LRRK2 Inhibitors May Benefit Parkinson’s Patients With and Without Genetic Mutation, Study Finds

LRRK2

Inhibiting the activity of LRRK2 kinase — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — may benefit patients both with and without this disease-related mutation, a study finds.

Molecules that block the activity of the LRRK2 kinase — such as DNL201 and DNL151, both being developed by Denali Therapeutics — are currently being tested in clinical trials.

The results of this study, “LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease,” were published in Neurobiology of Disease. The research was supported by the Michael J. Fox Foundation.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. Evidence indicates that in people with idiopathic Parkinson’s, in which the disease has no known cause, the LRRK2 protein is overly active, regardless of the patient’s mutation status — whether or not they have a mutated LRRK2. That overly active protein leads to the malfunctioning of lysosomes, the special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of  protein aggregates, or clumps, called Lewy bodies, which contribute to Parkinson’s and, therefore, neurodegeneration.

Therapies that can inhibit, or block LRRK2 are currently being tested in human clinical trials. However, it is still unclear whether blocking LRRK2 protein activity in people with idiopathic Parkinson’s can prevent lysosomal dysfunction and consequent neurodegenerative processes.

To learn more, investigators at the University of Pittsburgh now studied post-mortem brain samples, specifically from a motor brain region called the substantia nigra, which is severely damaged in Parkinson’s. The researchers characterized lysosomal abnormalities in the surviving dopaminergic neurons — the main source of dopamine, the loss of which is a hallmark of this disease — of idiopathic Parkinson’s patients.

When compared with healthy controls, Parkinson’s patients had more abnormal lysosomes. These changes occurred during the early stages of lysosomal development, the researchers found.

The team then investigated whether these post-mortem cellular findings could be replicated in an animal model of Parkinson’s. Rats were given two distinct dose regimens of rotenone, a pesticide that inhibits mitochondria, or the “powerhouses” of cells. Blocking mitochondria leads to cellular death and the onset of parkinsonian features.

Nine to 14 daily doses of rotenone reproduced many idiopathic Parkinson’s features, including lysosomal defects. This caused neurodegeneration in the striatum and substantia nigra, two brain areas involved in motor control.

Interestingly, five daily doses of the pesticide weren’t enough to cause cell death, but did increase the accumulation of Parkinson’s-related alpha-synuclein protein and produce changes in lysosomes.

“These data demonstrate that, in rotenone-treated rats, [alpha]-synuclein protein levels rise in the dopaminergic neurons prior to the onset of frank neurodegeneration,” the researchers said.

When overactive LRRK2 was blocked in rotenone-treated rats, the protein’s activity was reduced. That, in turn, improved the overall health of lysosomes and prevented the accumulation of alpha-synuclein. These effects were observed in animals without a genetic predisposition to develop Parkinson’s, suggesting that the LRRK2 kinase inhibitors may be effective beyond LRRK2-mutated patients.

“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” J. Timothy Greenamyre, MD, PhD, the study’s lead author, said in a press release.

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Brain Networks May Dictate Likelihood of Developing Impulse Control Disorders in Parkinson’s, Study Finds

impulsivity, Parkinson's

The way the brain of a Parkinson’s disease patient is wired may help doctors predict if he or she will develop impulse control disorders following dopamine replacement therapy, a study finds.

The results, “The structural connectivity of discrete networks underlies impulsivity and gambling in Parkinson’s disease,” were published in the journal Brain.

The main cause of motor symptoms in Parkinson’s disease is a lack of dopamine (a key brain chemical) resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements.

Higher doses of dopamine agonists — which act as a substitute for (or mimic) dopamine in the brain — and longer treatment periods have been shown to make Parkinson’s disease patients more prone to developing impulse control disorders, such as gambling, compulsive shopping, overeating, and compulsive sexual behaviors.

This impulsivity may be mediated by the patient’s inability to evaluate rewards appropriately or to inhibit inappropriate choices.

“Despite prior work suggesting that distinct neural networks underlie these cognitive operations, there has been little study of these networks in Parkinson’s disease, and their relationship to inter-individual differences in impulsivity,” the researchers noted.

To shed additional light on the matter, these investigators from the University of Queensland and QIMR Berghofer Medical Research Institute in Australia, evaluated microstructural changes in the brains of 57 Parkinson’s patients (19 women and 38 men; mean age of 62 years).

Using high-resolution diffusion magnetic resonance imaging, the team studied, on a microscopic and network-related level, how a patient evaluated rewards and inhibited responses, and how these were associated with dopamine replacement therapy.

Trait impulsiveness and compulsivity, disinhibition, and impatience were assessed by neuropsychological tests. Patients were also given access to a virtual casino, so that their explorative, risk-taking, or impulsive behaviors could be examined.

According to the researchers, “different components of impulsivity were associated with distinct variations in structural connectivity, implicating both reward evaluation and response inhibition networks.”

The reward system refers to a group of structures that are activated when a person is presented with rewarding or reinforcing stimuli (e.g. addictive drugs). Upon a rewarding stimulus, the brain increases the release of dopamine. Response inhibition refers to the ability to suppress behavior that is inappropriate or no longer required.

In the gambling scenario, larger bets were linked to greater connectivity within the reward evaluation network — more specifically, the nerve fibers connecting the ventral striatum and ventromedial prefrontal cortex.

The striatum is a crucial motor area that’s known to be damaged in Parkinson’s, while the prefrontal cortex is involved in planning complex cognitive behavior, and in personality expression and decision-making.

Patients who looked for alternative slot machines in the virtual casino had less connectivity within the response inhibition network. In addition, high-risk “double or nothing” bets were linked to reduced connectivity of the reward evaluation network.

“By combining data from brain imaging, behavior in the virtual casino, and the effect of dopamine-replacement medication, we were able to identify people who were susceptible to impulse-control behaviors,” Phil Mosley, MD, the study’s first author, said in a news release.

Although dopamine replacement therapy was effective for most of the study sample, around 17% (one out of six) of treated participants had trouble controlling their impulses.

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

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

These findings suggest that adapting a treatment regimen to minimize the side effects associated with dopamine agonists could potentially reduce the occurrence of these impulsive behaviors.

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Carrying a Heavier Load

load

Sometimes we must learn tough lessons. And that can be a good thing. Many of the life lessons I’ve learned have been through my journey with Parkinson’s disease.

On a recent afternoon, I went with my daughter in-law to a pumpkin festival at a nearby farm. She brought my grandson and another child, giving us two rambunctious 4-year-olds to keep in tow.

The children ran and ran, stopping long enough to paint a pumpkin before the farm closed up shop. One painted pumpkin turned into two painted pumpkins, which turned into three. When it was time to go, the pumpkins weren’t quite dry. I told my grandson’s friend that she would have to carry her coat so I could carry her wet pumpkins. 

Well, that didn’t go well …

She crossed her arms, pushed out her lower lip, and said, “I want my mom!” All because I told her she’d have to carry her coat. On the walk back to the car, which thankfully wasn’t too far away, she had another pouting fit. It was soon sidelined by a sand hill that had the kids running up and down, forgetting their woes.

Sometimes when I get tired and grumpy from this disease, the last thing I want to do is carry a heavier load. I don’t want to deal with tremors, or with dystonia in my legs and hands waking me up at night. Like our little friend, I just want to cry out, “I want my mom!”

A greater lesson to be learned

Life doesn’t always give us what we want. Instead, life often gives us what we need. We have to be the grown-up when we’d prefer to act like a child. We don’t always have our mom around to slap a bandage on our owies and make things all better. Sometimes we have to carry a heavier load — like a coat. Like a new symptom of this disease.

Josh Shipp, author of “The Grown-Up’s Guide to Teenage Humans,” says, “You either get bitter or you get better. It’s that simple. You either take what has been dealt to you and allow it to make you a better person, or you allow it to tear you down. The choice does not belong to fate, it belongs to you.”

It’s your choice.

***

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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Power and Strength Training Improve Muscle Performance, But Offer Little Functional Benefit in Parkinson’s, Study Says

physical training, Parkinson's

Both power and strength training can improve muscle performance in people with Parkinson’s disease, but these improvements may not translate to functional movement, a new study has found.

The study, titled “Power vs strength training to improve muscular strength, power, balance and functional movement in individuals diagnosed with Parkinson’s disease,” was published in Experimental Gerontology.

Strength and power training are forms of progressive resistance training (PRT) — what’s normally called “lifting weights,” although the process often involves more complex machinery than barbells —  where a muscle is worked against some form of resistance (e.g. lifting something heavy, in which case the resistance is gravity).

The difference between the two is that strength training focuses on increasing the total resistance that a muscle can move (lifting heavier weights), whereas power training is more concerned with doing lower-resistance reps at faster speeds.

In the study, researchers wanted to find out if PRT improves muscle strength in people with Parkinson’s disease and their ability to function independently. They conducted a clinical trial (NCT03434327) with 35 people with mild-moderate Parkinson’s disease (23 male, 12 female, average age was 71 years), who were randomly assigned to complete a 12-week course of either strength training or power training, consisting of two hour-long sessions per week.

The researchers then assessed the participants’ muscle strength (maximum weight they could move) and power (fastest speed they could move a not-maximum weight), as well as other assessments such as their balance and quality of life.

Patients in both groups showed a significant improvement after the 12-week intervention in their ability to perform chest and leg presses. However, there was no significant difference between the two groups.

The same pattern was observed for muscle power: Participants experienced significant improvement in both chest and leg presses, but there was no difference between the two groups.

Over time, both groups demonstrated a decrease in balance scores (measured via the Berg Balance Assessment) that, while statistically significant, was not considered clinically significant. In other words, the improvement in balance wasn’t due to chance, but it probably didn’t have much impact on the participants’ day-to-day lives.

Other functional measurements, including fear of falling (measured by the Modified Falls Efficacy Scale) and functional mobility (assessed via time-up-and-go test) did not differ between the groups over the course of the study.

Similarly, results from the Parkinson’s Disease Questionnaire-39, an assessment of quality of life for people with Parkinson’s, suggested no differences over time or between the groups in terms of ability to perform tasks required for daily living.

The fact that increased muscle performance didn’t translate into better functionality wasn’t entirely unexpected, the researchers said, noting that past studies have yielded conflicting results in the elderly, and in Parkinson’s patients.

“Given that subjects in both the [power training] and [strength training] groups demonstrated significant improvements in muscular strength and power, both PRT programs appear helpful in addressing these neuromuscular performance variables,” the researchers said.

“Since we did not observe any functional benefit in our sample, the inclusion of movement-specific training components that target balance, mobility and [activities of daily living] performance appears warranted in any PRT program,” they added.

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Active Ingredient of Overactive Bladder Treatment Eases Urinary Problems in Parkinson’s Patients, Study Suggests

fesoterodine fumarate

Fesoterodine fumarate, the active compound of a medication for overactive bladder, can help reduce urinary symptoms in Parkinson’s disease patients, a clinical study has found.

The findings, “Randomized, controlled trial of fesoterodine fumarate for overactive bladder in Parkinson’s disease” were published in the World Journal of Urology.

Although a high percentage (27% to 80%) of Parkinson’s patients experience lower urinary tract problems, little is known about effective treatments. Urinary symptoms such as urgency, frequency, nocturia (excessive urination at night), dysuria (pain or discomfort when urinating), and incontinence are indicative of an overactive bladder and can affect patients’ quality of life considerably.

A class of medications known as antimuscarinic drugs has been shown to effectively reduce overactive bladder symptoms. However, these medicines also affect the central nervous system and cognitive function. Antimuscarinics target receptors in the bladder’s smooth muscle, suppressing premature contractions and enhancing urine storage.

To date, there are not enough randomized controlled trials to allow doctors to confidently prescribe antimuscarinic treatment to manage lower urinary tract symptoms in Parkinson’s disease.

A team of Turkish researchers now evaluated the short-term effectiveness and safety of fesoterodine fumarate in Parkinson’s patients with overactive bladder symptoms. Fesoterodine fumarate is the active substance in Toviaz (fesoterodine) a medication for overactive bladder that also is an antimuscarinic treatment.

Sixty-three Parkinson’s patients (32 women and 31 men, aged between 46 and 87 years) with troublesome bladder problems were included in the randomized, double-blind and placebo-controlled study. Participants were first randomly assigned to either fesoterodine fumarate 4 mg (32 subjects) or placebo (31 subjects) for four weeks. This was followed by a one-week washout period and a four-week open-label extension phase in which all patients, including those who were on placebo previously, received 4 mg daily of fesoterodine fumarate.

“The researchers and the participants were unaware of the content of medication,” the team noted.

At the beginning of the study, most participants (96.8%) had urgency  incontinence and 4.7% of them also reported stress incontinence.

Following the first four weeks of treatment, the average daily number of urinations significantly decreased in the fesoterodine fumarate group, compared to the control sample (7.9 versus 18.7 urination episodes in 24 hours). Participants on fesoterodine also had their nocturia and urgency episodes reduced.

Four patients on the fesoterodine fumarate group recovered from urgency urinary incontinence and patients on placebo maintained their urinary complaints.

By the end of the open-label phase of the study, overactive bladder treatment was found to significantly decrease the number of urinations, urgency and urgency urinary incontinence episodes. The number of nocturia episodes remained unchanged.

Because of the previously described risk for cognitive impairment following antimuscarinic treatment, researchers evaluated the patients’ cognitive status, using the widely used Mini Mental State Examination (MMSE). Cognition was stable after one month of treatment.

The therapy was well-tolerated and caused no serious side effects. However, one patient on fesoterodine experienced dryness of the mouth and one other reported constipation, which resolved after treatment discontinuation.

“While short-term results from this study are encouraging, further studies with long-term follow-up are needed to evaluate the efficacy and safety of fesoterodine fumarate in PD [Parkinson’s disease] patients with OAB [overactive bladder],” the researchers concluded.

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Potential Therapy for Dopaminergic Neurons, CNM-Au8, Enter Phase 2 Trial in Parkinson’s Patients

CNM-Au8 studies

CNM-Au8, an investigational therapy by Clene Nanomedicine, improved the survival of dopaminergic neurons, helped prevent loss of mitochondria, and rescued motor function in a rat model of Parkinson’s disease, a study reports.

The effects of CNM-Au8 will now be assessed in an open-label (no placebo group) Phase 2 trial, called REPAIR-PD (NCT03815916). This pilot study is enrolling up to 24 patients who will undergo treatment at the University of Texas Southwestern Medical Center. More information can be found here.

Karen Ho, Clene’s head of translational medicine, presented the preclinical findings in the scientific poster, “Gold nanocatalysis as a novel therapeutic for neuroprotection in Parkinson’s disease,” during the recent 2019 Society for Neuroscience (SfN) Annual Meeting in Chicago.

Parkinson’s disease is characterized by the degeneration and death of a particular group of nerve cells — called dopaminergic neurons —  in two brain regions, the striatum and the substantia nigra.

To work as intended, these nerve cells require large amounts of energy, which is provided by mitochondria: small organelles within cells that work as their powerhouses. Failure to provide the energy cells need contributes to their death.

Another key player in Parkinson’s is oxidative stress, an imbalance between the production of harmful free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are produced during certain metabolic reactions in which mitochondria are involved, and damage cells.

CNM-Au8 is a suspension of nanocrystalline gold that acts to increase the speed of certain intracellular reactions. Specifically, CNM-Au8 is designed to increase the conversion of nicotinamide adenine dinucleotide (NADH) to its oxidized form (NAD+), resulting in greater production of ATP, a key energy-carrying molecule used by mitochondria. In addition, CNM-Au8 has antioxidant properties that may help to protect cells against oxidative stress.

In the preclinical study, researchers treated co-cultures of rat dopaminergic neurons and glial cells (cells that surround neurons and provide them with support) with CNM-Au8. This significantly increased the total intracellular levels of NAD+ compared to treatment with the control, a reaction that leads to greater release of ATP.

Exposing these co-cultures to two neurotoxins — substances that damage the nervous system and mimic what occurs in Parkinson’s — called MPP+ (1-methyl-4-phenylpyridinium) and 6-OHDA, led to damage and death of dopaminergic neurons. However, treatment with CMN-Au8 significantly increased these neurons’ survival and helped to preserve the network generated by nerve cells.

In cells exposed to 6-OHDA, use of CNM-Au8 led to fewer clumps of alpha-synuclein protein, an established hallmark of Parkinson’s disease.

CNM-Ai8 treatment also halted the accumulation of reactive oxygen species, and significantly lessened the loss of mitochondria induced by exposure to the neurotoxin MPP+.

“We are excited to share these latest Parkinson’s disease neuroprotection data regarding our lead nanocatalyst, CNM-Au8, with the neuroscience research community,” Rob Etherington, the president and CEO of Clene, said in a press release.

“Coupled with prior neuroprotection and remyelination data presented at major scientific congresses, this new Parkinson’s data demonstrate how improvements in bioenergetics with CNM-Au8 may preserve neuronal viability across multiple neurodegenerative disorders,” Etherington added.

CNM-Au8 was also tested in vivo (living organism) in a rat model of Parkinson’s disease. 6-OHDA was injected into the right side of the animals’ striatum. These rats were then given CNM-Au8 or a sham solution daily, delivered orally, beginning the next day (early treatment) or 14 days later (late treatment group).

Locomotor function in the rats was assessed using the vertical cylinder paw placement test after six weeks. Results showed that animals treated with CNM-Au8, either early or later, had improvements in motor activity compared to control (untreated) mice.

Early treatment with CNM-Au8 also reduced the number of apomorphine-induced rotations (circling, which signals problems) in rats with lesions at week six by 42% compared to control rats.

Notably, rats treated with CNM-Au8 in this test also showed better results compared to rats treated with carbidopa/levodopa, a standard Parkinson’s therapy.

“These data support our belief that treatment with CNM-Au8 may improve the survival of dopaminergic neurons in patients with PD, thereby helping slow the progression of this devastating disease. Disease modifying therapies remain a key, unmet treatment goal in Parkinson’s disease,” Etherington said.

CNM-Au8 was shown to be safe in a Phase 1 clinical trial involving healthy volunteers (NCT02755870).

In the REPAIR-PD study, participants will first undergo a four-week screening period, after which they will drink two ounces of CNM-Au8 daily each morning for 12 weeks. Treatment will be followed by a four-week follow-up period.

The study’s primary outcome is to determine improvements in oxidative stress in the central nervous system (brain and spinal cord), assessed by the ratio of NAD+/NADH measured using magnetic resonance spectroscopy (MRS).

Additional (secondary) measures include assessing the effects of CNM-Au8 on energy production and nerve cells’ metabolism. Results are expected by mid-2020.

“We are excited to be advancing CNM-Au8 into studies in Parkinson’s patients starting with the REPAIR-PD Phase 2 study,” said Robert Glanzman, Clene’s chief medical officer. “This study will advance our understanding how CNM-Au8 treatment affects central nervous system biomarkers related to bioenergetics, neuronal metabolism, and oxidative stress, as potential indicators of target engagement for CNM-Au8.”

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Alzheimer’s Treatment Not Seen to Aid Patients’ Balance After 6 Weeks, Small Study Suggests

Parkinson's and balance

Treatment with Aricept (donepezil) for six weeks does not seem to improve balance, either while standing or walking, for Parkinson’s patients with a minimal history of falls, according to results from a single-site Phase 2 trial.

The study, “Effects of augmenting cholinergic neurotransmission on balance in Parkinson’s Disease,” was published in the journal Parkinsonism and Related Disorders.

Motor and cognitive abilities depend on the coordinated interaction in the brain of two neurotransmitters — chemical substances that act as messengers and allow brain cells to communicate — called dopamine and acetylcholine.

In the brain of people with Parkinson’s, damage to neurons that produce dopamine and acetylcholine affect balance and gait. As the disease progresses, difficulties with such skills increase.

Impaired balance and gait impacts patients’ quality of life and risk falls. “Loss of mobility in the home and community affects tasks required for independent living and participation in family and community affairs. Falls cause minor to major trauma; the injuries restrict a person’s activities and add to the fear of falling which further reduces mobility,” the researchers wrote.

These symptoms cannot always be controlled by using dopaminergic therapies such as levodopa, suggesting the treatments targeting the production of acetylcholine might also help patients.

Aricept is a cholinesterase inhibitor that increases the levels of acetylcholine in the brain by preventing its breakdown. It is used to treat the symptoms of dementia caused by Alzheimer’s disease.

In a previous a small trial, Aricept (marketed by Eisai and Pfizer) was shown to lower the number of falls in Parkinson’s patients who were frequent fallers.

Researchers at Oregon Health & Science University hypothesized that measuring standing balance and dynamic (walking) balance, problems in both of which can cause falls, would allow them to assess if Aricept was of benefit to people with mild to moderately severe Parkinson’s disease.

Static balance is the ability to maintain postural stability and orientation with the body at rest, while dynamic balance is the ability to maintain postural stability and orientation while the body is in motion.

They designed a randomized, crossover Phase 2 trial (NCT02206620) in 49 Parkinson’s patients, mean age of 69. Participants were randomly assigned to a six-week treatment with Aricept, followed by a six-week treatment with placebo, or vice-versa, with six weeks of “washout” between each treatment. A washout period is the time in a clinical study during which a participant is taken off the investigative therapy, or other medication/placebo, so as to eliminate its effects on further treatment.

Oral capsules of Aricept were initially given at 5 milligrams (mg) a day, increasing to 10 mg a day after the first three weeks. Forty-five people completed the study; all had no or a limited fall history (could stand and walk unassisted for at least one minute) and reasonably healthy cognition.

The study’s main goal (endpoint) was to measure patients’ static and dynamic balance. Static balance was evaluated while they were standing with their feet together looking straight ahead at a fixed point with eyes open.

For dynamic balance assessments, participants were instructed to walk for two minutes at a comfortable pace up and down a 20-meter hallway.

As secondary goals researchers measured two parameters used as a readout of acetylcholine levels: the Attention Network Test, a 15-minute computerized test that measures attention and can determine whether changes in gait and balance are associated with changes in attention; and the Short Latency Afferent Inhibition (SAI), a transcranial magnetic stimulation method to evaluate cortical cholinergic activity.

Results showed that Aricept treatment had no effects on patients’ static and dynamic balance compared to the placebo. Secondary outcome measures of attention and SAI were also not significantly affected by treatment. Only one single parameter of static balance — postural sway — improved after treatment with donepezil.

“Contrary to our hypothesis, cholinergic augmentation with [Aricept] at 10 mg/day for 6 weeks did not affect measures of static or dynamic balance in people with PD,” the researchers wrote.

These results are in contrast with previous trials but a possible explanation, the researchers said, is the fact that “our participants may have had less impairment of cholinergic systems than the participants in the other studies.” Parkinson’s patients those studies, they added, all had an average history of at least one fall each week, and some had gait “freezing, indicating more advanced” disease.

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Finding Wisdom from an Unexpected Source

load

“I looked ahead and could not see a future I wanted to live.” 

These were the words of Chris Norton, co-author of “The Seven Longest Yards,” as he lay in his hospital bed and the truth of his condition sank deep into his soul. 

Quadriplegic. The day before, he was playing football for Luther College in Decorah, Iowa. Now he was trying to grapple with the fact that his chances of ever moving anything below his neck were 3 percent.

Not very encouraging.

Chris Norton’s story isn’t about Parkinson’s disease (PD). But those of us with PD would do well to heed his wisdom.

What some called a tragedy became multiple blessings for Chris and his wife, Emily. But those blessings came at a price. Their perseverance, faith, and steadfastness were tested every step of the way. And step by what felt like impossible step, they continued to move forward.

Imagine working out day after day, hoping to be in that 3 percent. Imagine going to the gym every day knowing there’s a 97 percent chance you will never get better.

Sound vaguely familiar in a different sort of scenario?

Those of us with Parkinson’s know we are not going to heal ourselves with exercise. We are trying to maintain our current status on the PD scale. At best, we hope to improve to some degree. It is that “some” that keeps us going. 

A big difference between Chris and many people with a chronic disease whom I have met is attitude. Our attitude can determine how well we will live with Parkinson’s. 

The power of attitude hit Chris strong. In his book, he writes that he wondered why he was feeling sorry for himself when he could be doing something to get better.

“… Everything changed when I switched my focus to what I could do. … I realized that my attitude had the power to change my reality. … I didn’t dwell on the laundry list of things I couldn’t do. I focused on what I could do.

There were dark days for Chris, especially when Emily struggled with depression. Her story within this story is worth the read for anyone struggling with mental illness.

If you long for an encouraging word by someone who can relate — even if on a different level — the Nortons’ book won’t be a disappointing read.

As Chris writes: “Your circumstances do not determine your future. Your responses to your circumstances do. … Don’t focus on what you can’t do. Focus on what you can do.”

Great words for all of us.

***

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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New Agent CM101 Could Potentially Treat Parkinson’s, Other Neurodegenerative Diseases, Mouse Study Shows

CM101, brain toxins

A newly developed compound called CM101 helps to clear toxic proteins in the brains of mice, and could be a viable avenue for the treatment of some neurodegenerative diseases, including Parkinson’s disease, researchers say.

This finding was recently presented at the annual meeting of the Society of Neuroscience, in a presentation titled, “Multi-kinase inhibition may have optimal effects on neurodegenerative pathologies via the tyrosine kinase discoidin domain receptors (DDRs).”

Many neurodegenerative diseases are characterized by the buildup of toxic proteins in the brain — for instance, alpha-synuclein in Parkinson’s disease and tau and amyloid-beta in Alzheimer’s disease.

Researchers have been looking for ways to induce neurons (brain cells) to turn on processes that help them clear unneeded proteins, which may help remove these toxic molecules. In a press release, Charbel Moussa, PhD, an associate professor of neurology at Georgetown University and senior author of the study, described this as turning on the “garbage disposal” in neurons.

Researchers had previously investigated tyrosine kinase (TK) inhibitors as a way to do this. TKs play many roles in normal cell functioning; for instance, they are critical in helping cells divide — which is why TK inhibitors, used at high doses, have been developed as treatments for some cancers.

“The idea with these frequent high doses is that controlling cell division or proliferation while keeping the garbage disposal working overtime will incinerate cells that are rapidly dividing. These cancer cells will cannibalize themselves,” said Alan Fowler, a PhD student at Georgetown and study co-investigator.

In experimenting with some of these cancer agents — namely Tasigna (nilotinib) and Bosulif (bosutinib) — the researchers determined that inhibiting the tyrosine kinases called discoidin domain receptors 1 and 2 (DDR1 and DDR2, or collectively, just DDRs) might be the best way to turn on the garbage disposal in brain cells affected by neurodegeneration.

Based on these findings, they synthesized a new compound, CM101 (also known as BK40143), which specifically inhibits DDRs. Initial experiments in mouse models of neurodegenerative diseases have lent validity to CM101 as a potential therapy for these conditions.

“This agent has undergone extensive testing in several animal models of neurodegeneration, and it represents a good candidate that should be investigated in first-in-human trials. We have so far shown that this agent has a superior efficacy to clear neurotoxic proteins in animals compared to similar agents, and we identified DDRs as a preferential and optimal drug target. The next step is to investigate drug toxicity in order to obtain regulatory permission for human application,” Moussa said.

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Diabetics Being Treated with Thiazolidinediones May Be at Lower Risk of Parkinson’s, Study Suggests

thiazolidinediones and Parkinson's

People with type 2 diabetes being treated with thiazolidinedione compounds, such as Actos (pioglitazone) and Avandia (rosiglitazone), may be at lower risk of Parkinson’s disease, a pilot study suggests.

However, more work is needed to confirm a potential to prevent Parkinson’s in an at-risk patient population.

The study, “Decreased risk of Parkinson’s disease in diabetic patients with thiazolidinediones therapy: An exploratory meta-analysis,” was published in the journal PLOS ONE.

Thiazolidinediones — also called TZDs and glitazones — are a class of chemical compounds that enhance the activity of a specific receptor, called peroxisome proliferator-activated receptor-gamma (PPAR-γ). This promotes the deposition of fat into tissues within the body, reducing fat concentrations in the blood and improving insulin sensitivity in people with type 2 diabetes.

Evidence from studies in animal models of Parkinson’s disease suggest that TZDs also hold anti-inflammatory and neuroprotective activities. Several other studies have also shown that having type 2 diabetes increases by nearly a third the risk of developing Parkinson’s disease.

A randomized and controlled clinical trial (NCT01280123) was conducted in patients with early Parkinson’s but not diabetes, and its results indicated that treatment with Actos was not likely to prevent Parkinson’s progression. So far, observational and retrospective studies have also failed to confirm the neuroprotective effect of TZDs. As such, its use to treat Parkinson’s disease in diabetics remains controversial.

A team of researchers in China reviewed clinical data available from five published studies, covering a total of 347,556 patients with type 2 diabetes. Three of these five studies took place in Norway, the U.S. and the U.K.; the other two were done in Taiwan.

Three studies showed that treatment with TZDs was associated with lower incidence of Parkinson’s, whereas the other two studies — including one in the U.S. — did not find such a link. Still, a new analysis of pooled data from all five studies found a 30% reduced risk of Parkinson’s among diabetic patients being treated with TZDs compared to those who were not.

“This exploratory meta-analysis supports the value of using TZDs in reducing Parkinson’s disease incidence in diabetic patients,” the researchers wrote.

Additional studies are needed to further explore the impact of different TZDs on Parkinson’s progression, as well as to better define treatment regimens that could represent the most benefit, they added.

“Further prospective observational studies with larger sample size and more strict inclusion criteria including controlling for diabetes complication severity index, hypoglycemic drugs combination, sex ratio, and comorbidity [the presence of more than one disorder in the same person] are needed to guide whether randomized clinical trials are warranted,” the team suggested.

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