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MRI Technique Helps Distinguish Between Parkinson’s and Progressive Supranuclear Palsy, Study Reports

MRI technique

A specific magnetic resonance imaging (MRI) measure can accurately predict the development of eye movement abnormalities, helping to identify patients who develop progressive supranuclear palsy with parkinsonism (PSP-P) after an initial diagnosis of Parkinson’s, a study shows.

The study, “Refining initial diagnosis of Parkinson’s disease after follow‐up: A 4‐year prospective clinical and magnetic resonance imaging study,” appeared in the journal Movement Disorders.

A clinical diagnosis of Parkinson’s may be inaccurate in the early stages of the disease, when its characteristic motor symptoms are not fully manifested. PSP-P has a similar clinical presentation to idiopathic Parkinson’s (of unknown cause), including bradykinesia (slowness of movement), limb rigidity, and tremor, leading to difficulty in differentiating between the two.

Recent diagnostic criteria defined probable PSP-P as vertical gaze abnormalities (VGA) — difficulty in moving the eyes up and/or down — associated with levodopa‐resistant parkinsonism, a term for neurological disorders that cause movement problems similar to those of Parkinson’s. However, patients with PSP-P may never develop VGA, meaning the prevalence of this disorder could be underestimated.

MRI has been a helpful tool to diagnose PSP and to predict the appearance of gaze abnormalities in people with PSP-P. A new version of the Magnetic Resonance Parkinsonism Index (MRPI), named MRPI 2.0, has shown high accuracy in distinguishing cases of Parkinson’s from those of PSP-P. The MRPI can be used in MRI studies to predict the presence of PSP in patients with clinically unclassifiable parkinsonism.

However, studies on the clinical features of PSP-P in patients initially diagnosed with Parkinson’s are still lacking.

To address this, researchers in Italy followed a group of 110 individuals — 73 of whom were men, with a mean age at examination of 62.9 years, and a mean disease duration of 4.4 years — with probable or possible Parkinson’s and 74 healthy individuals used as controls over four years.

The investigators conducted annual clinical evaluations to assess the appearance of VGA without early postural instability, which strongly suggests PSP‐P. MRI scans were performed at the beginning of the study and at the end of the follow-up period.

They also evaluated whether MRPI 2.0 helped predict the development of PSP-P in patients initially diagnosed with Parkinson’s.

At the start, 21 of 40 individuals with possible Parkinson’s and all 70 individuals with probable Parkinson’s were responsive to levodopa. Of all the patients, 100 retained their initial diagnosis, and 10 (9.1%) developed VGA and had their diagnosis changed to PSP-P, nine of whom only showed a moderate response to levodopa.

Specifically, all 10 patients whose diagnosis changed showed slowness of vertical saccades during follow-up, which refers to quick, simultaneous movements of both eyes that abruptly change the point of fixation. Vertical supranuclear gaze palsy (resulting from a cerebral impairment) in five patients was associated with higher imaging biomarkers values than slowness in vertical saccades. All 10 patients had at least three years of parkinsonism without postural instability.

All MRI measures — including MRPI and MRPI 2.0 — were significantly different between patients with Parkinson’s and those at PSP-P both at the start of the study and at the end of follow-up. At the beginning, MRPI 2.0 was the most accurate (100%) biomarker in predicting the appearance of VGA, “enabling [PSP-P] patients to be identified at the earliest stage of the disease,” according to the researchers.

Although the number of patients whose diagnosis was changed is small, the researchers said that their findings “demonstrate the usefulness of these new imaging biomarkers, and specifically of the MRPI 2.0, in predicting the development of VGA and the clinical evolution towards PSP phenotypes in patients with the initial diagnosis of [Parkinson’s].”

Most clinical variables — including motor function, assessed with the Unified Parkinson’s Disease Rating Scale–Motor Examination (UPDRS‐ME), and cognitive function, measured with the Mini-Mental State Exam — also showed a marked difference between the two groups at follow-up. However, clinical variables were less accurate than imaging biomarkers in predicting VGA.

Data further showed that disease progression was more signficant in patients with PSP‐P, as assessed with MRI and UPDRS‐ME.

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Iowa City is Next Stop for Parkinson’s Foundation’s Team Training Program

team training program

The Parkinson’s Foundation is bringing Allied Team Training for Parkinson’s (ATTP), its signature professional education program, to Iowa City, Iowa, on March 27-30.

The program is intended to help medical professionals from diverse disciplines learn the best techniques in Parkinson’s care. 

Using a dynamic team-based approach, the training program is geared toward physicians, physician assistants; nurses; social workers; nurse practitioners; and occupational, music, speech, and physical therapists.

The interactive curriculum is offered in partnership with the University of Iowa Hospitals & Clinics, a designated Parkinson’s Foundation Center of Excellence. These centers — there are 45 worldwide — have specialized teams made up of an array of healthcare professionals and others knowledgeable about the latest in Parkinson’s care.

“The Parkinson’s Foundation is committed to providing healthcare professionals with the latest research and best practices that improve care for people living with Parkinson’s disease,” John L. Lehr, president and CEO of the Parkinson’s Foundation, said in a press release.

He said attendees will learn how to provide personalized and patient-centered care, and at the right time, throughout the disease’s progression. The concept is based on the idea that because each patient experiences Parkinson’s differently, a diverse healthcare team fosters better symptom management.

Featuring a mix of online courses and an extensive in-person curriculum, the program offers continuing medical education credits and continuing education units to eligible participants. Led by an interdisciplinary faculty of senior movement disorder specialists, training includes interactive case presentations, care planning with patients and caregivers, discipline-specific and interdisciplinary team development sessions, and patient and caregiver panels.

“Building upon our strengths in providing world-class care for patients, and conducting leading-edge research, our support from the Parkinson’s Foundation is allowing us to expand our interdisciplinary care, to increase our community involvement and educational activities for other healthcare professionals and patients across Iowa, and to attain even greater heights in the treatment of everyone affected by Parkinson’s disease,” said Ergun Uc, MD, professor of neurology and director of the Division of Movement Disorders at University of Iowa Hospitals & Clinics.

By the end of the program, participants should be able to explain the complexity of Parkinson’s motor and non-motor symptom management for all disease stages, identify challenges with medication side effects, list six non-pharmacological management strategies for non-motor symptoms, discuss options available to support patients and their families, describe the complementary role of each discipline on their care team, and apply strategies for building inter-professional networks and community partnerships.

Since its 2002 inception, the ATTP has trained more than 2,000 healthcare professionals in the United States and Canada.

Future ATTP training includes the Medical University of South Carolina (fall 2019), Massachusetts General Hospital and Beth Israel Deaconess Medical Center (spring 2020), Struthers Parkinson’s Center (fall 2020), Oregon Health & Science University (spring 2021), and the University of Kansas Medical Center (fall 2021).

Visit this site for more information about the Iowa event, and to register. Registration fees are $500 per person; $450 per person for teams of three or more. Attendance is free for physician fellows and eligible students.

More information about the foundation’s professional educational programs is available here.

The Parkinson’s Foundation works to enhance patient care and advance research toward a cure. According to the organization, 60,000 U.S. residents are diagnosed with Parkinson’s each year.

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Behavioral, Metabolic Changes Linked to Sleep Restriction Could Foretell Parkinson’s, Animal Study Suggests

sleep restriction

Chronic sleep restriction alters movement, worsens cognitive dysfunction and induces changes in the levels of several amino acids — the building blocks of proteins — and other markers in rats with Parkinson’s, according to a new study.

According to researchers, these findings could enable the use of biomarkers to identify those at risk of developing the disease.

The study, “Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers,” was published in the journal Scientific Reports.

Non-motor symptoms of Parkinson’s typically appear years before significant loss of dopamine-producing neurons in the substantia nigra, an area of the brain key to motor control. One such symptom is impaired sleep. Both sleep disturbances and lifestyle-imposed sleep restrictions may contribute to cognitive decline and produce detectable alterations in the body.

However, it remains unclear whether sleep disturbances constitute a risk factor for developing Parkinson’s disease.

An international team of researchers from Brazil, the U.K. and the Netherlands used the rotenone-induced rat model of Parkinson’s disease to evaluate if chronic sleep restriction triggers metabolic changes, cognitive impairment, and changes in the circadian rhythm (the body’s internal clock).

When injected into the substantia nigra, rotenone, an agrochemical, induces similar changes to those seen in early Parkinson’s, including excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, insomnia, and disruption of spontaneous sleep.

The results revealed that, unlike rotenone, sleep restriction for 21 days (six hours per day) — by soft tapping or gently shaking the cage, or gently disturbing rats’ sleeping nest — did not induce loss of dopamine-producing nerve cells.

Animals subjected to sleep restriction did not show the decreased levels of locomotor activity (movement) observed in  rats injected with rotenone, as assessed using the open field test, which is an experimental test used to evaluate animals’ general locomotor activity levels, anxiety, and willingness to explore.

The object recognition task, which evaluates memory by measuring the time animals spend on a new object, revealed that sleep restriction aggravated rotenone-induced cognitive dysfunction. Sleep recovery for 15 days reversed rats’ memory deficits.

Sleep restriction also impaired the animals’ circadian rhythm, as they showed reduced activity during the first 75 minutes after lights-off (the night period  when rodents become more active) at weeks 2 and 3.

The investigators subsequently looked at biochemical alterations in blood plasma using two metabolic profiling approaches called global 1H nuclear magnetic resonance (NMR) spectroscopy and targeted liquid chromatography/mass spectrometry (LC/MS).

Sleep restriction increased plasma levels of amino acids leucine, isoleucine, valine, ornithine (reportedly increased in Parkinson’s), arginine, lysine, alanine, proline, phenylalanine (a precursor of dopamine) and carnitine, as well as 15 different phospholipids, which is a type of fat that is a key component of cellular membranes.

In contrast, sleep restriction lowered the levels of creatinine (a product of muscle metabolism), acetylcarnitine (a form of the amino acid L-carnitine), and kynurenine (a byproduct of the amino acid L-tryptophan and previously implicated in Parkinson’s), among other molecules.

When combined with rotenone, sleep restriction increased plasma concentrations of most of the same amino acids and also of 54 phospholipids, while decreasing creatinine and forms of amino acids such as acetylcarnitine. Sleep recovery completely eliminated the changes induced by sleep restriction and rotenone regarding these molecules.

A statistical analysis then revealed that the concentrations of isoleucine, leucine and kynerunine were different when comparing animals on sleep restriction to controls. Concentration of the amino acid methionine correlated with rats’ activities.

NMR data additionally showed rotenone alone induced higher levels of circulating triglycerides and lipoproteins as well as LDL cholesterol (the “bad” cholesterol). In contrast, sleep restriction alone did not alter biochemical parameters.

Combined with rotenone, sleep restriction led to a more pronounced increase in amino acids levels, including phenylalanine and tryptophan, whose metabolism has been found altered in early-stage Parkinson’s patients. Sleep recovery again eliminated these changes.

“If combined, our results bring a plethora of parameters that represents reliable early-phase [Parkinson’s] biomarkers which can easily be measured and could be translated to human studies,” researchers wrote. Identifying who is at risk of developing the disease “has the potential to improve therapeutic strategies and possibly delay or attenuate the onset of symptoms,” they added.

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ProMIS Neurosciences Develops Antibodies Targeting Toxic Forms of Alpha-Synuclein

ProMIS Neurosciences

ProMIS Neurosciences has identified several antibody candidates that specifically target the toxic forms of alpha-synuclein, a key component of Lewy bodies that underlie the development of Parkinson’s disease.

In vitro (in the lab) studies have shown that ProMIS’s antibody candidates for Parkinson’s disease have a high specificity for toxic forms of alpha-synuclein without binding to non-toxic essential forms of the protein. Moreover, these antibody candidates prevent the spreading (propagation) of toxic forms of alpha-synuclein.

“In preclinical studies, ProMIS antibody candidates showed a high degree of selectivity for only the toxic forms of alpha-synuclein in a side-by-side comparison with other alpha-synuclein targeting antibodies that are currently in development,” James Kupiec, MD, ProMIS chief medical officer, said in a press release.

Alpha-synuclein plays a key role in a healthy brain, regulating the release of synaptic vesicles — “bubbles” — filled with chemical neurotransmitters (chemical messengers). The synapse is the junction between two nerve cells that allows them to communicate. This regulation occurs when alpha-synuclein is in its healthy state, i.e., arranged in a tetramer — four units of the protein wrapped around each other.

In Parkinson’s disease, alpha-synuclein’s 3D structure is altered (misfolded) promoting its aggregation into clumps and causing the death of dopamine producing-nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, a critical neurotransmitter that regulates brain cell activity and function.

Traditional methods for generating antibodies are unable to specifically target the neurotoxic forms of proteins like alpha- synuclein. ProMIS Neurosciences developed a technology to design candidate antibodies that bind only to the toxic forms of misfolded proteins. That means these antibodies’ effectiveness is better and is linked with lower side effects.

“We used our proprietary discovery platform to generate several antibody drug candidates for Parkinson’s disease that precisely target only the toxic forms of alpha-synuclein,” Kupiec said.

“Selectivity represents the essential feature of a successful antibody therapy, for it is critical that treatment not hinder normal forms of alpha-synuclein that play an important functional role in the brain,” he added.

ProMIS Neurosciences’ lead antibody candidate, PMN310, being developed as a potential treatment for Alzheimer’s disease, was shown to attack only toxic forms of a protein linked to the disease — amyloid beta — and not normal forms. This investigational therapy is expected to enter Phase 1 clinical trials in 2019.

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L‐DOPA Treatment Prevents Age-related Iron Accumulation, Mouse Study Finds

iron accumulation

Levodopa (L-DOPA) therapy is neuroprotective and prevents age-related iron accumulation in the substantia nigra, a brain region involved in Parkinson’s disease.

The study with that finding, “L-DOPA modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson’s disease,” was published in the Journal of Neurochemistry.

L-DOPA is sill the primary pharmacological treatment for Parkinson’s disease motor symptoms. However, while the therapy provides symptom relief immediately following the onset of motor symptoms, during later stages of the disease certain non L-DOPA-responsive symptoms emerge that contribute to the rapid decline in quality of life.

Conflicting evidence also suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.

Several studies have established an association between iron build-up and both aging and neurodegenerative disorders like Parkinson’s disease. Apart from loss of dopamine-producing neurons, Parkinson’s also is characterized by pronounced iron accumulation in two brain regions: the globus pallidus and the substantia nigra.

It has been suggested that free iron molecules can induce dopamine oxidation and thus contribute to Parkinson’s disease development. Nonetheless, the exact mechanism of iron-induced dopaminergic degeneration is still unclear.

“Considering the substantial conflicts in the literature regarding whether L -DOPA is either neurotoxic or protective, and that [iron] has multiple well-established roles in both normal [dopamine] metabolism and neurotoxic oxidation,” researchers from the University of Melbourne, Australia, examined the effects of L -DOPA administration in three mouse models of Parkinson’s disease.

Mice fed with an iron solution from 10 to 17 days of age — mimicking early-life iron overexposure to accelerated age-related accumulation; a mouse model of Parkinson’s disease which over-expresses human A53T mutation (hA53T) in the alpha-synuclein protein, mimicking disrupted dopamine metabolism; and a mouse model combining these two experimental paradigms, i.e., hA53T transgenic iron-fed mice.

Animals were given L-DOPA in their drinking water from three to eight months of age. Researchers analyzed the therapy’s effect on brain iron levels, nerve cell numbers and motor function prior to the equivalent onset of clinical symptoms, in comparison to mice fed with clioquinol spiked food for the same period of time.

Clioquinol is a compound that binds to iron molecules suppressing their (harmful) chemical activity. Studies demonstrate clioquinol is beneficial in animal models of three neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

Results revealed L-DOPA did not increase neurotoxicity in any of the mouse models and prevented age-related iron accumulation in the substantia nigra, much like clioquinol.

In addition, researchers observed a potential neuroprotective effect, as in both the iron overload and the hA53T mouse models L-DOPA treatment significantly reduced iron levels in the substantia nigra, decreased protein carbonyls (biomarkers of oxidative stress), and prevented neurodegeneration.

“Chronic L -DOPA treatment showed no evidence of increased oxidative stress in [normal mice] midbrain and [normalized] motor performance, when excess [iron] was present,” researchers wrote.

Additionally, L-DOPA did not increase protein oxidation levels in hA53T mice, with or without excess iron accumulation in the substantia nigra, and showed evidence of neuroprotection.

At eight months, total iron levels did not increase in hA53T mice that did not receive L-DOPA, suggesting the mutant alpha-synuclein does not itself trigger harmful iron accumulation.

“When challenged with excess [iron] during a critical window of neurodevelopment [10-17 days of age], hA53T mice showed the expected increase in nigral [iron]. Interestingly, excess [iron] did not worsen or accelerate neuropathology,” researchers wrote.

Similar to clioquinol, L -DOPA was able to mitigate oxidative damage from excessive iron accumulation. This effect was not as pronounced in hA53T expressing mice, which are more susceptible to oxidative damage from iron exposure.

These findings suggest that alpha-synuclein dysfunction could be behind iron-mediated dopamine oxidation, with the latter being an early sign of parkinsonian neurodegeneration.

“We found no evidence in any of our model systems that L-DOPA treatment accentuated neurodegeneration, suggesting [dopamine] replacement therapy does not contribute to oxidative stress in the Parkinson’s disease brain,” researchers concluded.

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Vitamin A Supplement Fails to Protect or Treat Rats in Parkinson’s Disease Model, Study Says

retinol and neurons

Vitamin A, or retinol, given as an oral supplement did not prevent the loss of dopamine-producing neurons or lessen motor deficits in a rat model of Parkinson’s, a study reports.

Results also showed that retinol lowered levels of inflammatory markers in the blood and did not cause oxidative damage in the liver, but its use changed in potentially harmful ways the activity of inflammatory cells in the brain of rats without Parkinson’s.

The research, “The effects of retinol oral supplementation in 6-hydroxydopamine dopaminergic denervation model in Wistar rats,” appeared in the journal Neurochemistry International.

In the central nervous system, retinol (a type of vitamin A) plays diverse roles, including neuronal differentiation during embryonic development and long-lasting communication between neurons (nerve cells) in a key brain area involved in memory, the hippocampus.

Although in vitro (in the laboratory) and in vivo (with animal models) studies have reported that retinol has antioxidant and cell protective effects, and suggested a link between vitamin A deficiency and cognitive decline in Alzheimer’s, the use of retinol in prevent neurodegenerative disorders has not been fully explored.

To assess dietary retinol in Parkinson’s, researchers used a rat model in which a neurotoxin called 6-hydroxydopamine (6-OHDA) is injected into the brain’s substantia nigra, inducing the death of dopamine-producing nerve cells. This mimics hallmark changes in advanced Parkinson’s, leading to similar motor deficits.

The animals were given a form of retinol (retinyl palmitate, 3000 IU/kg per day, which is equivalent to 900 μg/day in an adult) orally over 28 days, followed by 6-OHDA injection. Their motor coordination, degree of neuroinflammation, and the content of dopaminergic neurons in the substantia nigra were then assessed.

As retinol supplements are also reported to have toxic effects, the scientists also looked systemic inflammation, liver toxicity, oxidative stress, and mutagenicity, or a toxic agent’s ability to cause mutations.

Data first showed no changes in 6-OHDA-induced oxidative stress or mutagenicity in the liver – the major organ in retinol storage – in treated animals. Retinol use also prevented a rise in blood levels of TNF-alpha and interleukin (IL)-1beta – two key mediators in the inflammatory response – in rats with Parkinson’s.

But retinol use did not protect against the loss of dopaminergic neurons and did not significantly ease motor deficits in the animal model. The rats’ motor function was tested 15 days after 6-OHDA injections.

In the substantia nigra, retinol administration was able to prevent the activation of microglia — key immune cells in the brain — but not of astrocytes, cells whose various functions include a role in the formation of the blood-brain barrier and response to injury.

However, rats without Parkinson’s-like disease (no 6-OHDA injections) and treated with retinol showed increased astrocyte activation. These cells can both work with and inhibit microglia, to boost or block neuroinflammation, the researchers said.

“These results, altogether, suggest that oral supplementation with retinol does not protect against dopaminergic toxicity in the [substantia nigra] and may disturb astrocytes and microglia functional homeostasis,” they concluded.

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Parkinson’s Foundation Will Gather Experts to Study Cannabis as Disease Therapy

Cannabis

These days, people with Parkinson’s disease tend to ask their doctors more questions about cannabis than any other subject; yet, few physicians have adequate answers for them.

So says a new survey announced by the Parkinson’s Foundation, which plans a conference on that subject next month in Denver.

The March 6-7 meeting will bring together about 40 top scientists, clinicians, physicians and marijuana industry executives, said James Beck, MD, the foundation’s chief scientific officer.

“There’s never been anything quite like this before,” Beck told Parkinson’s News Today by phone from his New York office. “Not a lot is known when it comes to Parkinson’s and medical marijuana. Our goal is to outline what we know and what we don’t know, what might be useful for Parkinson’s and what might not be useful.”

Cannabis2
Boxes of “Healer” CBD/THC cannabis drops await distribution at the Kind Therapeutics medical marijuana cultivation facility in Hagerstown, Maryland. (Photo by Larry Luxner)

He added: “Medical marijuana may have its utilities for treating some symptoms, but it isn’t a silver bullet.”

The survey, conducted jointly by the Parkinson’s Foundation and Chicago’s Northwestern University, found that 80% of Parkinson’s patients have used cannabis, and that 95% of neurologists have been asked to prescribe medical marijuana. But only 23% of doctors have ever received formal education on the subject.

In addition, 52% of the 56 experts who responded to the 73-item online survey took a neutral position on cannabis use with their patients, 9% discouraged its use, and 39% encouraged it.

“Having worked as a clinician for the past decade in Colorado — a state at the forefront of medical marijuana use — it is clear that people with Parkinson’s and their families are intensely interested in the potential of marijuana and cannabinoids in helping manage symptoms and other aspects of the disease,” Benzi Kluger, MD, a professor at University of Colorado Hospital and co-chair of the upcoming conference, said in a press release. “To date, there is more hype than actual data to provide meaningful clinical information to patients with Parkinson’s.”

Kluger wrote a review, “The Therapeutic Potential of Cannabinoids for Movement Disorders,” that was published in early 2015 in Movement Disorders.

Also presenting at the conference is A. Jon Stoessl, MD, co-director of the Djavad Mowafaghian Centre for Brain Health at the University of British Columbia in Vancouver.

“In order to move the field forward, we need to determine which cannabinoids are likely to be beneficial or harmful, whether people with Parkinson’s are at risk from side effects, what we are hoping to treat, and how to conduct informative clinical trials,” Stoessl said.

Finding answers

The Parkinson’s Foundation, founded in 1957, now has 120 full-time staffers and an annual budget of $33 million. It represents the roughly one million Americans with Parkinson’s, which now ranks as the second most common neurogenerative disease after Alzheimer’s.

Beck
James Beck, MD

Beck said his nonprofit hopes to “develop a path to understanding formulations of cannabis and the pharmacology behind it” for the benefit of Parkinson’s patients everywhere. Scientists have isolated more than 60 cannabinoids, including tetrahydrocannabinol (THC), the main psychotropic compound, and cannabidiol (CBD), a non-psychoactive chemical with potential therapeutic properties.

“What one buys over the counter is not consistent from batch to batch. It’s not produced in a regulated way,” Beck told us. “The weed that people may smoke today is 10 times more potent than what baby boomers were smoking in the ‘60s and ‘70s. It’s a natural product, and things like what ratios CBD and TCH should be are fundamental questions. We’ll have experts suggest what might be best.”

At the moment, 33 states and the District of Columbia have declared medical marijuana legal; that’s up from 20 states only four years ago. In D.C. and 10 states — Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont and Washington — recreational use is also allowed.

Cannabis1
Baby marijuana plants thrive at the Kind Therapeutics cannabis cultivation facility in Hagerstown, Maryland. (Photo by Larry Luxner)

“The problem is that the federal government still considers it illegal, and that makes it difficult for researchers,” Beck said. “As we move forward to what’s likely to be a more permissive environment, we want to ensure that as legislation changes, we have a clear plan to move forward with research.”

Cannabis may be useful for several non-motor symptoms such as anxiety and weight loss associated with advanced Parkinson’s, he said, as well as for pain and stiffness.

“However, people with Parkinson’s can have cognitive impairment; some have psychosis and paranoia, and balance issues,” warned Beck, noting that falls constitute the leading cause of death for Parkinson’s patients. “Cannabis can lower blood pressure, which can lead to lightheadedness and falls, as well as hallucinations and paranoia, which may exacerbate the situation. It can also cause fuzzy thinking.”

A recent report, “Special Issue: Cannabis in Medicine,” that was published in the European Journal of Internal Medicine, concluded that cannabis reduces spasticity — muscular stiffness or involuntary spasms — in MS patients.

And data from two trials in Italy and the Czech Republic support the idea that Sativex, developed by Britain’s GW Pharmaceuticals, is effective in treating moderate-to-severe spasticity. The oromucosal spray is a formulated extract of the cannabis sativa plant and has earned approval in Australia, Canada, Israel and more than a dozen European countries.

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Gut-Brain Connection Issues are Critical to Understanding Parkinson’s, Review Contends

gut-brain connection

Upon breaking down two decades of research about how the gut affects the brain in Parkinson’s disease, a vision for studying the gut-brain connection for the next two decades has been laid out in a review article published in the Journal of Parkinson’s Disease.

Specifically, the article, “The Gut and Parkinson’s Disease: Hype or Hope?,” focuses on developing the areas of research for alpha-synuclein pathology, biomarkers, and the gut microbiota and how it relates to the gut-brain connection in the context of Parkinson’s disease.

In addition to its presence in the brain, the first descriptions of alpha-synuclein disease-associated changes in the enteric nervous system (ENS) —the nerve system controlling the gut — dates back as far as the 1960s, and has been confirmed through decades of research.

Some studies in humans and mice have shown that alpha-synuclein can spread from the gut to the ENS. However, whether atypical alpha-synuclein is transmitted from the gut all the way to the brain and cause or influence Parkinson’s disease is still widely debated.

“Better understanding the role of the gut in Parkinson’s disease will help us to understand the origin of the disease and to improve treatments,” explained Filip Scheperjans, MD, PhD, in a press release. Scheperjans is with the department of neurology, at Helsinki University Hospital in Helsinki, Finland.

“There is accumulating evidence that at least in some Parkinson’s disease patients, the origin of the disease may lie in the gut with possible involvement of abnormal protein aggregates, local inflammation, and the gut microbiome. Therefore, further studies into the role of the gut in Parkinson’s disease are important and may reveal new possibilities for diagnosis and treatment,” Scheperjans said.

The authors outline the importance of using the next 20 years for understanding how alpha-synuclein and the gut-brain connection work together to cause or influence Parkinson’s disease. Specifically, they were interested in how Parkinson’s disease relates to prion diseases — rare neurodegenerative disorders of contagious misfolded proteins — because of their similarities in disease presentation.

For example, in variant Creutzfeldt-Jakob disease (CJD), there is little doubt about the occurrence of gut-to-brain propagation of prions — transmissible,  disease-causing, misfolded proteins. The disease-linked prion aggregates form first in the ENS and peripheral lymphoid tissues, and then spread through the nervous system. Importantly, the prion aggregates in peripheral organs of variant CJD show clear differences when compared to prions in brain tissues.

These types of prion-related processes have not been fully elucidated in the context of Parkinson’s disease. To this end, the authors proposed four main gut-brain issues in Parkinson’s disease to be addressed in the upcoming decade:

  1. Comparing ENS and central nervous system alpha-synuclein aggregates: Comparing alpha-synuclein aggregates in the ENS to the ones found in the brain might be critical in understanding the role of the gut in Parkinson’s disease pathogenesis. If they are similar, this may suggest that alpha-synuclein transmission between the ENS and brain is linked in Parkinson’s disease.
  2. Linking gut permeability to Parkinson’s disease severity: Intestinal permeability — porosity — has been suggested to increase with Parkinson’s disease; however, this research is unclear. This is important to understand because a more porous intestine may be succeptible to initial alpha-synuclein aggregation in the ENS.
  3. Developing biomarkers: Alpha-synuclein protein has been shown to be detectable in the ENS of Parkinson’s patients. However, the biomarkers used to detect alpha-synuclein deposits in the ENS of Parkinson’s disease patients have provided conflicting results. Therefore, there is an urgent need to develop more techniques to detect alpha-synuclein aggregates in the gut, ENS, and central nervous system.
  4. Diagnosing and harnessing the gut microbiota: Changes in gut microbiota composition in Parkinson’s disease have been seen in populations all over the world. Understanding how gut microbiota and Parkinson’s disease are related needs to be studied in huge groups across multiple locations, as well as in animal models, to come up with population-specific approaches for diagnosis and harnessing the gut microbiota in Parkinson’s disease. There is a lot of potential in using the gut microbiota for diagnostic and therapeutic purposes in Parkinson’s disease.

“Our understanding and appreciation of the importance of the gut-brain connection in Parkinson’s disease has grown rapidly in recent years. We are confident that the coming two decades of microbiome-gut-brain-axis research will see an even accelerated development in this area that will reshape our understanding of the pathogenesis of Parkinson’s disease,” researchers concluded.

“The gut has emerged as one of the new frontiers in Parkinson’s disease research,” wrote Patrik Brundin, MD, PhD, and J. William Langston, MD, editors-in-chief of the Journal of Parkinson’s Disease. “We predict there will be several advances regarding the gut in the coming 20 years. Changes in the gut might be utilized to diagnose Parkinson’s disease earlier; new therapies targeting these changes might slow disease progression, reduce constipation, and improve gut function in patients who have already been diagnosed.”

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Agomelatine Worsens Motor Function, Neuron Loss in Parkinson’s Rate Study

agomelatine

A common depression treatment called agomelatine worsens Parkinson’s-related loss of dopamine-producing neurons, motor dysfunction, and protein oxidation, according to research in rats.

The study with that finding, “Effects of Agomelatine in Rotenone-induced Parkinson’s Disease in Rats,” was published in the journal Neuroscience Letters.

Neuroinflammation, oxidative stress, loss of dopamine-producing neurons in a brain area called substantia nigra, and degeneration of nerve fibers in a connected region known as the striatum, all underlie Parkinson’s disease.

Despite positive results in preclinical studies, work in patients with Parkinson’s has revealed that treatment with the hormone melatonin, which has anti-oxidant and anti-inflammatory properties, failed to ease motor dysfunction.

Agomelatine, developed by Servier for depression and also used to treat sleep disturbances in Parkinson’s patients, is an agonist for both melatonin-1 and melatonin-2 receptors, and also a 5-HT2C serotonin receptor blocker.

An agonist is a molecule that binds to and stimulates a receptor. The 5-HT2C serotonin receptor,  a potential therapeutic target in Parkinson’s disease, is present on the surface of different brain cells and binds to serotonin — a chemical produced by nerve cells that can act as a natural mood stabilizer.

Scientists at Ondokuz Mayıs University, in Turkey, used a rotenone-induced Parkinson’s rat model  to assess the effect of chronic treatment with agomelatine on behavioral, molecular, and tissue-related parameters.

Damage in dopamine-producing neurons was evaluated 10 days after delivery of rotenone, an agrochemical, into the left substantia nigra and the ventral tegmental area, which is part of the brain’s reward system. Stimulation of this system, also controlling motivated behavior, induces the release of dopamine.

Agomelatine (40 mg/kg) was administered over 18 days in a separate group of rats. This dose had suggested anti-oxidant and neuroprotective properties in prior studies. Tests of motor coordination and activity (rotarod and pole test) were conducted 24 hours after the last dose.

In the rotarod test rats are placed on a rotating rod and investigators count the number of times they fall. In the pole test the animals are head up on top of a vertical rod and the scientists measure the time it takes them to descend to their home cage. Of note, the pole test is a common way to study bradykinesia, or slowness of movement.

The results revealed that treatment with agomelatine worsened (increased) the number of rotations induced by apomorphine, a dopamine agonist that inhibits dopamine-producing neurons in the substantia nigra. Agomelatine also worsened rats’ motor function in both tests.

As for molecular analyses, agomelatine caused a pronounced increase in the levels of the advanced oxidation protein product (AOPP) — a marker of oxidative stress — compared to animals given rotenone only and control rodents. In contrast, levels of malondialdehyde — a product of lipid (fat) oxidative damage — were unchanged.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to cells and are associated with a number of diseases, including Parkinson’s disease.

Agomelatine also increased the levels of the protein caspase-3 — a marker of apoptosis, which refers to programmed cell death, as opposed to death caused by injury — but not of the enzyme PARP-1, whose activation has been associated with DNA damage and neurodegeneration in Parkinson’s.

The data further showed that agomelatine aggravated the rotenone-induced decrease in dopamine-producing neurons and higher cell volume in the striatum.

“Our findings in the current study showed that decreased rotarod performance and impaired motor coordination most likely happened due to the induced loss of dopamine-containing neurons,” researchers wrote.

“Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson’s disease pathology [symptoms],” they concluded.

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Study Highlights Importance of Personalized Parkinson’s Treatment

DBS IJLI Apokyn comparative study

Invasive treatment approaches for advanced Parkinson’s disease have differential effects on disease-associated motor and non-motor symptoms, a real-life observational study shows.

These findings suggest that selection of a treatment should be based on each patient’s particular clinical profile, researchers say.

The study, “EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease,” was published in Movement Disorders.

Parkinson’s is a progressive neurological disease mostly recognized for its motor symptoms, such as tremor, bradykinesia (impaired body movement control), and muscular rigidity. In advanced cases, oral therapies may not be sufficient to control these motor symptoms and patients often require device-aided therapies.

There are three well-established, safe, and effective treatments to improve quality of life and alleviate motor and non-motor symptoms of Parkinson’s disease: deep brain stimulation, intrajejunal levodopa infusion (IJLI), and Apokyn (apomorphine) infusion (APO).

In deep brain stimulation, electrodes are surgically implanted in certain areas of a patient’s brain. Through electrical signals received from a small device, the electrodes will stimulate these brain areas to produce dopamine — the chemical compound (neurotransmitter) lacking in Parkinson’s disease.

IJLI is one of the most influential therapies used in patients with moderate to late-stage Parkinson’s disease, shown to have positive effects on both motor and non-motor symptoms and quality of life. This approach uses a portable infusion pump that continuously dispenses levodopa gel through a tube inserted into the intestine.

Apokyn is an engineered therapy that mimics dopamine’s ability to stimulate nerve cells. Unlike other dopamine agonist agents, Apokyn is administrated by injection or continuous infusion using a pump.

Despite the demonstrated efficacy of these therapies, there is little information comparing their impact.

An international group of researchers, on behalf of the EUROPAR and the Non-motor Parkinson’s Disease Study Group of the International Parkinson’s Disease and Movement Disorders Society, compared the differential effects of DBS applied to the subthalamic nucleus (STN), IJLI, and APO in patients with advanced Parkinson’s disease.

The study included 101 Parkinson’s patients who underwent bilateral STN-DBS, 33 who received IJLI, and 39 patients who received APO treatment. Patients had a mean age of 62.3 years and had been diagnosed with the disease for a mean of 12.1 years.

Six months after receiving the treatment, patients were evaluated to determine changes in Parkinson’s symptoms.

Significant improvements concerning non-motor symptoms and motor-related complications were noted in the three groups of patients six months after receiving the treatment, as determined by the Nonmotor Symptom Scale (NMSS) and Unified Parkinson’s Disease Rating Scale-motor complications (UPDRS-IV), respectively.

Significant changes in quality of life, as assessed by the Parkinson’s Disease Questionnaire-8 Summary Index (PDQ-8 SI), were also reported by all treatment groups during follow-up.

IJLI and APO treatments were found to effectively prevent disease worsening during the follow-up period, according to Hoehn and Yahr scores, which rate severity of symptoms in Parkinson’s disease.

STN-DBS treatment reduced the amount of daily levodopa use by approximately 52%. As expected, levodopa equivalent daily dose remained stable in infusion therapies.

The three treatment approaches were found to have similar effects on dyskinesia (involuntary movements)/motor fluctuation ratios. In contrast, they had different effects on patients’ non-motor symptoms.

A more detailed analysis showed that STN-DBS had a significant positive effect on sleep and fatigue, mood and cognition, perceptual problems and hallucinations, urinary symptoms, and sexual function.

IJLI had a positive effect on sleep, mood, and cognition, and gastrointestinal symptoms, while APO therapy significantly improved patients’ mood and cognition, lessened occurrence of perceptual problems and hallucinations, as well as improved attention and memory.

In general, STN-DBS and IJLI seemed to improve non-motor symptom burden, and APO therapy was favorable for neuropsychological and neuropsychiatric symptoms and improved quality of life.

Patients who underwent IJLI treatment had more frequent non-serious adverse events (abdominal pain and gastrointestinal symptoms) immediately after the procedure, compared to those in the other two groups.

“Distinct effect profiles were identified for each treatment option,” researchers said. “This study highlights the importance of holistic assessments of motor as well as non-motor aspects of Parkinson’s that could provide a means to personalize treatment options to patients’ individual disease profiles.”

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