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Is It Possible to Be Organized and Focused with Parkinson’s?

organized

Sherri Journeying Through

You ever try to go back to the way things used to be? Try to think the way you used to think when distractions didn’t compete for your attention? When you had some semblance of  “normality”? Things seemed somewhat organized or orderly and most things made sense.

I used to make lists and be organized. At least I think I was.

Now, I’m not so sure. How could I be so organized and sensible for so long, but then have it disappear?

I don’t make lists now, but every once in a while, I try to. One thing is certain: I sure don’t feel quite so organized as I once did. I should make lists because I forget everything, or so it seems. I don’t know. I can’t remember!

When I watched my grandkids every day, I didn’t feel like this, so scattered. I didn’t have to feel so scattered. I knew what I was going to do every day. That task kept me focused.

I would change a diaper. Love on my grandkids. Feed them breakfast. Play with them. Take pictures of them. Walk with them. Love on them some more and change another diaper.

Then I’d feed them lunch, play with them again, take more pictures, and make sure they knew they were loved.

I would read to them, change another diaper, rock them as I sang over them before they would fall asleep for their nap, watch “Rapunzel” or “Swamp People” as they woke up. We’d go for an afternoon walk, picking out four M&M’s, one always red. Always more love. Always more kisses. The daily routine of having my grandkids helped me feel more in control while having Parkinson’s disease.

Watching my grandkids was “easy” most days. But on the days when the pain didn’t let up and I felt wobbly and shaky and things didn’t work the way I want them to, well, those days were so much harder.

Distractions are immeasurable around here.

OK, around me anyway. They seem to follow me everywhere. Like the other day, my husband was telling me about something … I don’t remember exactly what. But then I saw this bird and … what was I saying? Or wait. What was he saying?  

When I had my grandkids around, I didn’t have to think about organization. I just did it. It just happened. Remembering? I had someone around to help me remember. She followed me everywhere and she helped me remember everything, such as where I had left her little brother’s dirty diaper. Just kidding. I never did that, you know, forgot where I left a dirty diaper. I’ve never been that distracted, I don’t think. I don’t know. I can’t remember!

Anyone else ever feel that way? Anyone ever been that way? 

***

 

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Grant Will Enable Pharmacologist to Expand Gaucher Disease Research to Parkinson’s

pharmacologist

As it sometimes happens in rare-disease research, a prospective therapy for one disorder has potential to help another. So it is that, at Temple University, molecular pharmacologist Marlene Jacobson, PhD, has been awarded a joint grant to explore how a discovery could affect Parkinson’s disease (PD) patients.

Specifically, The Michael J. Fox Foundation (MJFF) and The Silverstein Foundation for Parkinson’s with GBA want Jacobson to further study compounds that she found could reverse Gaucher disease Type 2, the most severe form of the lysosomal storage disorder caused by deficiencies in the glucocerbrosidase (GCase) protein due to mutations in the GBA1 gene.

Some 10 percent of PD patients carry the same mutation, making it the most common genetic disease risk. GCase allows brain cells to clear debris via lysosomes, which are special compartments within cells that digest and recycle different types of molecules. Patients with reductions in GCase activity can’t effectively remove debris, which scientists widely hypothesize is toxic to brain cells.

“I came to Temple because I wanted to make a difference in patients’ lives,” said Jacobson in a press release. “I wanted to use my drug discovery skills and apply them to help patients who are underserved.”

An associate professor of pharmacodynamics in Temple’s Department of Pharmaceutical Sciences, and associate director of its Moulder Center for Drug Discovery Research, Jacobson will expand her Gaucher research to include PD patient cells that have the GBA1 mutation. She joined Temple six years ago after 24 years in research and drug discovery for Merck Research Laboratories.

”The key is we have the full disease environment in the cell,” said Jacobson. “We’re very fortunate to have access to these patient cells, and we treat them with respect as they provide an advantage in demonstrating a compound’s potential to reverse a disease state.”

Parkinson’s patients with the GBA mutation develop the disease at an earlier age, she said, and their cognition symptoms are worse relative to patients without the mutation.

”The link between mutations in Gaucher disease and Parkinson’s disease suggests a common disrupted mechanism or pathway. We can translate the compounds we have found to improve Gaucher and Parkinson’s.”

Currently, there is no effective treatment for Gaucher disease Type 2. In Parkinson’s, available therapies are focused on raising dopamine levels in patients’ brains, or on controlling the symptoms themselves.

“This work is so exciting and so primed for discovery,” Jacobson said, adding that the pharmaceutical industry is increasingly looking to academic investigators for breakthrough ideas leading to new treatments.

The amount of the grant was not disclosed.

The MJFF aims to find a cure for Parkinson’s through an aggressively funded research agenda, and to help develop improved therapies for current patients. The Silverstein Foundation is focused on finding ways to prevent the onset of Parkinson’s in GBA-mutation carriers.

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Medical Marijuana ‘Can Help Everyone,’ Says Director at Maryland Cannabis Facility

cannabis plant

Warning the reporter accompanying him not to take any pictures, veteran horticulturalist Michael Castleman punches an electronic code and unlocks the door to Room 209, nicknamed the “Mother Room.”

Photography is indeed forbidden inside this living vault, which contains 20 phenotypes of cannabis plants thriving under the glare of 25 ceramic metal halide lamps for 18 hours a day. The plants, arranged in groups of four and narrowed down from an original 1,000 seeds, bear colorful names like Oro Blanco, Bubblegum Diesel, and Sunshine Daydream.

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Marijuana plants of the Oro Blanco variety dry in Room 212 of the Kind Therapeutics cannabis cultivation facility in Hagerstown, Maryland. (Photos by Larry Luxner)

“This is the heartbeat of the whole facility,” Castleman told BioNews Services, publisher of this website. “We keep mothers 12 to 16 weeks before we replace them, and we take cuttings every day. If anything happens to these plants, we’re out of business.”

That business is Kind Therapeutics USA of Hagerstown, Maryland — which holds a license to produce cannabis products in Maryland under a management agreement with MariMed, a publicly traded company based in Massachusetts. The venture’s various offerings contain both cannabidiol(CBD) and tetrahydrocannabinol (THC), the main psychoactive compound in cannabis.

The company occupies a newly renovated 180,000-square-foot facility and a 10,000-square-foot processing lab that for 130 years housed the Statton furniture factory. Located across the street from a livestock auction house, the sophisticated operation now ranks among the East Coast’s largest suppliers of cannabis for the U.S. medical marijuana industry.

“Hagerstown is very depressed — one of the most economically depressed areas in the state — so we’re bringing life and jobs to this area,” said Abigail Diehl, Kind Therapeutics’ director of business development and sales. “We’re already Maryland’s largest indoor cannabis grower.”

Kind’s product lines include Kalm Fusion powdered tincture and chewable tablets in either mango lime coconut or green tea lemonade. There’s also Nature’s Heritage extracts, concentrates, and vape pens, as well as six types of LucidMood vape pens advertised online under the slogan “Elevate your mood without clouding your mind.”

Medical use legal in 33 states and D.C.

With other entrepreneurs, Diehl is betting that the expanding U.S. legalization of cannabis for medicinal use will boost sales of the company’s products to treat everything from skin cancer to multiple sclerosis (MS).

At the moment, 33 states and the District of Columbia have declared medical marijuana legal; in D.C. and 10 states — Alaska, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington — recreational use is also allowed, even though the federal government still considers marijuana in all its forms illegal.

Cannabis7
Boxes of “Healer” CBD/THC cannabis drops await distribution at the Kind Therapeutics.

Internationally, Canada is now the world’s largest legal marijuana market, having legalized its cultivation and sale in October 2018 through the Cannabis Act. Uruguay became the first country to fully legalize marijuana in 2013, with sales permitted in local pharmacies.

Last month, Israel became the third country — along with the Netherlands and Canada — to allow the export of medical cannabis. Tikun Olam, which has given MariMed exclusive rights to produce its cannabis products in Maryland, is among Israel’s top cannabis producers.

“The laws are constantly changing, so it’s difficult to get an accurate number. But this is going to be a $70 billion industry in coming years,” said Diehl, whose family has been a major Maryland fruit and vegetable distributor for nearly half a century. “When the state legalized cannabis in 2016, my friends said I needed to get into this business too, so I jumped in full throttle.”

The U.S. Food and Drug Administration (FDA) made history when, in June 2018, it approved a first marijuana-derived therapy to treat any disease. In this case, the cannabidiol was Epidiolex — developed by Britain’s GW Pharmaceuticals — to be given to patients with Dravet and Lennox-Gastaut syndromes, both severe forms of epilepsy.

“This FDA ruling speaks volumes,” Diehl said. “They’re saying, ‘guys, cannabis is not just for people who want to get high. This is a real medicine that can help everyone, including children.’”

Hype vs. data

A 2018 report, “Special Issue: Cannabis in Medicine,” found that cannabis-based productscan reduce spasticity — muscular stiffness or involuntary spasms — in MS patients.

Data from two trials, in Italy and the Czech Republic, support the idea that GW’s Sativex is effective in treating moderate to severe spasticity. The oromucosal spray is a formulated extract of the cannabis plant, and has been approved in Australia, Canada, Israel, and more than a dozen European countries.

Cannabis4
Michael Castleman examines baby marijuana plants.

For those with cystic fibrosis, cannabis — in its edible but not smoked form — improves appetite, a key consideration since CF patients are often undernourished. Marijuana’s anti-inflammatory properties may also help reduce inflammation in the lungs, although its overall effects on those with CF remain to be seen.

Cannabis use has also generated vast interest among people with Parkinson’s disease, prompting the Parkinson’s Foundation to plan its first conference on that subject in Denver (March 6-7).

A recent studyjointly conducted by the nonprofit group and Northwestern University found that 80 percent of Parkinson’s patients report using cannabis, and 95 percent of neurologists have been asked to prescribe medical marijuana. But only 23 percent of doctors have received formal education on the subject.

“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 Hospitaland co-chair of the upcoming conference, said in a recent press release.

“To date, there is more hype than actual data to provide meaningful clinical information to patients with Parkinson’s.”

Legal and financial obstacles

This is an extremely regulated industry. In Hagerstown, the premises are under constant surveillance, all plants are accounted for, and all 61 employees had to pass a criminal background check before joining Kind Therapeutics.

Castleman, one of those employees, is happy to show off Room 205, which contains around 400 cannabis plants in living soil. Down the hall is Room 212 — the drying room — which contains upwards of 2,000 plants. Here they hang for exactly 21 days, at exactly 60 percent relative humidity.

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The entrance to the Hagerstown, Maryland, facility.

“We’re doing a slow cure on the flowers,” Castleman said. “A lot of companies do a ‘fast dry’ where they crank the temps up to 70 degrees and have everything dry in five days. But that degrades the integrity of the flower. Our system preserves the trichomes and increases the terpene profile.”

In partnership with Tikun Olam, Kind Therapeutics opened a seed-to-sale dispensary — known as First State Compassion — in Wilmington, Delaware, in 2015. MariMed also operates in Rhode Island, Massachusetts, Illinois and Nevada, and along with GenCanna produces hemp in Kentucky.

Because medical marijuana isn’t legal nationwide, Kind Therapeutics cannot do its banking with Wells Fargo, Bank of America, or any other multistate bank in the U.S. Instead, it’s turned to Severn Saving Bank, a local institution, for about 90 percent of its financial needs.

Medical regulation is another issue.

“In some states, if you have a prescription for opioids from your doctors, you can take it to any marijuana dispensary and get cannabis instead,” Diehl said. “Yet doctors are still pushing opioids, and a lot of them are scared to touch cannabis because of the federal ban.”

Looking to the future

Maryland, Diehl said, still needs to allow for cannabis in a variety of edible forms, like gummy bears or fruit chews, because many chronic disease patients don’t want to smoke. “So they’re making food on their own” like brownies and cookies, she added, and they don’t know the concentrations to do it right.

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Baby marijuana plants at the Kind Therapeutics cultivation facility.

Ryan Crandall, MariMed’s chief production officer and a veteran of the computer software industry, thinks it crucial that cannabis products be affordable as well as effective. For example, a 100 mg bottle of “Healer” tincture costs $32 and lasts one to two weeks.

“It’s a premium product at a very economical price point, because we want to get this medical product into patients’ hands economically,” he said.

Another product, known as Rick Simpson Oil (RSO), is named after the Canadian cannabis activist who developed it. RSO is notable because it’s a full-plant extract that contains higher levels of THC.

“The lion’s share of people using RSO are getting incredible medical benefits from it, and I’ve met two people in the last month alone who are on maintenance doses and have been cancer-free for years,” Crandall said. “One patient with stage 3 lung cancer was given six months or less to live. He was on chemo and his doctor recommended an RSO regime. He believes the thing that’s keeping him cancer-free is RSO.”

More than 83,000 patients are now registered with the Maryland Medical Cannabis Commission, which entitles them to buy cannabis products at an authorized dispensary. Yet Diehl said it’s been an uphill battle to persuade county authorities to approve new dispensaries around the state — though the landscape does appear to be changing as medical cannabis gains national acceptance.

“A lot of counties just treat us as a CVS now, which is how it should be,” Diehl said in a reference to the U.S. pharmacy chain store. “Some people are still completely opposed to it, and scared that it’s an illegal drug. They don’t want dispensaries in their back yard, but things change when it hits home, when someone they love gets sick and this is going to benefit them.”

Even so, she said, “I don’t want to have it come to that just to get them on board.”

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Parkinson Voice Project to Host Lecture on Making the Most of Exercise Routines

PVP exercise lecture

The Parkinson Voice Project (PVP) is hosting a complimentary educational lecture that will focus on optimizing exercise strategies for Parkinson’s disease patients and caregivers.

The presentation “Packing Some ‘Punch’ Into Your Parkinson’s Exercise Routine” will take place at 10:30 a.m. CST Feb. 9 at PVP, in Richardson, Texas. It will be live-streamed on the PVP website and on Facebook. A video of the lecture will be posted online by Feb. 15. (Those who wish to attend in-person may register here, or call (469) 375-6500 for more information.)

The session will address the importance of exercise for those with Parkinson’s in managing symptoms and maximizing function, as well as cutting-edge concepts in exercise strategies. The hope is that participants will better understand how to apply specific training to address specific impairments. The lecture also will explore why boxing training has become a popular way for patients to fight symptom progression.

By lecture’s end, it is hoped participants will be able to describe physical motor challenges associated with Parkinson’s disease, list three physical therapy exercises specifically developed to treat Parkinson’s, and describe three benefits of non-contact boxing for those diagnosed with the disease.

The lecture will be presented by Michael Braitsch — also known as “Dr. Mike”  — a board-licensed doctor of physical therapy, a former amateur boxer, a kinesiology professor, and an internationally certified fight referee. In addition to treating individual patients, Braitsch leads group exercise programs to help people with chronic conditions move and feel better. 

A board member of the Adaptive Martial Arts Association and the University of Texas Southwestern Medical Center Adaptive Sports Expo, he’s also actively researching the effects of non-contact boxing training on Parkinson’s-associated impairments. In addition, Braitsch offers Tai chi and South Paws boxing classes for Parkinson’s patients.

According to PVP’s website, Braitsch hopes to foster community wellness by changing the way physical therapy is structured for people with chronic and progressive conditions.

Held at PVP’s Clark and Brigid Lund Parkinson’s Education Center, the presentation is part of the Parkinson’s Lecture Series featuring disease experts. On Jan. 12, PVP hosted a lecture that emphasized nutritional health and disease management. More lectures this year will include “New and Emerging Therapies in Parkinson’s,” “Dance for Parkinson’s,” and “The Power of Perseverance for Living with Parkinson’s.” Visit this site for a complete listing.

The non-profit PVP aims to preserve the voices of those with Parkinson’s and other neurological diseases through intensive speech therapy, continued support, research, education and community awareness. It hopes to team up with other speech language pathologists to reproduce its SPEAK OUT! and LOUD Crowd therapy programs globally. By marrying speech, voice and cognitive exercises, the programs seek to lessen speech problems related to Parkinson’s.

In a related Parkinson’s News Today story, experts contend that exercise that motivates Parkinson’s patients to push limits can offer a range of benefits. 

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Nicotine May Protect the Brain from Toxic Trace Metals Linked to Parkinson’s, Cell Study Finds

nicotine study

Nicotine may protect the brain from manganese and iron metal trace elements thought to be involved in the onset of Parkinson’s disease, a study based on a disease cell model reported.

The study, “Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease,” was published in Neurochemistry International.

Parkinson’s is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — leading to motor and cognitive impairments.

Although the exact causes of Parkinson’s are not yet fully understood, scientists believe the accumulation of metal trace elements, such as manganese and iron, could play a role in its onset. At low concentrations, these elements are crucial for cell growth and physiological functions; indeed, they are important for all growth and healthy workings of the body. But at high levels, they become toxic, and have been associated with several neurodegenerative disorders, including Parkinson’s.

Nicotine, a potent stimulant originally found in plants that activates the nicotinic acetylcholine receptor (nAChR) in the brain, has been shown to protect dopaminergic neurons from damage caused by different types of toxins. However, no study had addressed possible neuroprotective effects of nicotine against specific metal trace elements.

The new study from Howard University College of Medicine examined the effects of nicotine on toxic manganese and iron elements in a neuroblastoma cell line (SH-SY5Y), a standard in vitro model to study Parkinson’s disease cells, due to their dopaminergic activity.

When researchers exposed SH-SY5Y cells to high concentrations of manganese or iron for a day, toxicity levels increased by 30% and 35%, respectively. Pretreatment with nicotine was seen to completely prevent these toxic effects.

As expected, nicotine’s neuroprotective properties against toxic trace elements were lost when researchers used different types of nicotinic receptor antagonists (molecules that block the activity of nAChRs). This was true for “dihydro-beta erythroidine (DHBE), a selective alpha4-beta2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist,” the study noted.  

“In summary, the results of this study provide evidence for neuroprotective effects of nicotine against toxicity induced by Mn [manganese] or Fe [iron] in a cellular model of PD [Parkinson’s disease],” the researchers wrote.

“Moreover, both high and low affinity nicotinic receptors (i.e., alpha4-beta2 and alpha7 subtypes) appear to mediate the effects of nicotine. Thus, utility of nicotine or nicotinic agonists in trace element-induced Parkinson-like syndrome may be suggested,” they concluded.

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Merger of New Mexico Parkinson’s Coalition, PMDAlliance Expected to Improve Patient Services

PMDAlliance merger

The recent merger of the New Mexico Parkinson’s Coalition (NMPC) and national nonprofit Parkinson & Movement Disorder Alliance (PMDAlliance) is expected to significantly boost support services for Parkinson’s patients in the New Mexico area, according to the organizations.

“I’m a firm believer in mergers when the organizations share similar missions and are compatible in their purpose and goals,” Sarah Jones, CEO of PMDAlliance, said in a press release. “Bringing everything under one virtual roof creates exponential benefit. It saves money and allows us to serve more people in need.”

As a result, the organizations expect a fourfold increase in the programs offered to patients with Parkinson’s and other movement disorders in New Mexico.

The coalition website states that “the tough decision was made knowing that there would be new, innovative programs and support brought to New Mexico as well as funds to hire a community engagement manager,” adding that more patients will have access to education, exercise programs, and events.

These improvements in services will be expanded to include smaller areas in the state rather than being limited to larger cities such as Albuquerque, Santa Fe, and Las Cruces.

“Working collaboratively, we can expand our reach in New Mexico, including extending services to our Native American neighbors and rural communities,” said Karen St. Clair, a former coalition board member. “PMDAlliance is passionate about services, just as the coalition is. By merging we can allocate more resources to service delivery instead of administration.”

Next year, the PMDAlliance will bring to the state educational events such as a support group for leadership training, a retreat for caregivers and their partners, and a program that focuses on new medical treatments.

The NMPC will be folded into the PMDAlliance umbrella, although it will continue to co-brand — using both organizations’ logos — until the transition is complete in about eight months, St. Clair said in a phone interview with Parkinson’s News Today. After that, its website will discontinue. The coalition was formed the year after the American Parkinson’s Disease Association’s decision in 2013 to leave New Mexico.

Operating nationwide but with no brick-and-mortar base, PMDAlliance provides educational workshops for organization leaders and those affected by movement disorders. Its overall mission is to improve patients’ lives.

According to the Parkinson’s Foundation, about 60,000 U.S. residents are diagnosed with Parkinson’s annually.

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Dopamine Depletion Not Associated with Non-motor Symptoms in Key Parkinson’s Brain Area, Study Shows

dopamine, Parkinson's, non-motor symptoms

Dopamine depletion in a brain region called the striatum does not correlate with the severity of non-motor symptoms in patients with Parkinson’s disease, according to a new imaging study.

The research, “Lack of association between dopamine transporter loss and non-motor symptoms in patients with Parkinson’s disease: a detailed PET analysis of 12 striatal subregions,” was published in the journal Neurological Sciences.

Loss of dopamine-producing neurons in a brain area called substantia nigra and reduced release of this neurotransmitter in the striatum —  a brain region that plays a critical role in motor and reward systems, as well as several aspects of cognition — leads to the development of hallmark Parkinson’s motor symptoms.

Abnormal accumulation of misfolded alpha-synuclein protein further leads to progressive loss of neurons.

In contrast to motor manifestations, the link between dopaminergic deficits in the striatum and Parkinson’s diverse non-motor symptoms — that may include sleep disturbances, constipation, depression, pain, fatigue, urinary difficulty or dementia — is still controversial.

To address this gap, researchers used an imaging technique called positron emission tomography (PET) with a radioligand (a radioactive-labeled chemical compound) to investigate the correlation between non-motor symptoms and dopaminergic deficits in 12 subregions of the striatum.

The scientists used diverse scales for symptoms that included depression, anxiety, fatigue, sleep quality, global cognition and executive function, which comprises goal-directed actions and adaptive responses.

The study included a total of 41 Parkinson’s patients (53.7% men, mean age 67.5 years, mean disease duration 2.3 years). Activity of the dopamine transporter (DAT) protein — responsible for the uptake of dopamine into neurons — and dopamine concentration were calculated in each subregion of the striatum.

“To the best of our knowledge, this study was performed with the most segmentalized subdivisions of the striatum as well as the most numerous nonmotor symptoms,” researchers wrote.

Motor symptoms were evaluated using the Unified Parkinson’s Disease Rating Scale-part III, cognitive function with the Montreal cognitive assessment, and executive function with the frontal assessment battery. The Beck depression inventory, Beck anxiety inventory, Parkinson’s disease sleep scale, fatigue scale, and non-motor symptoms scale (NMSS) also were used.

The results showed that the higher the dopamine depletion in all striatal subregions, the greater the severity of motor complications. As for non-motor symptoms, a simple statistical correlation revealed that depression was associated with dopamine depletion in the left anterior putamen (AP), bilateral posterior caudate nucleus (PC), posterior putamen (PP), and ventral putamen (VP); anxiety was linked with the left posterior putamen and VP; sleep disturbances were associated with the left anterior caudate nucleus (AC), bilateral PC, and bilateral PP; and the NMSS score correlated with left AC and ventral striatum, and bilateral PC, AP, PP and VP. Cognitive function and fatigue did not correlate with any striatal subregion.

However, upon using a more complex statistical method (multiple linear regression analysis) to determine which specific parameter might be independently associated with dopaminergic depletion of striatum, the team found that dopaminergic depletion in all 12 subregions was not related to any of the non-motor symptoms. In contrast, dopaminergic deficit in the right AP and PP were associated with motor symptoms’ severity.

“Striatal dopaminergic depletion was not significantly correlated with any of the various non-motor symptoms in [Parkinson’s],” researchers wrote.

Noting that a prospective study with more participants is required to confirm the findings and that dopaminergic medications may have affected non-motor symptoms, scientists added that the findings suggest that “non-dopaminergic systems are significantly implicated in the pathogenesis of non-motor symptoms in patients with [Parkinson’s].”

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MJFF and Blackfynn Collaborate on Parkinson’s Study to Discover Biomarkers

MJFF and PPMI

The Michael J. Fox Foundation (MJFF) and Blackfynn are joining forces to make optimal use of an initiative that could uncover Parkinson’s disease biomarkers and bring about new therapies.

Called the Parkinson’s Progression Markers Initiative (PPMI), the MJFF-backed effort is an ongoing observational study of more than 1,300 volunteer participants both with and without Parkinson’s to validate biomarkers and, over time, identify disease risk factors. Participants undergo a battery of tests and assessments.

Biomarker discovery is critical in the quest for therapies that can slow or halt Parkinson’s progression. Specifically, it would allow for earlier diagnosis, better disease tracking, and more efficient therapy tests. Current treatments only temporarily ease symptoms.

To glean as much as possible from patient data, Blackfynn will lead the PPMI Advanced Analytics Core, established to analyze biomarker discovery. The firm has a data integration and analysis platform it uses to drive development of therapies, and advance translational research for neurological diseases.

“The goal of the Advanced Analytics Core is to accelerate our analysis of the comprehensive within-subject data collected through PPMI,” Kenneth Marek, PPMI principal investigator, said in a news release.

“By combining this rich, multimodal data with Blackfynn’s platform and data science expertise, we hope to uncover insights into the determinants of [Parkinson’s disease] progression that will lead to new therapies and improved quality of life for patients.”

The Blackfynn infrastructure incorporates a full complement of medical and scientific data to enable swift assessment of data correlations and complex data visualizations. PPMI scientists plan to use the platform to interpret data, develop verifiable hypotheses, and better collaborate with the goal of more targeted translational research.

“Our work with MJFF and the PPMI investigators will maximize the value of this important patient dataset and help drive novel discovery with the potential to lead to the development of effective therapies for patients with PD,” said Amanda Christini, president of Blackfynn.

“Blackfynn will enable a new lens through which discoveries can be made, by looking at all raw and metadata together, in context, to find new patterns that are otherwise obscured when data are in isolation.”

Citing an unwieldiness caused by an abundance of Parkinson’s-related biomarker information, an editorial in the journal The Lancet Neurology heralded the efficiencies of collaborative research. Particularly, it applauded the Accelerating Medicines Partnership for its efforts to find a Parkinson’s cure.

As for the PPMI, five-year results have already shown that clinical trials in patients with early-stage Parkinson’s may benefit from assessing markers of disease progression — namely, changes in the Movement Disorder Society (MDS)-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and dopamine transporter imaging.

Launched in 2010, PPMI is underway in the United States, Europe, Israel and Australia.

The MJFF is dedicated to finding a cure for Parkinson’s by funding research and ensuring the development of improved therapies for those living with the disease. It has funded more than $800 million in research to date.

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Calcium Channels May Be Therapeutic Target in Parkinson’s, Stem Cell Study Suggests

calcium channels, Parkinson's

Targeting specific calcium channels in dopamine-producing neurons may be a therapeutic target for Parkinson’s disease, according to research involving cells derived from Parkinson’s patients.

The study, “T-type calcium channels determine the vulnerability of dopaminergic neurons to mitochondrial stress in familial Parkinson’s disease,” was published in Stem Cell Reports.

For most Parkinson’s patients, symptoms are idiopathic, or of unknown cause, making it difficult to understand the relationship between various factors that may cause disease. However, roughly 10% of patients show the familial incidence of Parkinson’s disease, which allows researchers to study the underlying mechanisms of disease in these patients, helping them understand common causes in all patients, as well as unravel potential therapeutic targets.

Prior generation of induced pluripotent stem cells (iPSCs) from patients with familial Parkinson’s successfully replicated the disease processes. iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

Aiming to provide iPSCs-based ways to treat neurological diseases, Keio University School of Medicine and Eisai started a collaboration in 2013. Their joint research led to the generation of dopamine-producing neurons — progressively degenerated in Parkinson’s, leading to its motor symptoms — from familial Parkinson’s patients’-derived iPSC.

They also established a drug library of more than 1,000 existing compounds to screen treatment candidates.

The study, partially funded by Eisai, used neural progenitor cells, which differentiate into brain cells, including neurons, derived from two familial Parkinson’s disease patients with mutations in the PRKN gene (PARK2 type). PRKN is the most commonly implicated gene in young-onset Parkinson’s disease.

“The current procedure is more advanced in terms of simplicity and robustness for neuronal differentiation, enabling us to perform screening without complicated work,” researchers noted.

The approach enabled the efficient generation of dopamine-producing neurons in vitro, which, compared to healthy neurons, had reduced size of projections, as well as increased oxidative stress and apoptosis, or “programmed” cell death, as opposed to cell death caused by injury.

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.

Gene editing in iPSCs to create similar mutations led to the same disease-related alterations.

Researchers also found that Parkinson’s-derived neurons were more susceptible to mitochondrial stress induced by rotenone, an agrochemical that acts as a mitochondrial inhibitor. Mitochondria are small cellular organelles that provide energy and are known as cells’ “powerhouses”.

Screening their library enabled the identification of several compounds able to suppress rotenone-induced apoptosis, particularly T-type calcium channel blockers benidipine (used for the treatment of blood pressure) and ML218.

These particular calcium channels are present in many neuronal cells within the central nervous system. They help mediate calcium influx into neurons after passing electrical impulses to communicate among themselves.

These blockers also were able to lower stress-induced apoptosis in dopamine-producing neurons derived from patients with a different type of familial Parkinson’s (PARK6), caused by a mutation in the PINK1 gene. These neurons also had higher levels of T-type calcium channels.

“These findings suggest that calcium homeostasis in [dopamine-producing] neurons might be a useful target for developing new drugs for [Parkinson’s] patients,” researchers wrote.

“In summary, we have established a robust platform to model [Parkinson’s] in a dish and revealed an additional layer of the pathogenesis of PD, offering a potential therapeutic target,” they added.

Future work will use experimental approaches to model the brain in vivo and to have different types of brain cells in the same dish with the goal of validating these therapeutic targets.

Of note, six of the study’s authors are employees at Eisai.

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New Technique Uses Beacon-like Signal to Treat Motor Impairments in Parkinson’s Mice

Parkinson's DART, HaloTag,

A new method called DART ensures a compound injected into a region of the brain will affect only specific cell types. This approach was able to reverse Parkinson’s-related motor impairments in mice, and may hold the potential to provide more effective treatments.

Although current research techniques such as gene editing and pharmacology provide detailed information of how specific genes or compounds affect brain cells, they are not able to reveal distinctive responses among diverse cell types.

Aiming to address this gap, Michael Tadross, MD, PhD, a biomedical engineer at Duke University, and his team have developed DART — Drugs Acutely Restricted by Tethering.

This method works by genetically programming a cell type to express a sort of GPS beacon — a cell surface receptor protein called HaloTag. This beacon — an enzyme derived from bacteria that is inert — then attracts compounds loaded into the brain “attached” to a special molecule that binds to HaloTag.

This delivery approach, which was previously published in the journal Science, enables researchers to use concentrations of therapeutic molecules that do not affect other cell types.

The DART method is being used to better understand the root causes of Parkinson’s disease. This disorder is characterized by progressive loss of dopamine-producing neurons that connect two key brain regions involved in movement control — the substantia nigra and the striatum. As a result, lower levels of dopamine in the striatum lead to Parkinson’s motor symptoms. Most current treatment strategies aim to restore dopamine levels.

Another brain alteration found in Parkinson’s patients is an increased strength of the sites of neuronal communication (called synapses) between neurons that express AMPA receptors, the most common type of receptor mediating excitatory nerve transmission in the brain.

Tadross and his team induced the death of dopamine-producing neurons in the striatum of mice, which led to Parkinson’s-related motor impairments. The team also engineered AMPA-expressing cells to produce the HaloTag protein.

Treating mice with a common AMPA receptor blocker bound to the HaloTag ligand reversed motor changes, enabling mice to move normally.

Overall, besides providing new insights into how the brain works, the findings suggest that designing effective treatments for Parkinson’s and other neuropsychiatric diseases may require better understanding of the relationship between specific types of cells and symptoms for more precise therapies.

“The approach may provide a platform whereby the mechanism of action for widely prescribed drugs can be examined with cellular specificity in animal models of several disorders,” researchers wrote.

“Such studies could inform new translational strategies by advancing nonobvious drug combinations, or by providing a road map for the design of bivalent therapeutics [that can simultaneously bind to two different targets],” they concluded.

Recently, Tadross received a $2.4 million National Institutes of Health (NIH) Director’s New Innovator Award, as part of its High-Risk, High Reward Research program. With this five-year award, Tadross will also use DART to study the molecular basis of addiction. Dopamine-producing neurons in mice will be targeted in an effort to have more knowledge about addiction and recovery.

“This program supports exceptionally innovative researchers who have the potential to transform the biomedical field,” NIH Director Francis S. Collins, MD, PhD, said in a press release.

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