established Montreal Cognitive Assessment (MoCA) test, which assesses cognitive decline.

The study, “Goalkeeper Game: A New Assessment Tool for Prediction of Gait Performance Under Complex Condition in People With Parkinson’s Disease,” was published in Frontiers in Aging Neuroscience.

Patients with Parkinson’s disease usually are diagnosed based on the presence of classical motor symptoms. However, there is an earlier phase — called the prodromal phase — in which signs and symptoms of the disease are present, though still insufficient to make a definite diagnosis.

Identifying patients in this prodromal phase would ensure they receive treatment early, before their disease progresses to more advanced stages and significantly affects daily activities.

The motor and cognitive decline seen in Parkinson’s patients often leads to gait impairments, and appears to be present already in the prodromal stage. In particular, gait “under-challenging” conditions — such as avoiding or climbing obstacles, adapting gait to unexpected targets, etc., — requires a higher interplay between cognitive and motor processes, and is more affected in Parkinson’s patients than the action of simply walking without obstacles.

That is why detecting early decline in gait performance under complex situations may help diagnose the condition earlier and make sure that patients receive timely treatment.

A team of Brazilian researchers  explored whether a video game — the Goalkeeper Game — could predict gait impairments under complex conditions in people with Parkinson’s, and subsequently enable early therapeutic interventions.

The game requires that players guess the position of the goal where the ball will go (left, right, or center) and is expected to mimic the decision-making process required for unexpected obstacles during walking.

The game consists of three phases, each evaluating distinct motor or cognitive components. First, patients are told the shooting direction and need only to select the correct direction; no decision-making is required. Then the learning phase requires them to identify the correct sequence of shooting directions, which has higher cognitive demand.

Finally, the third phase is designed to evaluate attention and memory, as patients are asked to memorize the sequence of shooting directions presented on a screen before starting the game.

The study included 74 Parkinson’s patients without dementia, who played the Goalkeeper Game 40 to 120 minutes after their L-dopa (levodopa) dose (“on”  period). They also underwent assessments with the MoCA test — a tool used routinely to evaluate cognitive decline in Parkinson’s patients — and the Dynamic Gait Index (DGI).

The DGI evaluates not only walking without obstacles, but also more complex abilities like walking while changing speed, walking while moving one’s head vertically and horizontally, and walking while stepping over an obstacle.

MoCA has been used to assess impairments in patients’ abilities to adapt gait to obstacles, and its ability to predict declines in gait performance in more complex situations — or DGI scores — was compared with that of the video game.

Researchers found that scores in the memory phase of the video game were strongly associated with DGI scores, meaning that patients who got more responses wrong in the memory phase had higher gait impairment in complex situations. MoCA, meanwhile, was associated only moderately with DGI scores.

While the video game was able to predict which patients had high or low DGI scores with a 65% accuracy, MoCA’s accuracy reached only 56%.

“The main finding of this study is that [Goalkeeper Game] had a slightly higher predictive power for decline in gait performance under complex situations than MoCA,” researchers wrote, adding that a free and friendly game such as this may help detect early decline in gait performance without the need for expensive screening tools.

Additional studies, they noted, are warranted to validate this tool as a potential marker of early gait decline in Parkinson’s patients.

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Study to Test MRI Technique for Possible Early Parkinson’s Diagnosis

MRI and diagnosis

A clinical study will test the potential of a specific magnetic resonance imaging (MRI) technique to diagnose Parkinson’s disease at early stages.

The 18-month project, supported by a grant from the Center for Clinical and Translational Science in the U.K., will take place at the University of Kentucky’s College of Medicine under the leadership of George Quintero, PhD, and Zain Guduru, MD. It is expected to open this year.

Parkinson’s disease is characterized by progressive loss of coordination and movement, and includes tremors, stiffness and slowing of movement. Currently, a person is diagnosed when those symptoms appear.

However, the brain undergoes alterations that precede symptom onset. Detecting these changes earlier would allow a quicker start of treatments for these symptoms, and possibly to slow disease progression.

Previous research by the same team showed that apomorphine, an FDA-approved Parkinson’s therapy, activates brain areas commonly affected by the disease. Brain activity was measured using a blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI), an imaging technique that assesses changes in oxygen in the blood.

Apomorphine stimulates the production of dopamine in the brain, a messenger molecule (called a neurotransmitter) that is produced by dopaminergic neurons. Dopaminergic neurons die in Parkinson’s, leading to the characteristic deterioration of motor and cognitive skills observed during this disease’s course.

In this new study, researchers will assess responses in the brain before and after taking apomorphine in Parkinson’s patients and in people with essential tremor, a similar movement disorder. These changes will be measured using BOLD-MRI.

The idea is to test whether this technique can accurately discriminate between the two different patient populations upon apomorphine treatment. Since essential tremor is not caused by inadequate dopamine production, only Parkinson’s patients, in theory, should show specific brain alterations in response to apomorphine.

Should results be favorable, BOLD-MRI could be a way of identifying Parkinson’s early and distinguishing it from similar disorders.

“If apomorphine causes a different brain response in the two groups of patients, it could be a promising method for earlier detection of Parkinson’s,” Quintero said in a press release. “And this leads to earlier interventions that can benefit patients.”

Test results may also inform how the disease progresses, and whether subgroups of Parkinson’s disease patients respond differently to treatment.

“This is truly a translational project. We often want to make that transition between basic science research to human research,” Quintero said. “CCTS provided the opportunity to continue this research.”

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APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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‘Sidekicks Anytime’ Offers Artsy Activities to Do at Home

Sidekicks program

With people everywhere hunkering down to avoid the newly identified coronavirus known as COVID-19, the Sidekicks Anytime program is offering creative, at-home activities tailored to people with Parkinson’s disease.

The program is an offshoot of Sidekicks, sponsored by the Davis Phinney Foundation and Lundbeck, a pharma company specializing in brain health. The program brings together youths and those living with Parkinson’s to share stories in ways that promote understanding and personal connection while having fun.

Sidekicks Anytime asks that patients join with a community partner — no age group is specified — to enjoy activities that can be done anytime and anyplace.

Because of COVID-19 infections risks, however, art projects can be completed alone, with an in-house partner, or with another using online services such as Skype or FaceTime. Each project requires specific art supplies.

One project is called Storyprints, which focuses on maintaining a positive outlook through gratitude and in-the-moment reflections on what makes life personally special.

Storyprints calls for participants to use a pencil to trace their hands on a piece of white paper, then label one drawn hand “gratitude.” The other tracing  is labeled “hopes and dreams.” Then, colored pencils or markers are used to fill in each hand with relevant pictures, words or symbols.

The project concludes by asking one another, or simply oneself, questions concerning the activity’s difficulty level, its focus on gratefulness, and its enjoyment factor. Visit this site for a Storyprints video.

Another activity, called Ideascapes, is designed to help build stronger and deeper personal relationships. The idea is to create an “Ideascape” by having a person list their favorite things, places to visit and activities, then using crayons and watercolor pencils to create art — an Ideascape — that best reflects that person. This activity also wraps up with questions. Here’s a demonstration.

Friendship Rocks is the other art project, with a theme of embracing positive social interaction with people of differing habits and thoughts. It involves cutting from magazines words or pictures that make someone think of special people in their lives, the qualities they seek in people, and how having friends makes them feel. The cutouts are then glued to rocks. If working with someone, participants are asked to share stories about important friends in their lives. This activity also ends with a question-and-answer portion. Go here for the corresponding video.

For more information, write to program manager Kayla Ferguson at kferguson@dpf.org. The program’s Facebook page may also be helpful.

An estimated seven to 10 million people worldwide have Parkinson’s, a disease marked by progressive loss of coordination and control over movement.

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Dyskinesia Trial Testing Dipraglurant Postponed Due to COVID-19

dipraglurant trial postponed COVID-19

Phase 2/3 trial (Study 301) testing Addex Therapeutic’s candidate dipraglurant for people with levodopa-induced dyskinesia associated with Parkinson’s disease (PD-LID) has been postponed — until further notice — due to the continued spread of COVID-19 in Europe and the U.S., where the trial was set to occur.

The intended patient population for this trial is among those with the highest risk for severe illness and death associated with the new coronavirus. As such, Addex is following the guidance of public health authorities that recommend people at high risk stay at home and avoid unnecessary exposure to COVID-19.

“As the situation with COVID-19 has evolved, we have stayed in close communication with study sites, vendors and colleagues and learned of new institutional precautions being put in place for clinical research,” Roger Mills, MD, chief medical officer of Addex Therapeutics, said in a press release.

“Sites are temporarily suspending on-site visits for monitors, vendors, and all other non-patient visitors and several sites have cancelled all non-essential patient visits,” Mills said.

“Priority is now rightly being placed on how to manage regular care for patients in the light of the increasing COVID-19 containment requirements,” he said. “We care about the well-being of all PD patients and do not wish to have them make the additional visits to doctors’ offices that are required in a clinical study, putting them at increased risk of contracting COVID-19.”

One of the gold standards in Parkinson’s treatment has long been therapy with levodopa, or L-DOPA — a precursor to the neurotransmitter dopamine, the increasing loss of which is a hallmark of the disease. However, levodopa therapy can lead to uncontrollable movements, a condition called levodopa-induced dyskinesia, or LID.

Dipraglurant is a new oral small molecule that inhibits the metabotropic glutamate receptor 5 (mGluR5), which has been shown to play a role in LID. The candidate therapy has a pharmacokinetic profile — meaning, its absorption, distribution, metabolism, and excretion in the body — that mimics the profile of levodopa, making it a potential treatment for LID.

The previous Phase 2 ADX48621-201 trial (NCT01336088) assessed the safety and tolerability of dipraglurant in 76 people with Parkinson’s and moderate-to-severe LID. The participants were randomly assigned to receive dipraglurant (from 50 mg once daily to 100 mg three times daily, 52 patients) or a placebo (24 patients).

The results showed that dipraglurant was in general safe. Moreover, it reduced PD-LID clinical symptoms, as measured by the modified Abnormal Involuntary Movement Scale, on day 1 (50 mg) and on day 14 (100 mg), and across a three-hour post-dose period on day 14. Treatment with dipraglurant did not worsen Parkinson’s symptoms.

Addex is continuing to work with the study sites to continue preparations so as to start the study as soon as it is “appropriate to do so.”

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Stalevo May Be More Effective Than Other Medications for Early Parkinson’s, Meta-analysis Shows

Stalevo for Parkinson's

Stalevo (levodopa, carbidopa, and entacapone combination therapy) may be more effective but seems to be associated with more side effects than other medications to treat early Parkinson’s disease, researchers report.

The study, “Levodopa/carbidopa/entacapone for the treatment of early Parkinson’s disease: a meta-analysis,” was published in Neurological Sciences.

Levodopa (L-DOPA) is the mainstay treatment for Parkinson’s. As the disease progresses, patients typically need to gradually increase their dosage. Even after that, symptoms sometimes reappear or worsen (“off” periods) due to the dopaminergic therapy’s gradual loss of efficiency. Administration of levodopa in combination with both carbidopa and entacapone (LCE, sold by Novartis as Stalevo) has been shown to lessen symptoms and the number of “off” periods.

Although a large number of studies have investigated the treatment of Parkinson’s motor and non-motor symptoms, “there are still many controversies about the diagnosis and treatment of early [Parkinson’s disease] patients,” the researchers wrote.

In the study, a team led by researchers at University of Electronic Science and Technology of China studied the available data regarding the efficacy and safety of Stalevo in people with early Parkinson’s disease. These patients were identified as having idiopathic (of unknown cause) Parkinson’s, Hoehn and Yahr scale stage 3 or less (indicative of mild symptoms in one or both sides of the body), no motor complications history, no treatment, or limited use (generally less than six months) of anti-Parkinson’s medications.

The researchers searched the records of four biomedical databases up through October 2018. They looked for randomized clinical trials, written in English, that used Stalevo to treat early Parkinson’s.

The team analyzed six randomized clinical trials, which involved 1,983 participants (mean age of 60 to 70 years), with a mean average disease duration of 5.3 years.

The Stalevo group consisted of 983 participants and the control group had 1,000 participants. One study used levodopa/dopa decarboxylase inhibitor/entacapone and the remaining five adopted a levodopa/carbidopa regimen in the control group.

In all studies, treatment duration ranged from six to 134 weeks (about 2.5 years).

The Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Disease Questionnaire (PDQ-39) were used to assess symptom severity and quality of life in four of the analyzed studies. The Clinician Global Impression of Change, which measures the change in a doctor’s global impression relative to the beginning of the study, was used as an outcome measure in two trials.

Stalevo was found to improve patients’ motor and non-motor experiences of daily living as measured by the UPDRS part 1 and 2, respectively.

Nonetheless, investigators did not notice any obvious differences between before and after treatment with Stalevo in the Clinician Global Impression of Change, which, according to the authors, could be explained “by a small amount of included studies.”

Also, when PDQ-39 was used as the outcome measure, Stalevo was found not to be as effective as levodopa-carbidopa alone. One possible reason for this is that using PDQ-39 scores may not be sensitive enough to detect changes in these measures in early Parkinson’s patients.

“LCE therapy also increased the risk of total AEs [adverse events], nausea, diarrhea, dyskinesia, dizziness, urine abnormality, and discontinuation risk when compared with traditional therapy,” the researchers wrote.

Around 80.4% of patients treated with Stalevo experienced side effects, compared with 66.8% of those in the control group. Importantly, patients on Stalevo had nearly three times the risk of developing urine abnormality at some point than controls.

Compared to other Parkinson’s medications, and despite the higher percentage of side effects, Stalevo appears to be more effective in the treatment of early Parkinson’s. Still, the researchers advise that these results should be interpreted carefully as this meta-analysis included only six studies.

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