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Science Parkinson's

mr peabody

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Clinical trial to repurpose ketamine for Parkinson's*

By Maria Cohut | Medical News Today | 20 July 2018

The drug used to manage some of the most salient symptoms of Parkinson's disease is known to expose patients to more motor issues, as part of its side effects. Researchers suggest that ketamine could be used to neutralize those side effects.

Parkinson's disease, a motor system disorder, is characterized by tremor, limb stiffness, impaired balance, and slowness of movement, as well as impaired movement coordination.

There is currently no known cure for this disorder, so treatments focus largely on managing the symptoms.

This helps people maintain autonomy and quality of life, as much as possible.

One of the main drugs used to treat Parkinson's disease is levodopa, which can help with limb stiffness and slowness of movement. But there is a caveat: patients for whom levodopa does work begin to experience potentially debilitating side effects after a few years on the drug.

"The problem is levodopa works great for a few years — we call that the 'honeymoon' period — but then you start getting these side effects," notes Dr. Scott Sherman, a neurologist at the University of Arizona College of Medicine in Tucson.

So what happens to many patients who take levodopa? They develop dyskinesia, or involuntary and uncontrollable movements that can affect the limbs, the head, or even the entire body, to various degrees of severity.

Once an individual develops levodopa-related dyskinesia, it does not go away unless treatment with this drug is discontinued altogether — though this may mean that their symptoms will no longer be managed.

But is there anything that could counteract levodopa's side effects? Dr. Sherman and colleague Torsten Falk believe that the answer may lie with ketamine.

Ketamine's effect on dyskinesia

Dr. Sherman and Falk found the first clues about ketamine's potential in offsetting dyskinesia when they tested it as a pain-relieving drug for patients with Parkinson's.

Their trial led them to observe an unintended yet welcome effect: dyskinesia was ameliorated, or even disappeared completely for a few weeks in the case of individuals on levodopa who were also administered ketamine.

When the researchers tried to duplicate these findings in a rat model, they found that the dyskinesia-offsetting effects of ketamine held strong.

This has led them to plan a controlled clinical trial in the hopes of discovering how — or whether — ketamine might best be used in conjunction with levodopa to treat patients with Parkinson's disease.

Ketamine's best-known side effect is dissociation (also known as disassociation), in which a person feels as though they are perceiving the world from some place outside of their own bodies. This uncanny effect is also why ketamine has notoriously been misused as a "party drug."

"Disassociation is a sort of 'out-of-body' experience. When people describe it, they have told me that they feel like they are in fish bowl," explains Dr. Sherman.

Another common risk of taking ketamine is raised blood pressure. However, the scientists are strategizing to keep these possible effects in check by carefully calculating dosage.

According to Dr. Sherman, "We are going to monitor blood pressure closely to make sure it doesn't get high. And," he continues, "we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson's disease will stay well below that level."

"Ketamine has been long overlooked. Now it could prove very useful for Parkinson's patients,"
said Dr. Sherman.

*From the article here:

 
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mr peabody

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Where does Parkinson’s disease start? In the brain, the gut, or both?

Neuroscience News | Nov 7 2019

Summary: Lewy body disorders, including Parkinson’s disease and Lewy body dementia, comprise of two distinct subtypes. One subtype originates in the peripheral nervous system (PNS) of the gut and spreads to the brain. The other originates in the brain, or enters the brain via the olfactory system, before spreading to the brainstem and PNS.

Does Parkinson’s disease (PD) start in the brain or the gut? In a new contribution published in the Journal of Parkinson’s Disease, scientists hypothesize that PD can be divided into two subtypes: gut-first, originating in the peripheral nervous system (PNS) of the gut and spreading to the brain; and brain-first, originating in the brain, or entering the brain via the olfactory system, and spreading to the brainstem and peripheral nervous system.

Per Borghammer, MD, PhD, DMSc, Nuclear Medicine & PET, Aarhus University Hospital, Denmark, and Nathalie Van Den Berge, MSc, PhD, Department of Clinical Medicine, Aarhus University, Denmark, explore the origins of PD onset. They review the evidence that Lewy body disorders (LBD), including PD and dementia with Lewy bodies (DLB), comprise two distinct subtypes: (1) a gut-first phenotype in which marked damage to the peripheral autonomic nervous system precedes measurable damage to the brain itself, including the dopamine cells; and (2) a brain-first phenotype, in which marked damage to the brain precedes measurable damage to the peripheral autonomic nervous system.

“Evidence from autopsy studies of brains from PD patients has suggested that PD may start in the peripheral nervous system of the gut and nose. The pathology then spreads via the nerves into the brain. However, not all autopsy studies agree with this interpretation,” explained Dr. Borghammer. “In some cases, the brains do not contain pathology at the important ‘entry points’ into the brain, such as the dorsal vagus nucleus at the bottom of the brainstem. The gut-first versus brain-first hypothesis posited in this review provides a scenario that can reconcile these discrepant findings from the neuropathological literature into one single coherent theory about the origins of PD.”

“The discussion about the origins of PD is often framed as an ‘either-or’, i.e., either all PD cases start in the gut or all cases start in the brain,”
added Dr. Van Den Berge. “However, much of the evidence seems compatible with both these interpretations. Thus, we need to entertain the possibility that both scenarios are actually true.”

The review summarizes existing evidence from imaging studies from humans and tissue studies from humans and animal models. The imaging and histology studies are generally compatible with the brain-first vs body-first hypothesis. If this hypothesis is correct, it suggests that PD is more complicated than originally thought. If the disease starts in the gut in only a fraction of patients, it is likely that interventions targeting the gut might only be effective for some PD patients, but not for individuals in which the disease starts in the brain itself.

“It is probable that these different types of PD need different treatment strategies,” commented Dr. Borghammer. “It may be possible to prevent the ‘gut-first’ type of PD through interventions targeting the gut, such as probiotics, fecal transplants, and anti-inflammatory treatments. However, these strategies might not work with respect to treating and preventing the brain-first type. Thus, a personalized treatment strategy will be required, and we need to be able to identify these subtypes of PD in the individual patient.”

PD is a slowly progressive disorder that affects movement, muscle control and balance. It is the second most common age-related neurodegenerative disorder affecting about three percent of the population by the age of 65 and up to five percent of individuals over 85 years of age. During the 20th century, PD was thought to be primarily a brain disorder characterized mainly by loss of pigmented dopaminergic neurons residing in the substantia nigra, a basal ganglia structure located in the midbrain that plays an important role in reward and movement. More recently, it has become clear that PD is highly varied and probably consists of several subtypes.

 
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Scientists find potential diagnostic tool, treatment for Parkinson's disease

by Stanford University Medical Center | Medical Xpress | Sep 26 2019

Investigators at the Stanford University School of Medicine have pinpointed a molecular defect that seems almost universal among patients with Parkinson's disease and those at a high risk of acquiring it.

The discovery could provide a way of detecting the neurodegenerative disorder in its earliest stages, before symptoms start to manifest. And it points to the possibility of halting the disease's progression. The defect appears to be exclusive to individuals with Parkinson's disease.

"We've identified a molecular marker that could allow doctors to diagnose Parkinson's accurately, early and in a clinically practical way," said Xinnan Wang, MD, Ph.D., associate professor of neurosurgery. "This marker could be used to assess drug candidates' capacity to counter the defect and stall the disease's progression."

The scientists also identified a compound that appears to reverse the defect in cells taken from Parkinson's patients. In animal models of the disease, the compound prevented the death of the neurons whose loss underlies the disease.

These steps are described in a study published online Sept. 26 in Cell Metabolism. Wang is the study's senior author. Postdoctoral scholars Chung-Han Hsieh, Ph.D., and Li Li, MD, Ph.D., share lead authorship.

Common neurodegenerative disease

Parkinson's, the second most common neurodegenerative disease, affects 35 million people worldwide. Whereas 5%-10% of cases are familial—the inherited result of known genetic mutations—the vast majority are sporadic, involving complex interactions of multiple unknown genes and environmental factors.

"So it's encouraging," Wang said, "that both the diagnostic marker and the treatment worked in cells from Parkinson's patients with either familial or sporadic versions of the condition."

An age-related progressive movement disorder, the disease stems from the mysterious die-off of a set of nerve cells, or neurons, in the brain that fine-tunes bodily movement. These neurons, which originate in a midbrain structure, the substantia nigra, are referred to as dopaminergic because they secrete a substance, dopamine, to transmit motion-modulating signals to other neurons. By the time a person starts manifesting symptoms of the disease, an estimated 50% of the substantia nigra's dopaminergic neurons have already died.

What makes these particular neurons die is unknown. A leading theory holds that the special intensity with which they perform their duties frazzles their mitochondria. These bacteria-sized cellular components generate energy for cells in exchange for a steady supply of raw materials: oxygen and carbon-rich carbohydrates or fats.

This process, known as respiration, has a downside: It inevitably generates toxic byproducts called free radicals, which not only can cause cellular damage but are extremely harmful to the mitochondria themselves.

Parkinson's is known to involve a defect in mitochondrial function. The harder a cell has to work, the more energy its mitochondria have to churn out—and the more likely they'll burn out. Dopaminergic neurons in the substantia nigra are among the body's hardest-working cells.

Mitochondria spend much of their time attached to a grid of protein "roads" that crisscross cells. Like old cars that can no longer pass a smog test because they can't stop spewing noxious exhaust fumes, defective mitochondria have to be taken off the road. Our cells have a technique for clearing mitochondrial clunkers: a series of proteins that shuffle them off to the cell's recycling centers. But first, those proteins have to remove an adaptor molecule called Miro that attaches mitochondria, damaged or healthy, to the grid.

Wang's group previously identified a mitochondrial-clearance defect in Parkinson's patients' cells: Their inability to remove Miro from damaged mitochondria.

In the new study, Wang's team obtained skin samples from 83 Parkinson's patients, five asymptomatic close relatives considered to be at heightened risk, 22 patients diagnosed with other movement disorders and 52 healthy control subjects. They extracted fibroblasts—cells that are common in skin tissue—from the samples, cultured them in petri dishes and subjected them to a stressful process that messes up mitochondria. This should result in their clearance, necessarily preceded by removal of Miro molecules tethering them to the grid.

Yet the researchers found the Miro-removal defect in 78 of the 83 Parkinson's fibroblasts and in all 5 of the "high-risk" samples, but not in fibroblasts from the control group or other or from patients with other movement-disorders.

Screening small molecules

Next, the investigators screened 6,835,320 small molecules, whose structures reside in a commercially available database, in collaboration with Atomwise Inc. The biotechnology company's software predicted that 11 of these molecules would bind to Miro in a way that would facilitate its separation from mitochondria and would, in addition, be nontoxic, orally available and able to cross the blood-brain barrier, the study reports.

After feeding these compounds to fruit flies for seven days, the researchers determined that four of them significantly reduced the flies' Miro levels without toxicity. They tested one compound, which appeared to target Miro most exclusively, on fibroblasts from a patient with sporadic Parkinson's disease. It substantially improved Miro clearance in these cells after their exposure to mitochondria-damaging stress.

The scientists also fed the compound to three different fruit-fly strains bioengineered to develop Parkinson's-like climbing difficulty. Administering the compound to those flies throughout their 90-day life spans produced no evident toxicity and prevented dopaminergic neurons' death in all three strains and, in two, preserved their climbing ability.

Wang said she believes clinical trials of the compound or a close analog are no more than a few years off.

"Our hope," she said, "is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who've tested positive for the Miro-removal defect but don't yet have Parkinson's symptoms, they'll never get it."

Stanford's Office of Licensing Technology has filed a provisional patent for the use of the study's lead compound in Parkinson's disease and other neurodegenerative disorders. Wang has formed a company, CuraX, with the goal of speeding its development.

 
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mr peabody

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Rutgers University


Discovery could help slow down or even stop the progression of Parkinson's*

by Jillian Prior | Rutgers University | 28 Jan 2020

A collaboration between scientists at Rutgers University and Scripps Research has led to the discovery of a small molecule that may slow down or stop the progression of Parkinson's disease.

Parkinson's, which affects 1 million people in the United States and over 10 million worldwide according to the Parkinson's Foundation, is a neurodegenerative disorder with no cure. Symptoms develop slowly over time and can be debilitating to patients, who most recognizably develop tremor, slow movements and a shuffling gait.

A key feature of Parkinson's disease is a protein named α-synuclein, which accumulates in an abnormal form in brain cells causing them to degenerate and die. However, it has been difficult to target α-synuclein because it does not have a fixed structure and keeps changing its shape, making it very difficult for drugs to target. Because higher levels of the protein in the brain speed the degeneration of brain cells, scientists have been looking for ways to decrease the protein production as a form of treatment.

In 2014, Parkinson's disease expert and scientist M. Maral Mouradian, William Dow Lovett Professor of Neurology and director of the Rutgers Robert Wood Johnson Medical School Institute for Neurological Therapeutics, contacted Matthew D. Disney, chemistry professor at Scripps Research in Florida, to explore a novel idea for treating Parkinson's disease using a new technology developed by Disney.

Disney's method matches RNA structure with small molecules or drug-like compounds. The two collaborators believed this innovative technology could be used to find a drug that targets the messenger RNA that codes for α-synuclein, which causes the disease, in order to reduce production of the protein in the brains of Parkinson's patients. Since the protein itself can't be treated with drugs, RNA could be a more robust and reliable target.

They were right. The NIH-funded study, which was published in the Proceedings of the National Academy of Sciences on January 3, showed that by targeting messenger RNA, the team found a compound that prevents the harmful Parkinson's protein from being made. This new compound, named Synucleozid, reduces specifically α-synuclein levels and protects cells against the toxicity of the misfolded form of the protein, suggesting that it has the potential of preventing disease progression.

"We found the molecule to be very selective at both the RNA level and the protein level," Disney says.

"Currently, there is no cure for Parkinson's disease, and it is truly a devastating disease. For the first time, we discovered a drug-like compound that has the potential to slow down the disease before it advances through an entirely new approach," said Mouradian. “Such a treatment would be most effective for people who are in the early stages of the disease with minimal symptoms,” she said.

"Several other experimental drugs currently being tested for Parkinson's disease are antibodies that target a very late stage of α-synuclein protein aggregates. We want to prevent these protein clumps from forming in the first place before they do damage and lead to advancing disease.," she said. "This new compound has the potential to do that and could change the course of life for people with this devastating disease."

Mouradian says this discovery is 'highly promising' and is eager for the next steps in optimizing and testing the compound. Additionally, this can benefit another devasting disease that also has α-synuclein clumps, known as Dementia with Lewy Bodies. Further, this new concept of targeting RNA to reduce protein production developed in Disney's lab at Scripps Research may be applied to other challenging diseases because of their similar undruggable proteins including Alzheimer's disease.

"The reach of our study could go beyond people with Parkinson's disease to many other neurodegenerative diseases. It is a classic example of how interdisciplinary research leads to significant change," she said.

 
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mr peabody

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UA clinical trial to repurpose ketamine for Parkinson’s patients

The best-known treatment for Parkinson’s disease isn’t perfect.

Named Levodopa, the drug can treat the stiffness and slowness of movement associated with the debilitating disease.

“The problem is Levodopa works great for a few years — we call that the ‘honeymoon’ period — but then you start getting these side effects,” says Scott Sherman, MD, PhD, a neurologist at the University of Arizona College of Medicine in Tucson.

40% of patients on Levodopa eventually will experience dyskinesia — uncontrollable and involuntary movements of the arms, legs, head or entire body. Severity can range from small, fidget-like motions to larger continuous bursts of movement.

Unless patients stop Levodopa treatment altogether, these movements do not go away.

Now, UA researchers are repurposing ketamine, a drug currently used to treat pain and depression, to try and reduce the involuntary movements brought on by Levodopa.

Led by Dr. Sherman and Torsten Falk, PhD, a neuroscientist in the UA Department of Neurology, the two will launch a small phase I clinical trial this summer at the UA College of Medicine – Tucson. The trial is supported by a three-year $750,000 grant from the Arizona Biomedical Research Commission (ABRC).

Drs. Sherman and Falk first got a glimpse of ketamine’s potential in Parkinson’s disease treatment more than five years ago.

The two were using ketamine to relieve pain in five hospitalized patients with Parkinson’s disease. The treatment worked, but the researchers noticed an unintended side effect: the patients’ uncontrolled movements while on Levodopa were noticeably reduced. One patient experienced complete resolution of these movements for a period of several weeks.

Intrigued, the researchers continued investigating and have since shown similar results in rodents with Parkinson’s disease.

Ketamine has been known to raise blood pressure and cause a feeling of disassociation in humans.

“Disassociation is a sort of ‘out-of-body’ experience,” Dr. Sherman explains. “When people describe it, they have told me that they feel like they are in fish bowl.”

In the past, ketamine has been abused by partygoers for this psychedelic effect, but Dr. Sherman is hopeful these side effects will not affect the clinical trial.

“We are going to monitor blood pressure closely to make sure it doesn’t get high,” he says. “And we know at what dosage ketamine causes this disassociation; we expect that the dosage needed in Parkinson’s disease will stay well below that level.”

Using 10 patients, this first clinical trial will verify that Dr. Sherman’s hunch holds true — that ketamine is tolerable and effective for treating dyskinesia.

In addition to supporting the clinical trial, grant funding from the ABRC will back a separate rodent study that examines exactly how ketamine affects the brain and reduces dyskinesia triggered by levodopa.

“We want to find out exactly what ketamine is doing to have this effect,” Dr. Sherman explains.

If the team achieves positive results in both the human and rodent studies, Drs. Sherman and Falk will be one step closer to their goal: establishing that ketamine can help patients with Parkinson’s disease.

Dr. Sherman says, “Ketamine has been long overlooked. Now it could prove very useful for Parkinson’s patients.”

https://uahs.arizona.edu/news/ua-cli...nsons-patients
 
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Support grows for medical device that improves communication for those with Parkinson's*

by Purdue University | Medical Xpress | Nov 20 2019

A growing number of people with Parkinson's disease are finding the ability to communicate with a wearable device developed by a Purdue University speech-language researcher and entrepreneur.

SpeechVive uses a reflex to improve communication. The device plays noise in a user's ear when they are talking, which elicits the reflex, resulting in speech that is automatically louder, clearer and lower.

"Since the wearable device elicits a reflex, the patient does not need to remember to use therapy techniques to communicate in everyday life," said Jessica Huber, a professor in Purdue's Department of Speech, Language, and Hearing Sciences, who developed SpeechVive. "When people with Parkinson's disease cannot be heard or understood, they withdraw from communication exchanges, leading to social isolation. This device makes it possible for patients to continue to communicate with their loved ones well into their disease."

SpeechVive Inc. commercialized the Purdue device to help the more than a million people in the United States who are diagnosed with Parkinson's, one of the most common degenerative neurological diseases. Veterans can receive the device through their local VA hospital as a part of their health care benefits.

"We are working to develop additional routes for individuals to obtain the device," said Huber. "I enjoy developing and testing devices and therapies that can improve the quality of life for people with Parkinson's disease."

*From the article here:

 
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Is anyone else with Parkinson's trying ibogaine?

I started a low dose regime of ibogaine a few days ago and the results are remarkable in just a few days. My neurologist is aware that I am doing this and was supportive. I was wondering if anyone else has tried it. I am taking two 20 mg doses per day. I am currently using ibogaine HCL but plan on switching to the plant extract when that runs out.

Tremors have steadily been diminishing. Steady decrease in shoulder and neck tension. Arms now swing naturally. Big improvement in speech. A "spring" in my step. Regaining sense of smell. Toe curling almost gone. Feeling of being in a fog is gone. Daily improvement in energy. These improvements have been getting better every day so far.

I am currently taking approximately 20 mg of ibogaine HCL twice a day together with a B vitamin complex that approximates the B vitamins in this patent for an ibogaine medication for treating PD:

The dose for treating addictions is known as a "flood" dose and is in the range of hundreds of milligrams not tens of milligrams. The abuse dosages are also in the hundreds of mg range. Micro-dosing is far different. I can tell you that I experience no inebriation at the dosage I am using.

The literature on ibogaine suggests that it "resets" the adrenaline, serotonin, and dopamine systems in the brain. There is a disagreement about whether the dopamine producing cells in the substantia nigra die or go dormant. Most seem to think they die, but a minority think they simply have gone dormant. I am hoping they are dormant and ibogaine provides a wake-up call.

If it is dormancy and not death, a long term treatment is not required. The course only needs to be pursued until reset. BTW this is the method used by the ibogaine addiction residential treatment centers. They only use a "flood" dose to reset and that is it. Sometimes multiple "flood" doses but not the micro-dose I use for PD.

Scoring is difficult. All I know is that I no longer experience toe curling, my tremor is greatly reduced, the stiffness in my neck and shoulders is greatly reduced, my feet don't feel so leaden when I walk, and my sense of smell has been returning. Before ibogaine I had incidents of toe curling and foot cramps almost every day. Some days I could barely walk. I have only had one mild instance of foot cramping since I began this experiment.

I have noticed no psychoactive effects from ibogaine. I am taking 20 mg twice a day together with an over the counter B vitamin cocktail that approximates the B vitamin complex that is in the ibogaine patent for PD.

My PD symptoms first showed up in 2008. I obtained a small quantity of ibogaine hcl and last November started taking 20mg daily. In December I quit the ibogaine for a few weeks until I got over a nasty virus. I had read a drug interaction warning about ibogaine and dextromethorphan, ingredient in otc cough syrup. Then I resumed taking it until March when I ran out.

The positive results were mostly a clearing of the 'brain fog' and a much higher energy level. My gross motor symptoms had always been in good control (most people couldn't tell I have PD), but I experienced a bit of improvement in what tremors and dyskinesia I had. I'm hoping to get some more ibogaine and continue my treatment.

There is a debate over whether the dopamine neurons in the substantia nigra have died or are dormant in PD. The effect of ibogaine is believed to be, at least in part, the revival of dormant cells and/or the neurogenesis of new cells. It is believed to do this by increasing the amount of GDNF in the brain. So this is why I want to eliminate sinemet, to remove the potential interference in the feedback mechanism that sinemet must interfere with. Also, sinemet metabolites are known to be toxic.

I'm giving this a 180 day trial, and I'm only 3 weeks into it, but am quite happy with the results so far.

-danfitz

https://healthunlocked.com/parkinsonsmovement/posts/137612000/anyone-else-trying-ibogaine
 
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How a protein wreaks havoc in those with Parkinson's*

by Ciara O'shea | Trinity College Dublin | 13 Feb 2020

What causes neurons to die in people with Parkinson's?

Parkinson's disease is a long-term (chronic) neurological condition that affects around 12,000 people in Ireland and between 7 and 10 million people worldwide.

The disease affects the way the brain co-ordinates body movements like walking and talking, but cognitive abilities are also affected.

There is currently no cure for the disease, but researchers at Trinity have recently published findings of a study which may lead to better treatments for this debilitating illness. The paper has been published in the international Cell Press journal, Structure.

Neurons in the part of the brain called 'substantia nigra' (dark matter) produce and release a hormone called dopamine. This hormone acts as a messenger between these cells in the substantia nigra and other parts of the brain which control body movements.

"If these specialized neurons become damaged or die, the amount of dopamine in the brain is reduced. This means that the parts of the brain that control movement cease to function normally. The only treatment for Parkinson's disease in the last 20 years has been dopamine replacement therapy. This involves providing a substitute to try to increase the levels of the hormone in the brain. However, the treatment is not completely effective and can wear off over time, and it also has side effects," said Amir Khan, Associate professor, School of Biochemistry and Immunology at Trinity. "The main reason why we lack new treatments is that we don't understand the fundamental mechanism of how neurons become sick and die. No one knows why these particular neurons in the substantia nigra are affected.”

"In the last few years, the field has completely changed. We have new insight into a gene called LRRK2, which is the most common cause of inherited Parkinson's disease. Although only 10% of Parkinson's cases are inherited, the enzyme that is produced by the LRRK2 gene seems to be overactive in both inherited and 'sporadic' cases."

"In other words, afflicted individuals may not have an LRRK2 mutation, but the enzyme 'runs amok' in their neurons anyway. Inhibitors of this enzyme are now in late clinical trials for treatment of Parkinson's disease."


The team at Trinity has studied the effects that LRRK2 has on other proteins in neuronal cells. To understand how LRRK2 affects the brain and leads to Parkinson's disease, the team has simulated the activity of the enzyme in the laboratory.

"The research allowed us to visualize the 3-D structure of a protein complex that is formed when LRRK2 is overactive. From these structural studies of proteins, we can understand how LRRK2 is able to impose its profound effects on neurons. We are the first group to report the effects of LRRK2 in 3-D detail using a method called X-ray crystallography," Professor Khan continued.

"An overactive LRRK2 runs loose in neurons and wreaks havoc on motor and cognitive abilities. In a way, we are chasing the footprints that LRRK2 leaves in the brain to understand what it does, and find ways to stop it."

"We are hopeful that these studies may eventually lead to new treatments for Parkinson's disease, for which there is currently no cure,"
he said.

*From the article here:

 
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University of Technology Sydney


Scientists discover medicinal cannabis substitute for treating Parkinson’s

University of Technology Sydney | Neuroscience News | Dec 20 2019

The drug – HU-308 – lessens the devastating involuntary movements called dyskinesias, a side effect from years of treatment for Parkinson’s.

The research, published today in Neurobiology of Disease, has been conducted by the Centre for Neuroscience and Regenerative Medicine (CNRM) at the University of Technology Sydney (UTS) and the Applied Medical Research Institute of St Vincent’s Hospital Sydney.

The study shows that in mice HU-308 is as effective as Amantadine, the only available treatment for dyskinesias. Furthermore, the combination of HU-308 with Amantadine is more effective than either drug used alone.

Professor Bryce Vissel, director of the CNRM and senior author of the study, said the findings present the possibility of new options for Parkinson’s patients.

“Our study suggests that a derivative of HU-308, either alone or in combination with Amantadine, may be a more effective treatment for dyskinesias and a much better option than using an unproven potentially harmful substance like cannabis,” Professor Vissel said.

“Currently there is limited evidence about the effectiveness of medicinal cannabis. One problem is that no cannabis preparation is the same and cannabis has numerous effects, some of which may not be beneficial in Parkinson’s disease.”

Cannabis works on several receptors in the brain – CB1 and CB2. The psychoactive effect is caused mostly because of receptor CB1.

Professor Vissel said the HU-308 drug explored by his team works only on receptor CB2, allowing medicinal benefits to be administered without causing psychoactive effects like drowsiness or highness.

Lead author Dr Peggy Rentsch said it is unclear whether medicinal cannabis itself can help Parkinson’s patients.

“Medicinal cannabis contains different compounds, some of which make you high and which can impact a person’s normal day-to-day activities,” Dr Rentsch said.

“Our research suggests HU-308 is an important prototype drug which we believe won’t interfere with patients’ day-to-day activities. They should maintain normal levels of mental sharpness on a treatment like this.”

Professor Vissel and his team are investigating ways to block inflammation of the brain to maintain and restore memory and slow the progression for both Parkinson’s disease and Alzheimer’s disease.

“HU-308 works by reducing inflammation in the brain, affecting the neurons and immune cells.”

“In neurological disorders, the immune cells in the brain can lose supportive function with adverse stimuli – including but not limited to trauma or obesity – and become ‘activated.’ Scientists at the CNRM believe that, after this activation, the immune cells backfire, kill the brain’s neurons, destroy them – and become dysfunctional."

“By reducing inflammation in the brain – such as with HU-308 – these immune cells can support normal neural function again, rather than inhibiting it.”


Study collaborator Dr Sandy Stayte said: “The fact that Amantadine has its own set of side effects, may not work in the long term, and is still the only drug available on the market that is approved for dyskinesias makes our study really exciting."

“First, our study shows HU-308 is equally affective so a drug like HU-308 will be useful for those people who can’t take Amantadine. Second, for those who can tolerate amantadine, taking the combination may have even greater benefits than taking either drug alone. That means we may end up with a much more powerful treatment than currently available by ultimately prescribing both.”


 

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Light-based deep brain stimulation relieves symptoms of Parkinson's

by Ken Kingery | Duke University | 27 April 2020

Biomedical engineers at Duke University have used deep brain stimulation based on light to treat motor dysfunction in an animal model of Parkinson's disease. Succeeding where earlier attempts have failed, the method promises to provide new insights into why deep brain stimulation works and ways in which it can be improved on a patient-by-patient basis.

The results appear online on April 20 in The Journal of Neuroscience.

"If you think of the area of the brain being treated in deep brain stimulation as a plate of spaghetti, with the meatballs representing nerve cell bodies and the spaghetti representing nerve cell axons, there's a longstanding debate about whether the treatment is affecting the spaghetti, the meatballs or some combination of the two," said Warren Grill, the Edmund T. Pratt, Jr. School Distinguished Professor of Biomedical Engineering at Duke.

"But it's an impossible question to answer using traditional methods because electrical deep brain stimulation affects them both as well as the peppers, onions and everything else in the dish. Our new light-based method, however, is capable of targeting just a single ingredient, so we can now begin teasing out the individual effects of activating different neural elements."

In Grill's metaphor, the meatballs are the neurons that make up the subthalamic nucleus, a small component of the basal ganglia control system that is believed to perform action selection. While its exact function remains unknown, research suggests that it holds muscular responses in check. The spaghetti in the bowl represents long nerve fibers called the hyperdirect pathway that extend into the region from neurons in the cerebral cortex, the thin outer layer of neurons responsible for most of the brain's information processing. And the peppers, onions and other ingredients are the various types of support cells found throughout the brain.

As Grill suggests, teasing out the role all of these various types of cells plays in mediating the effects of deep brain stimulation is nearly impossible using traditional methods. Individual types of cells cannot be singled out by electrical stimulation, and the electric pulses blind researchers' sensors for a crucial millisecond directly after firing.

In 2006, a team of researchers attempted to use optogenetics to skirt these issues. Optogenetics is a method of genetically modifying specific cells to express light-sensitive ion channels, allowing researchers to control their activity with flashes of light. The researchers embedded these light-sensitive ion channels into the subthalamic nucleus "meatballs" in rats and flashed pulses of light at the same rate used in deep brain stimulation. The treatment, however, failed to alleviate any of the rats' physical symptoms, leading the researchers to conclude that stimulating the subthalamic nucleus on its own is an inadequate treatment approach.

But the study never sat quite right in Grill's mind.

"Neurons being stimulated with optogenetics don't generally respond very quickly, and it seemed to me that the researchers were flashing their lights faster than the neurons could keep up with," said Grill. "The data bore this out, as the neurons appeared to be responding randomly rather than in sync with the flashes. And previous research that we conducted showed that random patterns of deep brain stimulation are not effective at relieving symptoms."

It took more than a decade for Grill to be able to test his theory, but two recent developments allowed him to follow his hunch. Researchers developed a faster form of optogenetics called Chronos that could keep up with the speeds traditionally used in deep brain stimulation. And Chunxiu Yu, a research scientist with expertise in optogenetics, joined Grill's laboratory. Also contributing to the work in Grill's laboratory were Isaac Cassar, a biomedical engineering doctoral student, and Jaydeep Sambangi, a biomedical engineering undergraduate.

In the new paper, Yu embedded the Chronos optogenetics machinery into the subthalamic nucleus neurons of rats that have been given Parkinson's disease-like conditions in one-half of their brains. This model helps researchers determine when a treatment is successful because the resulting physical movement symptoms only occur on one side of the rat's body. They then delivered deep brain stimulation using light flashes at the standard 130 flashes per second.

As Grill first suspected nearly 15 years ago, the technique worked, and the rats' physical symptoms were substantially alleviated.

According to Grill, their result has several important implications. One is that researchers need to consider the kinetic properties of how rapidly optogenetic approaches can act when designing their experiments and pay close attention to performance in their studies. Another insight was the way that other neurons outside of the subthalamic nucleus responded to the treatment. While there was not a large difference in their average activity levels, there was a dramatic shift in the pattern in which those neurons fired, which offers clues as to how deep brain stimulation works.

But perhaps the most important result is simply that the technique worked at all. Besides offering a much clearer look at neural activity by removing electrical artifacts, the ability to deliver deep brain stimulation to precise subsets of neurons should allow researchers to begin probing exactly which parts of the brain need to be stimulated and how therapies might be tailored to treat different motor control symptoms on a case-by-case basis.

As their next experiment in this line of research, Grill and his colleagues plan to recreate this same study but in the hyperdirect pathway—the spaghetti instead of the meatballs—to see what its individual contribution to relieving symptoms might be.

"This is very important because somewhere in that big bowl of spaghetti are some elements that are responsible for treating symptoms and some elements that generate side effects," said Grill. "And if we can figure out which is which, we can design electrode stimulation geometries and patterns to target the elements that suppress symptoms while leaving the others alone."

 

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Thanks to exciting novel therapies, there's hope on the horizon for individuals and families affected by Parkinson's.


Novel treatment for Parkinson's using patient's own cells

by McLean Hospital | Medical Xpress | 13 May 2020

Reprogramming a patient's own skin cells to replace cells in the brain that are progressively lost during Parkinson's disease (PD) has been shown to be technically feasible, reports a team of investigators from McLean Hospital and Massachusetts General Hospital (MGH) in the most recent issue of the New England Journal of Medicine.

PD is the second most common degenerative disease of the brain, and millions of people world-wide experience its symptoms, which include tremor, stiffness, and difficulty with speech and walking. The progressive loss of brain cells called dopaminergic neurons plays a major role in the disease's development. As described in the current report, the use of a patient's own reprogrammed cells is an advance that overcomes barriers associated with the use of cells from another individual.

"Because the cells come from the patient, they are readily available and can be reprogrammed in such a way that they are not rejected on implantation. This represents a milestone in 'personalized medicine' for Parkinson's," says senior author Kwang-Soo Kim, Ph.D., director of the Molecular Neurobiology Laboratory at McLean Hospital, the largest clinical neuroscience and psychiatric affiliate of Harvard Medical School.

The McLean-MGH team reprogrammed a 69-year-old patient's skin cells to embryo-like pluripotent stem cells (called induced pluripotent stem cells) and then differentiated them to take on the characteristics of dopaminergic neurons, which are lost in Parkinson's. After extensive testing of the cells, Kim applied for and gained approval under the FDA's single-patient, expanded-access protocol to implant the cells into the patient's brain.

Bob Carter, MD, Ph.D., chief of Neurosurgery at MGH and co-senior author, says: "This strategy highlights the emerging power of using one's own cells to try and reverse a condition—Parkinson's disease—that has been very challenging to treat. I am very pleased by the extensive collaboration across multiple institutions, scientists, physicians, and surgeons that came together to make this a possibility."

In a series of two separate surgeries in 2017 and 2018 at Weill Cornell Medical Center and MGH, the patient underwent transplantation of the replacement dopamine neurons. Lead author Jeffrey Schweitzer, MD, Ph.D., a Parkinson's specialized neurosurgeon and director of the Neurosurgical Neurodegenerative Cell Therapy program at MGH, designed a novel minimally invasive neurosurgical implantation procedure to deliver the cells, working in collaboration with Carter at MGH and Michael G. Kaplitt, MD, Ph.D., a neurosurgeon at Weill Cornell.


Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural
Lewy-body in the Substantia nigra in Parkinson's disease.


Two years later, imaging tests indicate that the transplanted cells are alive and functioning correctly as dopaminergic neurons in the brain. Because the implanted cells originated from the patient, they did not trigger an immune response and were not rejected without the use of an immunosuppressant drug. Kim also noted, "We have shown for the first time in this study that these reprogrammed cells are still recognized as self by the patient's immune system and won't be rejected." These results indicate that this personalized cell-replacement strategy was a technical success, with the cells surviving and functioning in the intended manner. The patient has not developed any side effects, and there are no signs that the cells have caused any unwanted growth or tumors.

As for how the patient feels, in the time that has passed since surgery, the patient has enjoyed improvements in his day-to-day activities and reports an improvement in his quality of life. Routine activities, such as tying his shoes, walking with an improved stride, and speaking with a clearer voice, have become possible again. Some activities—such as swimming, skiing, and biking, which he had given up years ago—are now back on his agenda. While it is too early to know whether this treatment approach is viable based on a single patient, the authors have the goal of continuing to test the treatment in formal clinical trials.

"Current drugs and surgical treatments for Parkinson's disease are intended to address symptoms that result from the loss of dopaminergic neurons, but our strategy attempts to go further by directly replacing those neurons," says Kim.

"As a neurologist, my goal is to make state-of-the-art treatments available to patients with Parkinson's," says Todd Herrington, MD, Ph.D., lead study neurologist at MGH and Parkinson's expert. "If the benefits seen in this proof-of-principle case are confirmed in formal clinical studies, this line of research could deliver an entirely new therapeutic approach to offer patients with Parkinson's."

While there is optimism about the future of Parkinson's disease treatments because of their work, Schweitzer cautions against declaring victory against the disease.

"These results reflect the experience of one individual patient, and a formal clinical trial will be required to show whether Parkinson's patients, in general, could expect improvements like this," says Schweitzer. "With that said, the outcome is extremely encouraging for the future prospects of this technique."

 
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