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Wearable Sensors Help Assess Medication State in Levodopa-treated Parkinson’s Patients

Wearable sensors

Wearable motion sensors can allow doctors to objectively assess medication states in Parkinson’s disease patients being treated with levodopa, a new study shows.

The study, “Assessment of response to medication in individuals with Parkinson’s disease,” was published in the journal Medical Engineering & Physics.

Levodopa is the most common medication used to treat motor impairment in patients with Parkinson’s disease.

Unfortunately, long-term treatment with levodopa causes troubling motor impairments that are attributed to frequent fluctuations in the “on” and “off” periods. This refers to a phenomenon in which patients on levodopa switch between mobility and immobility, the latter developing when the dose has worn “off” but it is not yet time for the next dose.

The current method to address this problem is by adjusting therapy (i.e. medication frequency and dosage). However, this requires the doctor to know when the patient in the on and off state. This information is frequently obtained from patients’ self-reports, which can be biased.

The development of a wearable, sensor-based assessment system that can detect information about patients’ duration in medication on and off states can help improve therapy adjustment for Parkinson’s patients. Not only would this strategy help reduce motor fluctuations, but it would also improve associated healthcare costs.

Researchers from Florida Atlantic University’s College of Engineering and Computer Science have combined an algorithm and a sensor-based assessment system that can detect patients’ responses to treatment and medication states.

To test the system, researchers recruited 19 Parkinson’s patients and mounted two wearable KinetiSense motion sensors on their most affected wrists and ankles.

The team then collected movement signals as the participants performed daily activities, including resting, walking, drinking, dressing, hair brushing, unpacking groceries, and cutting food, in their medication off and on states.

The algorithm was trained using approximately 15% of the data from four activities and then tested on the remaining data. Hence, data from the two sensors can provide objective measurements instead of a patient diary or self-report.

“In a real-life scenario, the developed algorithm will be trained during a patient’s first visit. Then it will be used to detect the response to medication (on/off medication states) on a continuous basis and report objective information about the duration in on and off states to the treating neurologist for remote medication adjustments,” researchers said.

The algorithm was able to detect the response to medication during subjects’ daily activities with an average of 90.5% accuracy, 94.2% sensitivity, and 85.4% specificity.

Furthermore, the algorithm performed equally well for all the activities, with an average accuracy of 91.3% for the activities in the training phase and 88.4% for the new activities.

“The developed sensor-based algorithm could provide objective and accurate assessment of medication states that can lead to successful adjustment of the therapy, resulting in considerably improved care delivery and quality of life of patients,” researchers said.

The authors stress that this approach is novel in that it is customized to each patient rather than a “one-size-fits-all” approach.

“Once the algorithm is trained, it can readily be used as a passive system to monitor medication fluctuations without relying on patient or physician engagement,” Behnaz Ghoraani, PhD, an assistant professor in FAU’s department of computer and electrical engineering and computer science, said in a press release.

“There is a great need for a technology-based system to provide reliable and objective information about the duration in different medication phases for patients with Parkinson’s disease that can be used by the treating physician to successfully adjust therapy,” said Stella Batalama, PhD, dean of FAU’s College of Engineering and Computer Science.

“The research that professor Ghoraani and her collaborators are doing in this field could considerably improve both the delivery of care and the quality of life for the millions of patients who are afflicted by this debilitating neurodegenerative disease.”

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Antioxidants Protect Against Levodopa Toxicity, Mouse Study Shows

antioxidants

Antioxidants like vitamin C may protect against the toxic effects of levodopa, researchers report.

Their study, “Reducing oxidative toxicity of L-dopa in combination with two different antioxidants: an essential oil isolated from Rosa Damascena Mill., and vitamin C”, was published in Toxicology Reports.

Levodopa (L-DOPA) treatment effectively reduces early motor symptoms in Parkinson’s disease, but conflicting evidence 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, resulting in cellular damage as a consequence of high levels of oxidant molecules.

In theory, combining levodopa therapy with antioxidants may decrease treatment-related side effects and help relieve symptoms.

Investigators from Trakia University in Bulgaria investigated whether L-DOPA-induced oxidative stress could be reduced by combining two distinct antioxidants — an essential oil isolated from Damask rose, and vitamin C.

To do so, healthy mice were divided into four groups. All animals, except the ones in the control group, received two intraperitoneal injections (injected directly into the body cavity) of L-DOPA and, after that, benserazide, a compound that increases the amount of L-DOPA crossing into the brain and its subsequent conversion to dopamine.

Two of the four study groups were pre-treated with injections of either rose oil or vitamin C before they were treated with L-DOPA and benserazide.

Scientists then screened for the presence of oxidative stress by measuring blood concentrations of particular proteins and lipids (fatty acids) that are known oxidative stress markers.

In comparison to the control sample, L-DOPA-only treated animals had a significant increase in molecular markers of oxidative stress, meaning that levodopa treatment induced oxidative stress in healthy animals.

Importantly, those same markers were significantly decreased in both groups pre-treated with antioxidants, compared to control animals.

“It must be emphasized, that Rosa damascene [Damask rose] oil exhibited behavior very similar to the classic antioxidants – vitamin C, making it potential candidates for extensive experimental research to their possible use as protectors against oxidative toxicity triggered by drug therapy of neurodegenerative diseases,” researchers 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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Finding Words to Describe Parkinson’s Pain

pain

Parkinson’s disease (PD) pain is unique, so finding words to describe it is difficult. Not all those with a diagnosis experience pain. But for some, like me, pain is the major, disabling symptom. It is important to find words that describe the pain experience as clearly as possible. There is no “grin and bear it,” nor is this “a pity party.” Instead, this is a search for accurate articulation of the pain experience to help maintain quality of life.

Pain may be an early symptom of PD, according to a study presented at the 2018 World Congress on Parkinson’s Disease and Related Disorders titled “Pain: A marker of prodromal Parkinsons disease?” The American Parkinson Disease Association published research that supports the connection of pain with Parkinson’s, suggesting that if the pain is relieved with dopaminergic medication and the patient has a pattern of painful sensations that correlate to “off” episodes, more credence can be given to the idea that the pain is PD-related.

PD pain can resemble pain from other disease processes, especially as the patient ages and faces a multitude of other pain-causing conditions such as arthritis, spine degeneration, poor muscular conditioning, and such. In my case, PD pain is distinguished by the following:

  • The progression of body pain correlated with the progression of the disease over time.
  • Levodopa, a dopaminergic therapy, successfully reduces the pain.
  • The pain is worse during “off” periods.

My PD pain also has a particular characteristic: stinging (sometimes knife-jabbing), irritating tingling, burning, and muscle heaviness with increased pain on movement. This pain happens over large regions of the body and varies in severity. At its worst, it can last several days and reach level 7, inducing spontaneous tears.

PD with episodic chronic pain is disabling in several ways. First, high levels of pain obstruct clear thinking. Second, high levels of pain induce the fight-or-flight response, which interferes with emotion management. Third, the amount of energy necessary to manage it is very tiring (even more so in the face of the deep fatigue associated with PD). Chronic PD pain entails much more than body symptoms.

Parkinson’s pain is a total experience that touches thoughts, feelings, and relationships. Even when it’s a struggle, finding the words to describe pain experiences is imperative to maintaining quality of life in the face of a difficult diagnosis. Finding the right words helps one communicate the pain experience to care providers, family, and friends — a network of relationships that help form the foundation for quality of life. By communicating the pain, those close to me are more understanding of why I act the way I do, which helps to maintain those relationships.

Over the years, I have watched my PD progression. I have taken the warrior stance to do all I can to slow the progression. My hardest battle is with the total experience of chronic PD pain. Large blocks of time disappear into the fog of war. Over time, I have learned the importance of communicating about the pain daily, sometimes multiple times a day. My partner asks, “Where are you today?” I will say, “I’m at level 5,” followed by a quick mention of the most bothersome symptoms. In the past, I kept track of the pain levels throughout several months to create benchmarks. This is all part of finding the words to describe the Parkinson’s pain experience.

I have been a “communicator” most of my life, but it remains a struggle to find words that describe the unique character of PD pain. If you experience PD pain, please share your descriptors in the comments. Together we may find a common dialogue that will help others.

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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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Levodopa Shows No Disease-modifying Effects in Parkinson’s, Study Finds

levodopa study

Levodopa/carbidopa treatment is effective in managing Parkinson’s motor symptoms, but does not protect against disease progression among patients with early disease, a study shows.

The research, “Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease” was published in The New England Journal of Medicine.

Levodopa is the main treatment for Parkinson’s disease. However, neurologists might delay prescribing levodopa for different reasons, including concern about the development of levodopa-induced dyskinesias (abnormal, uncontrolled, involuntary movements), which is one of the most common dose-limiting side effects of this treatment approach.

However, almost all patients eventually receive levodopa to control their motor symptoms.

In an earlier clinical trial, called ELLDOPA , 361 patients with early Parkinson’s disease received levodopa or placebo for 40 weeks. Two weeks after that, clinical examination showed that the participants who had received levodopa had a slower disease progression than those on placebo. However, brain imaging studies revealed that levodopa had either accelerated the death of dopaminergic neurons, or it had modified the protein responsible for the transport of dopamine in brain nerve cells.

“Therefore, whether levodopa has an effect on the progression of Parkinson’s disease beyond its immediate benefit with respect to symptoms remains unknown,” scientists wrote.

Now, researchers from the University of Amsterdam designed a multicenter, randomized, placebo-controlled, delayed-start trial to assess levodopa’s effect on patients with early Parkinson’s disease who had insufficient disability to receive anti-Parkinson medication: the Levodopa in Early Parkinson’s Disease (LEAP) study (ISRCTN30518857).

Patients who had received their diagnosis within the previous two years were randomly assigned to an early-start group (207 subjects): levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks; or to a delayed-start group (210 participants): placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks.

During Phase 1 (the first 40 weeks of the trial), patients received levodopa or placebo. During Phase 2 (the second 40 weeks) patients in both trial groups received levodopa. Assessments were made at baseline (trial initiation) and at weeks 4, 22, 40, 44, 56, 68, and 80.

The study’s primary endpoint (goal) was the difference in the mean change, from trial initiation to week 80, in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). That tool assesses both motor and non-motor symptoms associated with Parkinson’s disease (higher scores indicate more severe disease).

Secondary outcomes included the progression of symptoms between weeks 4 and 40 and between weeks 44 and 80, as measured by the category scores on the UPDRS; disability; cognitive impairment; depression; and disease-related quality of life.

At week 80, there was no significant difference between the early-start and delayed-start group regarding motor and non-motor symptoms, as measured by the UPDRS, indicating that levodopa had no disease-modifying effect.

To test if early treatment initiation was prognostically better than a delayed one or vice-versa, scientists compared symptoms’ progression rate in week 4-40 and week 44-80. Once again, no significant changes were observed between groups in either study period.

No significant changes in therapy-related motor fluctuations, including dyskinesias, were found between groups. During the first 40 weeks, patients on the early-start group complained more of nausea (23%), compared to the participants on the delayed-start group (14.3%).

Also, no significant differences were observed regarding disability, cognitive impairment, depression and disease-related quality of life between the groups.

“We conclude that treatment with levodopa at a dose of 100 mg three times per day in combination with carbidopa at a dose of 25 mg three times per day had no disease-modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks. Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson’s disease warrants evaluation in future trials,” researchers concluded.

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‘Bananas and Beans, not Burgers’: High-Protein Meals and Levodopa

protein

No one told me that breakfast bacon, ham, or sausage would make me feel awful!

I had seen my off-periods worsen after a heavy meat meal, but I shrugged it off as “just a bad off-period.” Now, after being on levodopa for five years, I am positive that animal protein meals are a serious issue. Overlapping a high meat meal with levodopa can result in not just an off-period, but also one that lasts much of the day.

“Bananas and beans, not burgers” is the mantra to remind me that diet is very important in the development of a rehab plan for folks with PD. I am not a nutritionist. I am writing from the perspective of a PD patient warrior and rehab clinician.

Research suggests that changes to your diet could help alleviate some symptoms of your PD. The American Parkinson Disease Association (APDA) notes that levodopa crosses the wall of the small intestine via molecules in the intestinal wall that transport amino acids. When dietary protein (beef, chicken, pork, fish, eggs, nuts, and dairy) is also present in the small intestine, fewer transporters are available for levodopa to use. We may experience the “protein effect” when the medication competes with a high-protein meal.

One of the most compelling statements in a 2014 study published in Frontiers in Aging Neuroscience is that a “growing body of evidence suggests that nutrition may play an important role in PD.”

The study “Irregular gastrointestinal drug absorption in Parkinson’s disease” in the journal Expert Opinion on Drug Metabolism & Toxicology states that levodopa transit time in the small intestine is approximately three hours. Therefore, gastric emptying is a major determining factor for the onset of symptom relief. When PD delays gastric emptying, it has the potential to cause motor fluctuations, known to us as off-periods.

Research also shows that with your microbiome (the microorganisms in your body), a relationship exists between Parkinson’s disease and improved gut health. In “Parkinson’s disease and bacteriophages as its overlooked contributors,” published in the journal Scientific Reports, George Tetz and his colleagues examined the viruses that live in the gut, as well as the role the microbiome may play in Parkinson’s disease. According to Parkinson.org, “this has sparked the idea that we might be able to improve the symptoms if we change the microbiome through diet or other ways. … These bacteria play a role in the processes that produce dopamine and affect the intestine’s ability to absorb.”

Like many aspects of Parkinson’s symptoms, the protein effect is highly variable. Some people do not experience it at all. Others are extremely sensitive to protein’s effect on medication absorption. This diet concern was presented at my local PD support group, and the group’s PD warriors and caregivers agreed almost unanimously with having experienced or witnessed the adverse effects.

It typically becomes more of an issue as PD progresses. The APDA suggests that if someone experiences the protein effect, two potential strategies might help. One is to refrain from eating protein during the day, eating it at night instead, when the medication’s effect is less critical. The second is to distribute protein intake evenly throughout the day so that medication absorption is enhanced during that time.

The solution I have found that works best for me has two parts. First, I space the levodopa dosing so that it occurs between meals to minimize absorption issues. Second, I eat the day’s moderate meat meal at lunch, not dinner or breakfast.

Reducing meat in your diet may be beneficial not just to levapoda absorption. An amazing study on diet and overall health by Thomas Campbell and T. Colin Campbell, called “The China Study,” clearly showed that decreasing meat intake is a good change for all of us. Bananas and beans, not burgers.

What diet changes have you found to be helpful? Share in the comments below.

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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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Add-on Azilect Safe and Effective in Levodopa-treated PD Patients, Phase 3 Trial in Japan Shows

Azilect, levodopa

Using Azilect (rasagiline) as an add-on therapy to levodopa was safe and improved motor function over one year in Parkinson’s patients with off periods, according to a Phase 3 trial in Japan.

The study, “Long-term safety and efficacy of adjunctive rasagiline in levodopa-treated Japanese patients with Parkinson’s disease,” was published in the Journal of Neural Transmission.

Progressive loss of dopamine-producing neurons in a brain area called substantia nigra and subsequent reduction of dopamine levels are hallmarks of Parkinson’s disease. As a result, most pharmacological Parkinson’s treatments aim to ease symptoms by boosting the amount of dopamine in the brain.

Long-term use of levodopa, the standard Parkinson’s medication, may lead to the resurgence of symptoms by a gradual decline in levodopa’s efficacy, known as off periods. In such cases, Japanese and international guidelines recommend adjusting levodopa’s dose and/or formulation, or using add-on treatments such as inhibitors of monoamine oxidase-B (MAO-B), an enzyme that breaks down dopamine.

Azilect, a selective MAO-B inhibitor, is currently indicated outside Japan as an adjunctive therapy for people with Parkinson’s.

In prior studies conducted by a team of Japanese researchers, adding Azilect to levodopa reduced the duration of mean daily off periods, eased Parkinson’s symptoms — as assessed with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) — and improved the quality of life of Japanese patients up to 26 weeks.

To provide insights for clinical practice, the same team now evaluated the long-term (up to 52 weeks) safety and efficacy of combining 1 mg/day Azilect with levodopa in patients with Parkinson’s.

In the multi-center, open-label Phase 3 trial (NCT02337764) — sponsored by Takeda, which obtained a license to market Azilect in Japan from Teva Pharmaceutical Industries — a total of 222 participants (mean age 68) recorded their off periods, on periods (motor symptoms under control) with or without troublesome dyskinesia — involuntary, jerky movements — and sleeping time in 30-minute intervals over 24 hours during the seven days prior to visits at weeks 0, 6, 10, 18, 26, 34, 42, and 52.

All included patients (mean Parkinson’s duration nearly seven years) were experiencing wearing-off or weakened effects of levodopa. The primary goal was the incidence of treatment-emergent adverse events (TEAEs).

Secondary goals included the MDS-UPDRS Part II (motor aspects of daily living) and Part III (motor examination), total scores during on periods, and mean daily off-time for patients with wearing-off periods at the start of the study. Assessments of quality of life and non-motor aspects of daily living were also conducted.

At baseline, 77.8% of patients required a dose of levodopa above 300 mg/day. The mean duration of levodopa treatment was approximately 4.6 years. Also, 116 patients (52.3%) had wearing-off periods, with a mean duration of nearly three years. Dopamine agonists were the most frequently used concomitant therapy for Parkinson’s (163 patients, or 73.4%).

A total of 599 TEAEs were reported by 185 patients, most (586) being mild or moderate. Forty-seven patients (21.2%) discontinued treatment because of TEAEs. The most common TEAEs were fall (16.7%), nasopharyngitis — inflammation of the pharynx and nasal cavities — (14%), and dyskinesia (10.8%).

The incidence of TEAEs was higher (52.3%) during days 1–83 after starting Azilect, subsequently decreasing over time. No new safety concerns were found.

Forty-seven serious TEAEs were reported in 39 patients, 22 of which led to study discontinuation and 24 were considered treatment-related. No deaths occurred.

Combining Azilect with levodopa improved patients’ on state throughout the study, with a clinically meaningful mean change of -7.6 MDS-UPDRS Part III points from baseline to week 52. Among patients with wearing-off periods, Azilect led to a nearly one-hour reduction in daily off periods after six weeks, which was maintained throughout the study.

Using Azilect with levodopa also improved quality of life. This was most evident in mobility, activities of daily living, stigma, and bodily discomfort domains.

Overall, “mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline (azilect) treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks,” scientists stated.

They cautioned that the absence of a placebo group complicates the assessment of the combination therapy’s benefits. However, the fact that the results were similar to the investigators’ prior findings suggests that these benefits were treatment-related, they said. Studies beyond 52 weeks may be needed, they said.

Three of the study’s authors are employees of Takeda, four served on advisory boards for Takeda, and two conducted Takeda-sponsored research.

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My DaTscan Results Made My PD Diagnosis ‘Real’

DaTscan

When I was first diagnosed with Parkinson’s disease (PD) in 2015, I asked the neurologist if there was a definitive test to confirm a PD diagnosis. I mentioned a DaTscan, but he said the test is not entirely conclusive. He also indicated that DaTscan results likely would not change his prescribed course of treatment for me.

His view was that the best way to confirm a PD diagnosis is to give a patient the medication levodopa to see if PD symptoms disappeared. Other neurologists I consulted for second opinions concurred with his assessment.

What is a DaTscan?

DaTscan is a medication that is injected into the bloodstream to assess dopamine-containing neurons that are involved in controlling movement. The contrast agent ioflupane (123I) is distributed around the body in the bloodstream and accumulates in the area of the brain called the striatum, where it attaches to the structures that transport dopamine. The patient then has a single-photon emission computed tomography (SPECT) scan.

The DaTscan test was designed to differentiate parkinsonian syndromes from essential tremor. PD is the most common form of parkinsonian syndromes, but there are other forms, including multiple system atrophy and progressive supranuclear palsy.

My DaTscan

A comparison between a normal and an abnormal DaTscan can be viewed here. A normal DaTscan will show two distinct comma-like or crescent shapes. An abnormal DaTscan will have two period-like or oval shapes, or a combination of period and comma shapes, indicating a reduced uptake of DaTscan in certain areas of the brain. Parts of the image that are “lit up,” indicate more surviving brain cells. Dark areas could mean either PD or parkinsonism.

My DaTscan image showed that the right side of my brain is less “lit up” than the left side. The right hemisphere of the brain coordinates the left side of the body. The left side of my body is the one most affected by PD, so it makes sense that my right side brain is less “lit up.”

Am I convinced that I have PD?

Three years after my diagnosis, I am still struggling to find relief from my symptoms and slow the progression of this disease. I exercise, eating a mostly vegan and gluten-free diet, take Sinemet (carbidopa-levodopa), and use the Neupro transdermal patch. I am working with my current neurologist to fine-tune my medication “cocktail.”

I had wondered whether I did have PD since I’ve never had an “aha” moment in which I feel somewhat normal after taking medications. People tell me I look fine and they don’t observe any external signs of the disease. However, my tremors are internal and I feel horrible and constantly fatigued.

Why now?

I am subjecting my body to what I believe are toxic medications to treat a disease that I feel has been subjectively diagnosed. My symptoms have not been completely alleviated with my current exercise, diet, and prescription medication regimen. I wanted more concrete evidence that I have PD, so my neurologist prescribed a DaTscan. Much to my dismay, the results were abnormal and compatible with Parkinson’s syndrome.

Seeing my brain image with areas not “lit up” where they should be, when contrasted with a normal DaTScan, made my diagnosis very real for me. I have a form of parkinsonian syndrome — most likely PD.

Would I still have gotten a DaTscan?

It was important for me to have confirmation other than my symptoms of abnormalities in my brain. I think this scan can be used as a baseline to follow my disease progression.

So, yes, I would have still gotten this test, although the $2,000 out-of-pocket cost upfront may have given me pause.

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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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Key Parkinson’s Brain Area Implicated in Memory Loss, Study Suggests

substantia nigra, memory

Neurodegeneration in the substantia nigra, a critical area of the brain involved in Parkinson’s, leads to memory deficits, according to a study that explored the effects of levodopa on a rat model of the disease.

Findings of the study, titled “Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease,” also illustrated the key role dopamine plays in memory. It was published in the journal Behavioral Brain Research.

Similar to motor symptoms, loss of dopamine-producing neurons in the substantia nigra — a brain area implicated in motor function — has been proposed as the cause of neuropsychiatric manifestations in Parkinson’s disease. This has been shown in animal models, in which bilateral lesion of the substantia nigra (which selectively affects this region only) resulted in anxiety- and depression-like behaviors, as well as motivational, memory and social interaction deficits.  A study in rats also reported psychosis-like behavior in animals subjected to bilateral lesion.

Prior research has shown that chronic dopamine replacement therapy (DRT) — which compensates for the lack of dopamine and represents the standard treatment for different Parkinson’s motor symptoms — leads to impaired ability of neurons to fine-tune their responses in animals and is associated with Parkinson’s-related neuropsychiatric disorders in patients.

After lesion of the nigrostriatal pathway — including the substantia nigra and the dorsal striatum — DRT led to compulsive behavior in animals, which was associated with cellular alterations in brain regions involved in cognitive/affective information processing. Progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.

While chronic administration of levodopa worsened lesion-induced anxiety and depression in rats, lesioned primates showed psychotic-like behavior only after dopaminergic treatment.

Biotrial Pharmacology researchers have now evaluated the impact of substantia nigra neurodegeneration, repeated exposure to dopaminergic medication, and the combination of both on the development of neuropsychiatric symptoms of Parkinson’s. The team hypothesized that repeated exposure to levodopa could promote brain remodeling and avoid cognitive-like and affective-like deficits.

The team used a rat model based on bilateral substantia nigra injection of a toxin called 6-hydroxydopamine, which induces selective lesions of specific dopaminergic neurons that do not provoke motor deficits.

A subgroup of animals was repeatedly administered with levodopa (20 mg/kg per day) and benserazide (5 mg/kg daily) via under-the-skin injection over 10 consecutive days (chronic exposure), starting 10 days after partial substantia nigra lesion. Benserazide is an inhibitor of an enzyme called DOPA decarboxylase, which converts levodopa into dopamine.

Behavioral tests were started three weeks after the lesions. These included assessments of spontaneous locomotor activity; forelimb voluntary movement with the stepping test; anxiety-like behavior with the elevated plus maze, in which increased time spent on an open arm correlates with greater anxiety; social interaction, as indicated by the amount of time spent in active non-aggressive social behavior with another rat; memory through novel object recognition; and amphetamine-induced hyperlocomotion (AIH), used to assess responses to psychostimulants.

All animals (both with and without chronic levodopa exposure) received single acute injections of levodopa (12.5 mg/kg)/benserazide (15 mg/kg) before the elevated plus maze and novel object recognition tests.

Results revealed that, in contrast to preserved motor function, lesioned rats showed a significant memory deficit as well as anxiety-like behavior. Social interaction and AIH were unchanged. These animals also demonstrated a 48% decrease in the number of dopaminergic cells within the substantia nigra, whose extent did not correlate with the memory and anxiety results.

Researchers found that a single injection of levodopa/benserazide reversed the memory deficit, but not the anxiety-like behavior. According to the scientists, this suggests that dopaminergic pathways “were less directly involved in lesion-induced anxiety-like behavior.”

Chronic administration of levodopa did not change the results seen in lesioned rats (not chronically exposed), which was contrary to the team’s hypothesis. The investigators attributed this finding to having induced a partial lesion. Studies in more severely injured animals and with longer administrations of levodopa would be of interest, they believe.

The results in the memory test indicate “a not previously clearly identified critical role in cognition for the [substantia nigra],” and illustrate “the critical role of [dopamine] in this behavioural outcome,” the researchers wrote.

According to the team, the findings are in accordance “with clinical data suggesting that a panel of non-motor impairment including cognitive deficit and anxiety may be used as prodromal (early) markers of early stages of [Parkinson’s].”

The post Key Parkinson’s Brain Area Implicated in Memory Loss, Study Suggests appeared first on Parkinson’s News Today.

IRL790 Is Safe, Reduces Levodopa-induced Dyskinesia in Parkinson’s, Phase 1b Trial Shows

IRL790 and Parkinson's

IRL790, Integrative Research Laboratories‘ investigational treatment for Parkinson’s disease patients, was safe and reduced levodopa-induced dyskinesia, a Phase 1b trial shows.

The results were published in the journal npj Parkinson’s Disease in the study, “Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial.”

Parkinson’s disease is a central nervous system disorder characterized by low levels of dopamine, causing tremors, stiffness, or slowing of movement.

Levodopa, a medication that helps counteract the shortage of dopamine in the brain, is the gold standard for treatment of Parkinson’s patients. But more than half the patients who use levodopa experience abnormal, involuntary movements — dyskinesia — within the first five years of treatment.

Studies have shown that long-term treatment with levopoda increases levels of a dopamine receptor, called dopamine D3 receptor, that seems to correlate with levodopa-induced dyskinesia.

IRL790 is a central nervous system medication that mainly targets the dopamine D3 receptor. In rat models of Parkinson’s disease, the treatment reduced involuntary movements caused by levodopa treatment without compromising the animals’ locomotion. Also, IRL790 showed anti-psychotic properties, suggesting its potential for treating both dyskinesia and psychosis in Parkinson’s patients.

In a prior Phase 1 trial, researchers tested ascending doses of IRL790 in healthy male volunteers. The treatment had a very good safety profile, with no serious adverse events reported, even at doses higher than those planned for patients.

Now, a team at the Karolinska Institutet in Sweden conducted a Phase 1b trial to determine the treatment’s safety and efficacy in Parkinson’s patients experiencing levodopa-induced dyskinesia.

The study (NCT03531060) included 15 Parkinson’s patients (nine men and six women) who randomly received oral capsules of IRL790 (11 patients) or an oral placebo (four patients) for four weeks. During the trial, all patients continued receiving their regular medication.

The study’s main objective was to assess the treatment’s safety — measured through the number of adverse events, physical examination, electrocardiogram, heart rate, blood pressure, and other laboratory measurements — after four weeks.

Secondary measures included changes from baseline in dyskinesia, measured with the Unified Dyskinesia Rating Scale (UDysRS), and Parkinson’s scores, measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Kinetigraph.

Thirteen patients completed the 4-week study, with IRL790 given at an average daily dose of 18 mg.

Overall, 14 patients (93.3%) reported 62 adverse effects. Most were reported during the first two weeks — when the dose of IRL790 was adjusted to each patient — and were mild to moderate, easily mitigated by dose adjustments. No serious adverse effects were reported in any of the groups.

Patients taking IRL790 had a mean reduction of 8.2 percent in dyskinesia scores compared to those taking a placebo.

“Among patients treated with IRL790, 55.5% were assessed as having an improved global clinical condition, as compared with baseline (much improved/minimally improved),” researchers stated.

There were no changes in symptoms relating to parkinsonism, either in the UPDRS or in measurements from the Parkinson’s Kinetigraph, a wrist-worn device that evaluates bradykinesia (slowness of movement) and dyskinesia during activities of daily living.

The results show that “IRL790 can be safely administered to patients with advanced PD,  which will now “be of guidance for the design of phase 2 studies,” researchers said.

IRL790 is already being tested in a Phase 2 trial (NCT03368170), which will assess whether the treatment can reduce dyskinesia in a larger population (74 patients). The trial will also help establish the optimal dose for further testing.

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