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Coronavirus and treatment for Parkinson’s

July 1, 2020 Awareness, Education, Life

What do we know about the relationship between coronavirus and Parkinson’s?

Joaquim Ferreira, neurologist, Portugal: There is still scarce information regarding many clinical aspects of this infection and its potential short- and long-term complications. We know that the majority of people with Parkinson’s are elderly, and age is a risk factor for the more severe forms of Covid-19. On the other hand, we recognise that patients might be affected indirectly by the lockdown physical restrictions, the psychological impacts and the compromised healthcare.

Miriam Parry, senior Parkinson’s Disease nurse specialist, UK: We do know that people with Parkinson’s are more prone to pneumonia and infections. Parkinson’s can cause respiratory issues for some people – if you have lived with Parkinson’s for a long time, you are more likely to have breathing and respiratory difficulties. This is why people with Parkinson’s are described as being at greater risk of severe illness if they get coronavirus. As such, their caregivers need to take precautions.

Rick Helmich, neurologist, the Netherlands: We know very little, but knowledge is rapidly increasing. Parkinson patients who develop Covid-19 seem to suffer from the same symptoms as other people and to approximately the same degree. However, patients who get sick from coronavirus may suffer from a worsening of their Parkinson symptoms. This is a well-known finding that also occurs when Parkinson patients develop other non-coronavirus infections. The current pandemic also has effects on Parkinson patients that are not so visible, such as increased stress levels and less physical exercise due to the social isolation measures.

How has the coronavirus crisis affected how you and your colleagues carry out your roles, and interact with patients?

Emma Edwards, Parkinson’s specialist nurse, UK: The coronavirus crisis has meant that our face-to-face appointments were stopped with immediate effect. We knew that telehealth technology was due to be implemented in our work area over a planned period of about seven months. When the crisis happened, that roll out took about seven days! In May, I started to see some patients again in their homes. Those allocated for this type of review were people that were running into problems with their Parkinson’s that we couldn’t resolve over the phone or via the virtual clinics.

Helmich: For a few months, I have been working mainly from home, and all my contacts with patients were through video-conferencing and by phone. It took some time to adjust, but I am actually very happy with how it turned out now. It is amazing how much you can see and discuss via a good video connection. On the other hand, more subtle things are better seen in real life, so I am happy that we are allowed to see more patients at our hospital in the next weeks.

Ferreira: The major implications of visit cancellations for patients that were hospitalised, or doing rehabilitation programmes as inpatients, should also be mentioned. This situation forced all health professionals to be involved in facilitating communication and minimising the consequences of not seeing family and friends.

How has the coronavirus crisis affected access to treatment for people with Parkinson’s?

Helmich: This is a topic that many patients are worried about: access to health care. Many Parkinson patients are treated by a whole team of professionals, including a neurologist, a Parkinson nurse, a physical therapist, and sometimes a psychiatrist, speech therapist, or occupational therapist. Access to these health care providers has been restricted by the isolation and social distancing measures. Not all people have good access to internet, and not all treatments can be given through video conferencing. So, I believe that the care for Parkinson patients has certainly suffered from the coronavirus pandemic.

Ferreira: The coronavirus pandemic severely affected the follow-up of people with Parkinson’s disease. The regular consultations were cancelled, making it more difficult or impossible the access to physicians and other health professionals. Pharmacological prescriptions were more difficult to obtain. Sessions of physiotherapy, speech therapy and other therapeutic interventions were cancelled, and physical activity and exercise was highly reduced for many patients. Many deep brain surgeries were deferred, and patients included in research studies and clinical trials saw their consultations being moved to phone contacts or videocalls.

Edwards: Face-to-face sessions such as our Parkinson’s exercise groups, have also been postponed but luckily the staff that ran those groups produced a brilliant DVD of the common exercises they undertook in class. These were distributed out to homes at the beginning of the outbreak and were warmly received by many people with Parkinson’s.

What actions should people with Parkinson’s take at the moment?

Ferreira: The most important recommendation for people with Parkinson’s and their close friends and family is to follow the general public health recommendations that apply to the elderly population. At the current stage of the pandemic, when governments are lowering the confinement measures, the most important message is to alert everybody that this pandemic is not over and the general measures that are being recommended for the general population should be followed strictly in the next months.

Parry: When you leave the house, for any reason, you should avoid busy spaces and keep a distance of around two meters from people you do not live with, while wearing a face mask. You should also continue to follow good hygiene practices, including handwashing, not sharing crockery and cutlery, wiping down surfaces, and not entering other people’s homes. You can ask your local pharmacist to deliver medication to your home address or ask family members or friends to help.

Edwards: I would really advocate for people, if they can, to exercise. It has proven benefits not just for physical health in Parkinson’s but for promoting good mental health. I’ve been really impressed with the exercise classes available online to people with Parkinson’s whilst the group classes have been postponed.

What should people with Parkinson’s do if they have hospital and GP appointments during this period?

Parry: If you’re in the UK, please call the GP’s practice and ask for further information and direction pending the reasons for the appointments. The GP practice will be able to advice you whether it is urgent or offer you a phone or video consultation. Routine hospital appointments have now changed to virtual clinics using phone and video link consultations.

Ferreira: During this crisis, health institutions in Portugal have changed their procedures in order to implement safety circuits for those who will need to attend their routine visits or need to go to the hospital in an urgent situation.

Edwards: I would imagine as we come out of the lockdown, clinical outpatient appointments in the UK will look very different to what people are used to. Certainly, in our area, personal protective equipment will be worn by staff and visiting patients are encouraged to wear face masks. If people with Parkinson’s need advice on managing their condition and are not sure when their next review will be, they should contact their local Parkinson’s service and ask for help. Be proactive!

How can people with Parkinson’s look after their mental wellbeing?

Ferreira: All health professionals that follow patients with Parkinson’s recognise that this has been a difficult time, not just for the patients but for all around them. The most important thing for the community is strengthening support and continuing care, keeping the links between patients, their families, caregivers and health professionals.

Helmich: This is different for everyone. Some of my patients even like certain aspects about the current situation, such as a reduction in workload, deadlines, or social obligations. In general, I think it is good to try to stay in touch with your loved ones. Find a new structure for your day that works for you and develop new exercise routines. There are many online events available for Parkinson patients, such as online dancing or singing classes. So, it might be worthwhile to have a look online to see what is out there or ask someone to help you do so. Don’t be afraid to speak about your worries or fears.

Edwards: Being able to connect with others has been a challenge during the lockdown, but as restrictions are eased, I really encourage people to meet others again, albeit in a safe way. For many during coronavirus, that has been via online forums like Zoom or having a socially distanced chat over the garden fence to family and friends. I’m also a massive advocate for mindfulness. It’s a way to be fully present, having an awareness of where we are and what we are doing and feeling, without being overwhelmed by what’s going on around us.

Parry: It is normal and expected to feel a range of emotions during this pandemic including fear, increased anxiety, anger and sadness. There is guidance on looking after mental wellbeing during this time from mental health charity Mind, as well as support on the Parkinson’s UK and Parkinson’s Foundation websites.

What is the advice for those living with a vulnerable person?

Parry: Visitors and people who provide care for those with Parkinson’s should protect them and reduce their risk by staying at home as much as possible. They should work from home, if they can, and limit contact with other people.

Ferreira: It is a good principle to assume that everybody who we are in contact with may be infected, even if they don’t present any suspected symptoms. No one can be sure that they are not infected or do not have a risk of infecting others. This is even more relevant for health professionals, caregivers, family members and those that have close contact with vulnerable populations.

Edwards: I knew from the moment I re-started my home visits that I had not fully been picking up the impact that the coronavirus and subsequent lockdown has had on care partners. It was harder to pick up the subtleties of care partner stress on the telephone or even on the telemedicine appointments. I’m certainly more mindful that we need to continue to address this area as digital medicine becomes more accessible for people with Parkinson’s and potentially less contact is had with partners or carers during these interactions.

Helmich: Be aware that vulnerable people are sometimes less able to cope with new or threatening situations. Be patient if your loved ones are anxious, worried, or experience a worsening of their symptoms.

Do you think the coronavirus crisis will have a long-term impact on people with Parkinson’s?

Ferreira: The limitations induced by the Covid-19 pandemic are here to stay and we need to be prepared to adapt for the next months.

Parry: The Covid-19 pandemic could potentially have a long-term impact on the physical and mental health of people with Parkinson’s, and many studies are currently taking place looking at the effect of this pandemic.

Edwards: I think lots of clinicians were hoping that we could eventually use technology in how we review our patients, and this crisis has pushed that to the forefront. I like being able to offer our patients a wider range of ways that they can access information and advice – from virtual clinics to wearing digital technology – but also being able to offer more traditional face-to-face home visits if needed.

Need to know

Emma Edwards: I’m a mental health nurse in the UK – however for the last 10 years I’ve worked as a Parkinson’s specialist nurse in the community. I had worked in a large rural area for many years, but more recently have moved to a post in a city. Due to the lockdown on clinical work environments, my dining room is currently my office!

Joaquim Ferreira: I am a neurologist mainly working in the field of Parkinson disease for the past 25 years. I am also professor of neurology and clinical pharmacology at the University of Lisbon, Portugal. More recently, I founded CNS, Campus Neurológico Sénior, which is a movement disorders centre focused on the multidisciplinary care and rehabilitation for Parkinson’s patients.

Miriam Parry: I work as senior Parkinson’s Disease nurse specialist (PDNS) at King’s College Hospital NHS, Parkinson’s Foundation Centre of Excellence in London, UK. My role is to provide a holistic approach to care and seamless service to people with Parkinson’s and their family and carers, providing ongoing support, educating and empowering patients to become experts in their condition. Above all, I aim to engage people with Parkinson’s with King’s rich research portfolio on offer, as without it we would not have the knowledge and the care pathways that we do.

Rick Helmich: I live in Nijmegen, the Netherlands and work as a neurologist and neuroscientist at the Radboud University Medical Centre. I specialise in Parkinson’s, and in my research at the Donders Institute, I use brain imaging to help understand symptoms and phenomena I see in my patients. Lately I’m intrigued by the effects of stress on patients with Parkinson’s, both the causes and the consequences.

Information from Parkinsonlife.eu.

Phlegm-busting Drug Ambroxol Shows Promise in Parkinson’s

March 1, 2020 Research

One of the major genetic risk factors believed to contribute to the development of Parkinson’s disease (PD) is having a mutation in the gene called GBA1 (glucocerebrosidase). Unable to do its job correctly, this damaged gene leads to the build-up of unhealthy, misfolded clumps of alpha-synuclein in the brain. These clumps, called Lewy bodies, impact dopamine production and are the hallmark of PD. What if there was a way to prevent the build-up of Lewy bodies in the first place?

A 2020 study published in JAMA Neurology, titled, “Ambroxol for the Treatment of Patients with Parkinson Disease with and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial” (Mullin et al., 2020), investigated whether an over-the-counter cough syrup, called Ambroxol, may be the key. The cough syrup, specifically, an expectorant, is used to break up phlegm.

This 186-day clinical trial of 17 people with PD ― with and without the GBA1 mutation ― involved participants taking progressively increasing doses of Ambroxol in the form of an oral tablet. Baseline measurements included physical and neurological examination, an electrocardiogram, blood sampling and spinal fluid examination obtained by lumbar puncture. Three additional in-person clinical visits were held on day 11, day 93, and day 186. Of note, at baseline, Ambroxol was undetectable in both the blood serum and spinal fluid. All study participants continued their normal L-dopa therapy throughout the trial.

Results
In study participants both with and without the gene mutation:

Ambroxol successfully crossed the blood-brain barrier.
Ambroxol was safe and well-tolerated at the administered dose.
Ambroxol successfully bound to the mutated genes’ protein, which physically helped the protein function properly.
Healthy levels of alpha-synuclein increased in the spinal fluid.

What Does This Mean?
This study showed that Ambroxol is safe to use as a treatment in people with Parkinson’s. Ambroxol may slow the progression of Parkinson’s disease. How? Taking Ambroxol as a medication can prevent the negative effects of the GBA mutation ― including possibly reducing the formation Lewy bodies at the source. Ambroxol shows promise, and warrants further investigation ― including conducting larger, placebo-controlled trials.

Of note, while Ambroxol has been used as a safe and effective over the counter expectorant for adults and children in more than 50 countries for 30-plus years, the administered dose in this trial was approximately 10 times the specified dosage. Additionally, Ambroxol is currently not approved for prescription or over the counter use by the U.S. Food and Drug Administration (FDA) for any indication, at this time.

Article from Parkinson.org.

Why some Parkinson’s patients develop harmful addictive behaviours

January 1, 2020 Education, Life, Research

A QIMR Berghofer study has discovered how the medications given to people with Parkinson’s disease cause some patients to develop addictive behaviours such as problem gambling, binge eating, hypersexuality and excessive shopping.

Medicines that increase dopamine levels in the brain are the cornerstone of treatment for symptoms of Parkinson’s disease. This neurodegenerative disorder damages nerve cells that produce dopamine in the deep structures of the brain.

QIMR Berghofer Medical Research Institute lead researcher and St Andrews Hospital neuropsychiatrist Dr. Phil Mosley said while dopamine replacement therapy was effective for most people diagnosed with Parkinson’s disease, about one in six people treated with the medication developed impulse-control behaviours, such as gambling.

“We found people who developed these addictive behaviours differed in the way their brain structure interacted with dopamine-containing medication, which gave rise to the impulsive behaviour,” Dr. Mosley said.

“None of these people had a history of addictive behaviours before diagnosis and only developed them after they began treatment with dopamine-replacement medications.

“There is currently no way of predicting which individuals are at risk of these terrible side-effects.”

More than 80,000 Australians are living with Parkinson’s disease, with most people diagnosed after the age of 65, although about 20 percent are of working age, according to Parkinson’s Australia.

Dr. Mosley said the study recruited 57 people with Parkinson’s disease from St Andrews War Memorial Hospital in Brisbane, in collaboration with neurologist Professor Peter Silburn.

“We used an advanced method of brain imaging, called diffusion MRI, to reconstruct the connections between different regions of the brain, akin to developing an individualised brain “wiring” diagram for each person in the study,” Dr. Mosley said.

“We asked our participants to gamble in a virtual casino, which gave us a readout of impulsive and risk-taking behaviour in real time.

“By combining data from brain imaging, behaviour in the virtual casino, and the effect of dopamine-replacement medication, we were able to identify people who were susceptible to impulse-control behaviours.

“More broadly, we found a clear link between the strength of the connections in the brain, within circuits that we think are crucial for making decisions and suppressing impulses, and impulsive behaviour, even in people without clinically-significant impulse-control behaviours.”

Dr. Mosley said the study findings indicated that brain imaging and computer-based testing could be used in the future to determine which individuals were at risk of developing these harmful behaviours when treated with dopamine-replacement drugs.

“These disorders are often a second blow to people and their families living with Parkinson’s disease. Some individuals suffer financial problems or relationship breakdowns because of these harmful behaviours,” he said.

“We could offer targeted education to at-risk individuals, or adapt their treatment regimen to minimise the potential harms from these therapies.”

The study’s co-author Professor Michael Breakspear said the findings could also have implications for other psychiatric conditions that are marked by impulsivity, such as ADHD, alcohol and drug addiction.

Article from MedicalXpress.

Can We Repair the Brain?

March 1, 2019 Research

Cell replacement may play an increasing role in alleviating the motor symptoms of Parkinson’s disease (PD) in future. Writing in an open access special supplement to the Journal of Parkinson’s Disease, experts describe how newly developed stem cell technologies could be used to treat the disease and discuss the great promise, as well as the significant challenges, of stem cell treatment.

The most common PD treatment today is based on enhancing the activity of the nigro-striatal pathway in the brain with dopamine-modulating therapies, thereby increasing striatal dopamine levels and improving motor impairment associated with the disease. However, this treatment has significant long-term limitations and side effects. Stem cell technologies show promise for treating PD and may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.

“We are in desperate need of a better way of helping people with PD. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” explained co-authors Claire Henchcliffe, MD, DPhil, from the Department of Neurology, Weill Cornell Medical College, and Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; and Malin Parmar, PhD, from the Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden. “If successful, using stem cells as a source of transplantable dopamine-producing nerve cells could revolutionize care of the PD patient in the future. A single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications.”

The authors have analyzed how newly developed stem cell technologies could be used to treat PD, and how clinical researchers are moving very quickly to translate this technology to early clinical trials. In the past, most transplantation studies in PD used human cells from aborted embryos. While these transplants could survive and function for many years, there were scientific and ethical issues: fetal cells are in limited supply, and they are highly variable and hard to quality control. Only some patients benefited, and some developed side effects from the grafts, such as uncontrollable movements called dyskinesias.

Recent strides in stem cell technology mean that quality, consistency, activity, and safety can be assured, and that it is possible to grow essentially unlimited amounts of dopamine-producing nerve cells in the laboratory for transplantation. This approach is now rapidly moving into initial testing in clinical trials. The choice of starting material has also expanded with the availability of multiple human embryonic stem cell lines, as well as the possibilities for producing induced pluripotent cells, or neuronal cells from a patient’s own blood or skin cells. The first systematic clinical transplantation trials using pluripotent stem cells as donor tissue were initiated in Japan in 2018.

“We are moving into a very exciting era for stem cell therapy,” commented Dr. Parmar. “The first-generation cells are now being trialed and new advances in stem cell biology and genetic engineering promise even better cells and therapies in the future. There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.”

“With several research groups, including our own centers, quickly moving towards testing of stem cell therapies for PD, there is not only a drive to improve what is possible for our patients, but also a realization that our best chance is harmonizing efforts across groups,” added Dr. Henchcliffe. “Right now, we are just talking about the first logical step in using cell therapies in PD. Importantly, it could open the way to being able to engineer the cells to provide superior treatment, possibly using different types of cells to treat different symptoms of PD like movement problems and memory loss.”

“This approach to brain repair in PD definitely has major potential, and the coming two decades might also see even greater advances in stem cell engineering with stem cells that are tailor-made for specific patients or patient groups,” commented Patrik Brundin, MD, PhD, Van Andel Research Institute, Grand Rapids, MI, USA, and J. William Langston, MD, Stanford Udall Center, Department of Pathology, Stanford University, Palo Alto, CA, USA, Editors-in-Chief of the Journal of Parkinson’s Disease. “At the same time, there are several biological, practical, and commercial hurdles that need circumventing for this to become a routine therapy.”

Article from IOS Press.

How gut bacteria affect PD treatment

February 1, 2019 Education, Research

Patients with Parkinson’s disease are treated with levodopa, which is converted into dopamine, a neurotransmitter in the brain. In a study published on 18 January in the journal Nature Communications, scientists from the University of Groningen show that gut bacteria can metabolize levodopa into dopamine. As dopamine cannot cross the blood-brain barrier, this makes the medication less effective – even in the presence of inhibitors that should prevent the conversion of levodopa.

‘It is well established that gut bacteria can affect the brain’, explains Assistant Professor in Microbiology Sahar El Aidy, lead investigator of the study. ‘There is a continuous chemical dialogue between gut bacteria and the brain, the so called gut-brain axis.’ El Aidy and her team investigated the ability of gut microbiota to influence the bioavailability of levodopa, a drug used in the treatment of Parkinson’s disease.

The drug is usually taken orally, and the levodopa is absorbed in the small intestine and then transported through the blood stream to the brain. However, decarboxylase enzymes can convert levodopa into dopamine. In contrast to levodopa, dopamine cannot cross the blood-brain barrier, so patients are also given a decarboxylase inhibitor. ‘But the levels of levodopa that will reach the brain vary strongly among Parkinson’s disease patients, and we questioned whether gut microbiota were playing a role in this difference’, says El Aidy.

In bacterial samples from the small intestines of rats, Aidy’s PhD student Sebastiaan van Kessel found activity of the bacterial tyrosine decarboxylase enzyme, which normally converts tyrosine into tyramine, but was found to also convert levodopa into dopamine. ‘We then determined that the source of this decarboxylase was Enterococcus bacteria.’ The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of the amino acid tyrosine, the main substrate of the bacterial tyrosine decarboxylase enzyme.

As Parkinson’s patients are given a decarboxylase inhibitor, the next step was to test the effect of several human decarboxylase inhibitors on the bacterial enzyme. ‘It turned out that, for example, the inhibitor Carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase’, says El Aidy.

These findings led the team to the hypothesis that the presence of bacterial tyrosine decarboxylase would reduce the bioavailability of levodopa in Parkinson’s patients. To confirm this, they tested stool samples from patients who were on a normal or high dose of levodopa. The relative abundance of the bacterial gene encoding for tyrosine decarboxylase correlated with the need for a higher dose of the drug. ‘As these were stool samples, and the levodopa is absorbed in the small intestine, this was not yet solid proof. However, we confirmed our observation by showing that the higher abundance of bacterial enzyme in the small intestines of rats reduced levels of levodopa in the blood stream’, explains El Aidy.

Another important finding in the study is the positive correlation between disease duration and levels of bacterial tyrosine decarboxylase. Some Parkinson’s disease patients develop an overgrowth of small intestinal bacteria including Enterococci due to frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms associated with the disease. Altogether, these factors result in a vicious circle leading to an increased levodopa/decarboxylase inhibitor dosage requirement in a subset of patients.

El Aidy concludes that the presence of the bacterial tyrosine decarboxylase enzyme can explain why some patients need more frequent dosages of levodopa to treat their motor fluctuations. ‘This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment.’

Article from University of Groningen.

Protein might become candidate for drug development

October 1, 2018 Research

Researchers have modified the protein Nurr1 so that it can enter cells from the outside. Nurr1 deficiency may be one of the causes of Parkinson’s disease. Even though Nurr1 has been discussed as a potential target for the treatment of Parkinson’s disease, it is unusable in its normal form, as it cannot penetrate cells. A team from Ruhr-Universität Bochum and the US-American National Institutes of Health (NIH) deployed a bacterial import signal in order to deliver Nurr1 into cells. The researchers also demonstrated that the modified protein may have a positive effect on the survival of dopamine-producing nerve cells. They describe their results in the journal Molecular Neurobiology from 18 August 2018.

For the study, Dennis Paliga, Fabian Raudzus, Dr. Sebastian Neumann, and Professor Rolf Heumann from the work group Molecular Neurobiochemistry collaborated with Professor Stephen Leppla from the NIH.

Bacterial protein building block as import signal

Nurr1 is a transcription factor; this means the protein binds to DNA in the nucleus and regulates which genes get read and translated into proteins. Thereby, it controls many properties in cells that produce the neurotransmitter dopamine and that are affected in Parkinson’s disease. Dopamine withdrawal in certain brain regions is responsible for the slowness of movement that is associated with the disease.

Since the Nurr1 protein does not usually have the capability of entering cells and, therefore, cannot take effect in the nucleus, the researchers were searching for ways of furnishing the protein with an import signal. They found what they were looking for in bacteria and attached a fragment of a protein derived from Bacillus anthracis to Nurr1. In the bacterium, that protein ensures that the pathogen can infiltrate animal cells. “The fragment of bacterial protein that we used does not trigger diseases; it merely contains the command to transport something into the cell,” explains Rolf Heumann. Once the modified protein has been taken up by the cell, the bacterial protein building block is detached, and the Nurr1 protein can reach its target genes by using the cell’s endogenous nuclear import machinery.

Nurr1 has a positive effect on the key enzyme of dopamine synthesis

The researchers measured the effect of functional delivery of Nurr1 by monitoring the production of the enzyme tyrosine hydroxylase. That enzyme is a precursor in dopamine synthesis – a process that is disrupted in Parkinson’s patients. Cultured cells that were treated with modified Nurr1 produced more tyrosine hydroxylase than untreated cells. At the same time, they produced less Nur77 protein, which is involved in the regulation of programmed cell death.

Protein protects from the effects of neurotoxin

Moreover, the researchers tested the effect of modified Nurr1 on cultured cells that they treated with the neurotoxin 6-hydroxydopamine. It causes the dopamine-producing cells to die and is thus a model for Parkinson’s disease. Nurr1 inhibited the neurotoxin-induced degeneration of cells.

“We hope we can thus pave the way for new Parkinson’s therapy,” concludes Sebastian Neumann. “Still, our Nurr1 fusion protein can merely kick off the development of a new approach. Many steps still remain to be taken in order to clarify if the modified protein specifically reaches the right cells in the brain and how it could be applied.”

Article from Ruhr University Bochum.

Could caffeine in the blood help diagnose Parkinson’s?

March 1, 2018 Life, Research

Blood caffeine levels could be promising diagnostic biomarkers for early-stage Parkinson’s, Japanese researchers reported in the journal ‘Neurology’ earlier this month.

The study found that people with Parkinson’s had lower levels of caffeine and caffeine metabolites in their blood than people without the disease, at the same consumption rate.

Caffeine concentrations also were decreased in Parkinson’s patients with motor fluctuations than in those without Parkinson’s. However, patients in more severe disease stages did not have lower caffeine levels.

The study’s authors, Dr David Munoz, University of Toronto, and Dr Shinsuke Fujioka, Fukuoka University, suggested that the “decrease in caffeine metabolites occurs from the earliest stages of Parkinson’s.”

They added: “If a future study were to demonstrate similar decreases in caffeine in untreated patients with Parkinson’s […] the implications of the current study would take enormous importance.”

Article from Parkinson’s Life.

LRRK2 Drug Trial Shares Promising Results

February 1, 2018 Education, Research

In December, Denali Therapeutics announced positive results from its first-in-human LRRK2 inhibitor clinical trial. The experimental treatment is safe, and it lowers LRRK2 protein activity in humans’ body cells. This is a meaningful milestone in the clinical development of a drug with potential to slow or stop Parkinson’s progression (something no currently available treatment can do).

Denali also shared it is testing a second compound in a separate Phase I trial in control volunteers. Following completion of both trials, one of the two compounds will move into studies in people with Parkinson’s carrying a LRRK2 mutation.

In a press release, the company announced its first trial showed greater than 90 percent inhibition of LRRK2 activity at peak drug levels. This is a critical early step in testing a drug — does it do what you want it to do in the cell? Denali used two tests to measure inhibition, including one based on a finding from a Michael J. Fox Foundation-organized consortium linking LRRK2 to another protein.

“Mutations in LRRK2 are a major risk factor for Parkinson’s disease. Targeting this degenogene represents a promising approach to develop disease-modifying medicines,” said Ryan Watts, PhD, Denali CEO.

Article from Michael J. Fox Foundation for Parkinson’s Research.

Duopa device among newer treatments for Parkinson’s disease

January 1, 2018 Awareness, Life, Research

Until August, Kern Jackson avoided going out in public.

Parkinson’s disease had progressed far enough that the levadopa pills he’d taken since 2008 weren’t as reliable to ease the symptom of his muscles freezing up. In the past two years, he had to take the medicine more frequently as it wore off quickly, leaving him unable to move.

“I was taking pills every two hours, and during the night,” said Jackson, 70, a retired physician who lives in Medical Lake. “It would take 20 to 45 minutes to be effective, then I’d be moving normally for about an hour. It was hard to plan to do anything.”

So in August, Jackson chose to get a newer Duopa device through Dr. Jason Aldred, a neurologist at Northwest Neurological. The Spokane clinic partners with Inland Imaging, where patients go in for an outpatient procedure to make a small incision in the stomach wall and insert a tube in the small intestine.

The external Duopa device has a pump for continuous delivery via the tube of a levadopa gel, contained in a medication cartridge that patients reload once a day into the device.

According to Aldred, the Duopa device first became available in 2015 after U.S. Food & Drug Administration approval, and it’s among a couple of newer developments for Parkinson’s treatment. The clinic also is participating in two clinical research trials that are attempting to slow disease progression.

The day after his outpatient procedure, Jackson saw Aldred at Northwest Neurological to program the system’s medicine dosage. Clinic staff observed Jackson’s movements for a day during office hours to make sure the new system was syncing correctly for his ability to get around.

Jackson now wears the device in a belted pack around his waist, and he said it’s helped him be more active. He and his wife, Diana, have since traveled by airplane and walked on the Centennial Trail.

“I feel much more confident going somewhere,” Jackson said. “I just went to a men’s retreat in Idaho with my son-in-law, and things went well.”

Although estimates vary, about 1 million people in the U.S. live with the disease, according to the Parkinson’s Foundation. Symptoms include tremor, rigidity, extreme slowness of movement and impaired balance.

Levadopa, now used for more than 50 years to treat Parkinson’s, is often considered the most effective for treatment of motor symptoms.

“Levadopa is turned into dopamine in the brain and replaces dopamine,” Aldred said “That’s huge because dopamine is the natural chemical in the brain that’s low in Parkinson’s patients, so we literally have the ability to replace something that’s low to bring about remarkable improvement in movement, stiffness and tremor.

“However, it doesn’t slow the progression. It treats symptoms remarkably for years or decades. Parkinson’s progresses slowly, but it does progress, and it can cause horrible quality of life issues.”

The Duopa device is offered as a choice for some patients with moderate to advanced Parkinson’s if levadopa in a pill form becomes less reliable, Aldred said. Other patients might be candidates for deep brain stimulation, a therapy that’s been around since 1997, he said.

“As the disease advances for moderate to advanced Parkinson’s, the medicine kicks in and wears off,” said Aldred, adding that also long-term, the disease affects other nerves outside of the brain including in the stomach, so medicine is less effectively moved into the small intestine for absorption.

“We call it dose failure,” he said. “That’s actually a big problem; the medicine is sitting in the stomach and doesn’t move. With the Duopa device, the tube mechanically bypasses the stomach and goes into the small intestine, and the medicine is released physically past the stomach.”

Aldred said the Duopa device is new enough that, so far, just over 30 of its clinic patients have one.

“This is a very new treatment and largely people are slow to warm up to it,” he said, adding that some people might have a stigma about having a tube inserted, a procedure that’s sometimes associated with end-of-life issues.

The small amount of tubing that’s external is flexible, Aldred said, and it’s hidden often under clothing. It can be disconnect for up to two hours if needed.

However, Aldred said current treatments, including Duopa, only partially relieve symptoms, so the two research trials are attempting approaches that might slow or stop the disease’s progression.

Both trials are seeking to stem what is thought to damage cells in the brain that regulate behavior, cognition and movement. A main research focus is finding a way to stop or clear out Lewy bodies, which are abnormal aggregates of protein that develop inside nerve cells in Parkinson’s.

“We have some interesting, cutting-edge NIH, Michael J. Fox Foundation-affiliated clinical research trials,” Aldred said.

One is a vaccine trial using anti-bodies in an attempt that might prevent the spread of Lewy bodies in the brain. A second phase of that study started this month involving a handful of clinic patients.

The other trial will test Nilotinib, a FDA-approved medicine used in treatment for a form of leukemia, but with a fraction of the dose applied for patients with mild Parkinson’s.

“This is a medication that may enhance the clearing of Lewy Bodies from the brain that we think is destructive,” Aldred added.

“We’re trying to get to the point before it spreads,” he said. “That’s a novel way of treating Parkinson’s. These two trials if they’re proven to work, which they haven’t been yet, may be safe and effective ways to slow the disease progression or potentially halt the disease progression.”

There’s also a new device that came out this year for deep brain stimulation, Aldred said. “It was developed by St. Jude’s Medical (since acquired by Abbott). We can aim the electrical current more precisely in the brain to get better effect.”

The DBS treatment requires surgery to implant a wire with four electrodes that deliver an electrical current in the brain to regulate abnormal impulses and smooth out “on time” and “off time” experienced by patients as the impact of medication rises and falls.

The DBS treatment and the Duopa device haven’t been studied head to head on whether one is more effective than the other, Aldred said.

“If someone has moderate cognitive issues, we’d never want to do DBS,” he said.

Alternatively, he added that the Duopa device might be a choice for some patients who aren’t comfortable with DBS.

“I tell patients this is a heavy diagnosis, but there is lot we can do, and one of the things is exercise, ” said Aldred, who encourages physical therapy and regular exercise to maintain better movement and quality of life.

Article from The Spokesman-Review.

Longtime Antidepressant Could Slow Parkinson’s

November 1, 2017 Life, Research

Michigan State University scientists now have early proof that an antidepressant drug that’s been around for more than 50 years could slow the progression of Parkinson’s.

In a proof-of-concept study, published in the journal Neurobiology of Disease, the drug nortriptyline, which has been used to treat depression and nerve pain, stopped the growth of abnormal proteins that can build up in the brain and lead to the development of the disease.

“Depression is a very frequent condition associated with Parkinson’s, so we became interested in whether an antidepressant could modify how the disease progresses,” said Tim Collier, lead author of the federally funded study and a neuroscientist at MSU.

Collier and collaborator Katrina Paumier, an assistant professor of molecular medicine, began looking at previous patient data to see if individuals who were on antidepressants experienced any delay in their need to go on a standard Parkinson’s therapy called levodopa. This type of therapy increases levels of dopamine, a natural chemical in the body that sends signals to other nerve cells and can significantly decrease in cases of Parkinson’s.

The medication also treats many of the symptoms associated with the disease such as tremors and poor muscle control.

“We found that those on a certain class of antidepressant, called tricyclics, didn’t need the levodopa therapy until much later compared to those who weren’t on that type of antidepressant medication,” Collier said.

Collier then began testing rats with the tricyclic antidepressant nortriptyline and found that it indeed was able to decrease the amount of abnormal protein that can build up in the brain. This protein, known as alpha-synuclein, can cause the brain’s nerve cells to die when in a clustered state and is a hallmark sign of the disease.

To further back up his research, he enlisted the help of his colleague and co-author Lisa Lapidus, who in previous studies had already detected whether certain compounds could bind to alpha-synuclein and stop it from accumulating.

“Proteins are constantly moving and changing shape,” said Lapidus, a professor in the Department of Physics and Astronomy. “By using a test tube model, we found that by adding nortriptyline to the alpha-synuclein proteins, they began to move and change shape much faster, preventing the proteins from clumping together. The idea that this clustering effect is controlled by how fast or slow a protein reconfigures itself is typically not a standard way of thinking in research on proteins, but our work has been able to show these changes.”

Understanding how these proteins can clump together could point researchers in new directions and help them find other possible drugs that could potentially treat Parkinson’s.

“What we’ve essentially shown is that an already FDA-approved drug that’s been studied over 50 years and is relatively well tolerated could be a much simpler approach to treating the disease itself, not just the symptoms,” Collier said.

Collier is already looking for funding for the next phase of his research and hopes to lead a human clinical trial using the drug in the future.

The National Institutes of Health, as well as the Michael J. Fox and Saint Mary’s Foundations, funded the study.

Article from Michigan State University.

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Longtime Antidepressant Could Slow Parkinson’s