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Science Parkinson's

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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mr peabody

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Scientists find potential diagnostic tool, treatment for Parkinson's

by Stanford University Medical Center | Sep 26 2019

Investigators at the Stanford 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 to be 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 (94 percent) 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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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:

https://patents.google.com/patent/US20160331759

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
 

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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