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Mobile Genetic Elements Crucial for Neuron Development, Study Indicates

mobile genetic elements

Genetic elements that are able to “copy and paste” themselves into different sections of DNA help to control the development of neurons, a new study suggests. Understanding this process could have important implications for designing therapies for neurological conditions such as Parkinson’s disease.

The study, “Transdifferentiation of Mouse Embryonic Fibroblasts into Dopaminergic Neurons Reactivates LINE-1 Repetitive Elements,” was published in Stem Cell Reports

L1 retrotransposons are genetic elements that are able to “copy and paste” themselves throughout the genome — all of the genetic information contained in our DNA. These elements constitute a large portion (15–20%) of the genome in mammals, including humans.

Normally, the activity of L1 retrotransposons is limited, but previous research has shown that these elements are active during the development of the nervous system. The reasons for this activity, however, have not been well-understood.

In the new study, researchers examined a cell model in which embryonic mouse skin cells (fibroblasts) were directly converted into dopamine-producing neurons by activating a select suite of cellular factors. This model was chosen because it allowed researchers to compare the two cell states (i.e., fibroblast vs neuron) without having a stem cell intermediate. That could make the results harder to interpret, since any observed difference could be the result of going through an intermediate step, not a true difference between the two cell types.

Usually, fibroblasts are first converted into stem cells, called induced pluripotent stem cells, which are then differentiated in the lab to give origin to a number of different cell types, including neurons.

L1 activity was significantly higher in neurons than in fibroblasts from which they originated — that is, there were more copies of L1 elements distributed throughout the genome. Furthermore, when L1 activity was blocked, the fibroblasts were unable to be fully converted into neurons.

These data support the idea that L1 activity is necessary for the development of neurons, substantiating previous findings.

The researchers then sequenced (a type of “genetic mapping”) the cells’ genomes to see where the new L1 elements were being inserted. They found numerous “hotspots,” where L1 elements were most commonly inserted, suggesting that the process isn’t random. Many of these hotspots also were in or near genes that are known to be active in neurons.

“Taken together, these results show that neuronal fate induction is accompanied by L1 retrotransposition, affecting regions of the genome, relevant for neuronal lineage commitment and neuron function,” the researchers wrote.

The researchers also determined that many of these genes (32%) were differentially expressed in neurons compared to fibroblasts; the activity of these genes was significantly different between the two cell types. This suggested that the L1 elements might be controlling the genes’ activity.

Notably, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Further investigation suggested that the insertion of L1 retrotransposons specifically altered DNA accessibility. Within cells, DNA molecules are compacted in loop-like structures. Conceptually, L1 insertion pushes these loops apart, making them less tightly wound. This makes it easier for the cellular machinery that ‘”reads” DNA to get to the part it needs to read, which likely contributes to the alterations in gene expression observed.

This study highlights the importance of L1 elements in neural development, and adds to scientific understanding of how they work.

The findings also could have implications for the development of therapies to treat disease — for instance, cell-based therapies intended to replace dopamine-producing neurons that are lost in Parkinson’s disease.

“Aberrant L1 activity could threaten the viability or safety of any such product, while optimizing L1 function could enhance the manufacturing and consistency of this type of regenerative treatment,” study co-author Francesco Della Valle, PhD, a postdoctoral researcher at King Abdullah University of Science & Technology, said in a press release.

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‘Microsteretcher’ Technique May Advance Parkinson’s Research

microstretcher technique

Researchers have developed a way to closely study the function of a cell’s transportation network, made up of structures called microtubules, that appears to be impaired in people with Parkinson’s disease.

This technique, called “microstretcher,” may help to better understand microtubules’ deficits and their underlying causes in Parkinson’s, as well as to identify new therapeutic targets.

“Our experimental set-up enables us to study the relationship between the deformation of microtubules and their biological functions,” Akira Kakugo, PhD, the study’s senior author at Hokkaido University, in Japan, said in a press release.

The new method was described in the study, “Regulation of Biomolecular-Motor-Driven Cargo Transport by Microtubules under Mechanical Stress,” published in the journal ACS Applied Bio Materials.

Microtubules are hollow tubular structures that provide structure not only to cells, but also form highways to transport molecules and organelles inside cells. This transport is mediated by motor proteins, namely dynein and kinesin, which move in opposite directions along microtubules’ “tracks.”

In nerve cells, microtubules are particularly involved in the transport of vesicles filled with neurotransmitters (chemical messengers used in nerve cell communication) down the axon, or nerve cell fiber, to be released as signals to other nerve cells.

Increasing evidence suggests that defective regulation of microtubules may have a role in the development of a broad range of neurodevelopmental, psychiatric, and neurodegenerative diseases, including Parkinson’s.

Microtubule dysfunction was shown to precede axon transport deficits and death of dopamine-producing nerve cells — a hallmark of Parkinson’s disease. In addition, several Parkinson’s-associated proteins, such as tau, alpha-synuclein, parkinpink1, and LRRK2 regulate or appear to affect microtubule stability.

However, there was no experimental set-up to properly study the transport process in microtubules and the effects of disturbances in that process, until now.

Researchers at Hokkaido University and the National Institute of Information and Communications Technology, in Japan, developed a unique technique to control microtubular physical deformation and observe its effects on their transport function.

The microstretcher consists of a horizontal plate with flexible medium inside, which can be “stretched” or “compressed” using a computer system.

The team first used specific proteins to attach microtubules to the pre-stretched medium in a way that the microtubules lied parallel to the surface area and “stretching” axis. Next, dyneins bound to a fluorescent cargo were added to the microtubules.

With this system, researchers were able to evaluate the effects of stretching and compressing the flexible medium, and consequently straightening and bending the microtubules, in dynein-associated transport.

Results showed that the dynein-cargo moved faster as the microtubules began to bend, but only until the compressive strain reached about 25%, “beyond which the dynein-driven transport is retarded,” the researchers wrote.

From that point onward, the speed of dynein-associated transport started to decrease and eventually the deformation led to microtubule collapse and no dynein movement. Different speeds of motion also were observed along distinct areas of the bended microtubules.

The team noted that dynein’s faster motion in slightly bended, rather than straight, microtubules may be associated with the protein’s “walking-like” movement. Also, they believe these physical characteristics of microtubules may contribute to their functions in regulating many cellular processes.

“This work offers a technical advantage for a systematic study of the correlation between the deformation of MTs [microtubules] and its biological functions, i.e., cargo transport, as well as an opportunity to explore the interaction of deformed MTs with MT-associated proteins such as (…) tau,” the researchers wrote.

This new technique is “expected to help explain the [underlying disease-associated mechanisms] of traumatic brain injury, which mechanically stresses cells, and neurological conditions like Huntington’s and Parkinson’s diseases, in which microtubules are known to malfunction,” said Syeda Rubaiya Nasrin, the study’s first author.

Next, the team hopes to evaluate the effects of microtubule physical deformation in kinesin-driven transport along their “tracks.”

“The more we understand this process, the closer we might get to designing new nature-inspired materials that can act in a similar way,” Kakugo said.

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7 Ways to Make Your Home Safer

There are several things you can do to improve your daily routine while living with Parkinson’s. Many of these changes include small adjustments and renovations to your home, which should be your safe place now more than ever.

To help you with all these overwhelming changes, we’ve put together a list of tips based on suggestions from the Michael J. Fox Foundation. These tips will help you improve your life and safety while living and coping with Parkinson’s symptoms.

1. Don’t change all at once: It’s important that you don’t change the whole scene all at the same time; do it at a slow pace and start by making small changes.

Remove potential obstacles that could be dangerous for someone who has a hard time walking and balancing on their own. If you have big, fluffy rugs that could become a tripping hazard, consider moving them out of main rooms or walkways. Don’t forget to always leave space in between pieces of furniture, so that your loved one can walk freely and safely around the perimeter.

2. Improve the lighting in your household: Some people may not like having a lot of light around them, but having a well-lit house can be very beneficial for people living with Parkinson’s disease.

It makes navigating each room easier and helps avoid undesired bumps and stumbles. If you can, install touch lights and lights that are sensitive to movement and sound.

3. Give your bathroom a makeover: Make sure you have a non-slip mat in the shower or bath tub.

If you can afford to upgrade your toilet, an elevated toilet seat is something several patients’ agree makes their lives a little bit easier. The extra elevation can make it easier to stand back up. Also install safety rails to help patients get up.

4. Switch your chairs to some that might be easier to get out of: Adjustable recliners or chairs with straight backs, firm seats and arm rests are the perfect choice.

Firm cushions can add height and help with standing up, as well.

5. Plan on installing railings along walls and hallways: Those living with Parkinson’s disease may have trouble walking or even just keeping their balance. To help with the mobility of patients, install railings and supports along the walls and hallways of the house.

If you can afford these home improvements, invest in them. They can be extremely helpful with improving balance and preventing falls.

6. Plan on making more significant renovations: Even though it might be expensive, if you can afford to, try and adapt your house as much as possible.

Building ramps, stair lifts and wider doorways can make an enormous difference to someone living with Parkinson’s.

7. Don’t forget to invest in comfort: Rest is very important and one can only rest well if they feel comfortable. Make sure your bedroom is the most comfortable room in the house; invest in your mattress, bedding, window treatments.

 

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 other 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.

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Stopping the Spread of Loneliness

shelter in place, loneliness

Many symptoms are representative of Parkinson’s disease, the more widely known being external tremors and an unusual gait — or “walking funny,” as some might say. There is one other less visible symptom that can be connected to having the disease: loneliness.

Loneliness can be a shortcut to depression. What makes depression more volatile is to mix it with something like COVID-19. That can be a destructive combination, to say the least.

Quarantine, isolation, and social distance strategies have been used to contain COVID-19. For many, isolation is known as loneliness and loneliness for a person with Parkinson’s is an especially tough struggle.

Loneliness causes a feeling of emptiness, of being alone. Lonely people often yearn for human contact. Fulfilling human contact is somewhat hard to come by when met with an elbow bump, a face mask, a slight bow, or another means by which we greet one another or express farewells during this unsettling time.

The person living with Parkinson’s already feels distanced from others. They can feel ostracized and ashamed. They opt to stay inside because of symptoms and side effects like tremors, cognitive struggles, or speech problems. Staying inside can add fuel to the fire of loneliness and create a deeper pit in which they sit, engulfed by and surrounded in darkness. While some people take isolation as an opportunity to slow down, others fear the worst while sitting alone in their homes, dwelling on the negativity. Focusing on the what-ifs can trigger worsening Parkinson’s symptoms.

Instead of succumbing to the what-ifs, fill your mind with positivity. Begin by taking a break from social media, even if only for a day during this crazy time. Eat well, keep up your exercise regiment as much as able, get plenty of sleep, and don’t stop talking with other people, even if it is just a message here and there or a video chat.

What we allow ourselves to become depends on the choices we make. So, get out of the dark and get out into the sunshine for a walk. Turn off the television for an hour and listen to the birds sing. Read an inspiring book and share what you’ve learned with someone over the phone.

Let’s stop the spread of loneliness.

***

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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Chia Seed Extract May Lower Inflammation in Brain, Study Finds

chia seeds and inflammation

Compounds extracted from chia seeds could lower the inflammatory activity of brain immune cells, a study suggests.

Although additional research is needed, these findings could have implications for patients with neurodegenerative diseases such as Parkinson’s.

The study, “Neuroprotective effect from Salvia hispanica peptide fractions on pro‐inflammatory modulation of HMC3 microglial cells,” was published in the Journal of Food Biochemistry.

Microglia are a type of brain cell that play important roles in nervous system immunity. While these cells are crucial for protecting the brain from infectious invaders, once over-activated, they can also help drive inflammation in the brain. This neuroinflammation is believed to contribute to numerous neurological conditions, including Parkinson’s disease.

Chia (Salvia hispanica) is a plant species native to Central America. The consumption of chia seeds has increased over the years because they are high in mega-3 fatty acids and dietary fiber.

“A byproduct during the production of chia oils is the protein portion, which is a promising source of bioactive peptides [small proteins], with application in the prevention and treatment of chronic metabolic diseases,” the researchers wrote in the study.

In fact, some studies have suggested that compounds in chia seeds could lower inflammation.

To examine this, the researchers investigated the effect of proteins extracted from chia seeds on microglia. Specifically, they used the HMC3 cell line. This is a line of microglia that have been immortalized (engineered to divide indefinitely), which makes the cells easier to study in dishes in a lab.

The cells were treated with various fractions of chia seed extract. Essentially, the researchers isolated proteins from chia seeds, then divided the proteins based on size (in kilodaltons, or kDa). One fraction held all peptides under 1 kDa, one included those between 1 and 3 kDa, and one had peptides between 3 and 5 kDa.

None of the chia peptide fractions significantly decreased cell viability — that is, they weren’t toxic to the HMC3 cells. The researchers then tested how pre-treatment with the fractions affected how the cells responded to various stresses.

First, they treated the cells with tert-Butyl hydroperoxide (TBHP), an oxidative chemical that damages many cell structures. In cells with no pre-treatment, cell viability (the percent of living cells) was lowered to about 40%. Pre-treatment with all of the chia fractions significantly reduced the number of cells that died.

According to the researchers, “no peptide fraction … reported a cytotoxicity of less than 80%,” establishing them as safe for biological studies, since a given treatment with a viability of 80% or above is generally considered non-toxic.

TBHP treatment prompted the HMC3 cells to produce reactive oxygen species (ROS). These are unstable, highly reactive molecules that microglia make to help fight off bacteria, though they can also be highly damaging to surrounding neurons in the context of the brain.

Pre-treatment for 48 hours with any of the chia peptide fractions significantly lowered TBHP-induced ROS production. The most effective in this regard was the 1-3 kDa fraction, which returned ROS levels to nearly what they were without TBHP treatment.

Because microglia become activated in response to infection, the researchers also treated the HMC3 cells with a bacterial molecule called lipopolysaccharide (LPS) that activates them.

In response to LPS treatment, the HMC3 cells produced increased levels of ROS, as well as other pro-inflammatory molecules, including nitric oxide, tumor necrosis factor alpha, and various interleukins.

Pre-treatment with the chia protein fractions significantly decreased all LPS-induced inflammatory processes. The greatest reductions across all of these inflammatory markers were seen after pre-treatment with the 1-3 kDa fraction.

This study supports the anti-inflammatory action of proteins in chia seeds, particularly peptides in the 1-3 kDa fraction. This fraction, “is an important study target for future research on the neuroprotective effect,” the researchers wrote.

Future investigations will be needed to understand exactly which protein(s) in this fraction are responsible for the observed effect and how they work.

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Dopamine Infused Directly to Brain Eased Symptoms in Monkeys

dopamine infusion

An oxygen-free (anaerobic) formulation of dopamine infused directly into the brain of monkeys with induced Parkinson’s safely improved both their motor and cognitive symptoms, according to a new study.

These findings support a proof-of-concept clinical trial of this treatment approach, adapted to people with the disease.

The study, “Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson’s disease,” was published in the journal Neurobiology of Disease.

The hallmark of Parkinson’s disease is the loss of dopamine-producing neurons in the substantia nigra, a brain region that controls movement and balance.

Dopamine supplementation as a treatment strategy is not possible, because it cannot cross the digestive mucosa and the blood-brain barrier. As such, oral administration of dopamine’s precursor levodopa is a treatment option, because L-dopa can cross that barrier.

Of note, the blood-brain barrier is a semipermeable membrane that protects the brain against the external environment, including threats like viruses carried on circulating blood. It can also be a major barrier to delivering medications that need to reach the brain and central nervous system.

Drawbacks to levodopa, however, are known: it does not last long, it has limited and variable absorption into cells, and it requires the action of an enzyme in the brain, converting L-dopa into dopamine, that declines with disease progression. 

Continuous administration of dopamine directly to the brain could prevent swings in the levodopa levels between doses, better matching normal biological processes. 

In animal models, the direct infusion of high doses of dopamine into the brain ventricles (four interconnected cavities within the brain) increased dopamine levels and improved motor function. The same technique was applied independently to two Parkinson’s patients using low-dose infusions, and also eased motor handicaps.

But dopamine can be oxidized when exposed to oxygen, which can both diminish therapy response and cause toxic side effects. 

Scientists with the University of Lille in France formulated a solution of dopamine — called A-dopamine — in a device with nitrogen gas while maintaining a minimum level of oxygen — less than 1% — to avoid oxidation (an anaerobic formulation). 

A-dopamine was continuously infused into non-human primates (macaques) close to the striatum, the region of the brain that receives dopamine from the substantia nigra.

These primates had been given a chemical called MPTP that destroys dopamine-producing neurons and mimics Parkinson’s symptoms. 

The catheter used to administer A-dopamine to the brain was implanted surgically under anesthetic and time was allowed for recovery. 

Researchers conducted separate experiments to measure the effects of low and high A-dopamine doses, a long-term infusion, and infusion of anaerobic L-dopa (A-L-dopa) and a similar molecule called A-ME-L-dopa.

A low A-dopamine dose, that matched the dose given previously to the two Parkinson’s patients, showed a good safety profile with no adverse events but did not lessened motor symptoms. An increase in the low dose over time also failed to show improvement. 

An initial high dose of A-dopamine, followed by an increasing dose over time, showed an improvement in both motor skills and cognitive function. Some monkeys were able to tolerate a very high dose without obvious side effects for up to 10 days. 

An A-dopamine infusion was done over the course of 60 days to define the therapeutic index — a comparison of the amount of dopamine needed to achieve a therapeutic effect to the amount that causes toxicity. 

An initial dose was given that showed motor and cognitive improvement, and increased over 60 days. Over this time, efficacy was maintained without an adverse event and no evidence of a lesser response to the therapy. 

Use of A-L-dopa and A-ME-L-dopa showed no substantial improvements in motor function. 

Post-mortem analysis found no abnormalities in monkeys’ heart, lungs, kidneys, or liver, regardless of the dose given. A microscopic assessment of whole brains showed no signs of neuronal loss or inflammation. 

“To conclude, the study was set to test the safety limits of a new therapeutic strategy of A-dopamine in order to anticipate the constraints of feasibility and safety in humans,” the researchers wrote.

“These include slow titration dose limits [gradual dose increase over time] that do not result in dyskinesia,” they added.

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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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