Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

Gulcin Pekkurnaz, PhD, is a Stanley Fahn Junior Faculty Awardee who is working to understand how aging affects dopamine in Parkinson’s.

Parkinson’s disease develops when the cell’s energy factories, called mitochondria, start to fail in dopamine neurons or nerve cells. Dopamine is a brain chemical messenger that carries information between neurons and helps us to move smoothly. People with Parkinson’s have low levels of dopamine in the brain due to dopamine neurons dying.   

People with Parkinson’s do not develop disease symptoms until later in life. This indicates aging-associated changes are involved in the development of the disease. With aging, both mitochondrial function and cellular metabolism decline. We hope to gain a better understanding of why this happens.

Dr. Pekkurnaz at University of California San Diego received a research grant to study the mitochondria from dopamine nerve fibers in animals. Her goal is to identify what happens to dopamine neuron mitochondria before Parkinson’s symptoms start. To accomplish this, she will develop new technology that will allow us to analyze unique mitochondrial features from dopamine neurons as a function of age.

We hope to gain fundamental insights into how the dopamine neuron energy supply works and they start to fail. These findings can lead to potential drug targets for Parkinson’s.

The Parkinson’s Foundation Stanley Fahn Junior Faculty Award helps ensure promising early career scientists stay in the PD research field. This award provides junior investigators the support they need to develop their own independent funding source.

What’s Next: Reporting Our Findings

Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. Scientists submit yearly progress reports to the Parkinson’s Foundation, and we report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.

Since its launch in the late 1960s, carbidopa/levodopa (brand name SINEMET®) is still the most effective Parkinson’s disease (PD) motor symptom treatment. However, it doesn’t address all facets of the disease. Medications to bolster its effectiveness and treat PD-related non-motor symptoms are newly available or just on the horizon.

This article is based on a Parkinson’s Foundation Expert Briefings webinar exploring innovative PD treatments by Rajesh Pahwa, MD, Director, Parkinson and Movement Disorder Division, University of Kansas Medical Center, a Parkinson’s Foundation Center of Excellence.

Pioneering Medicine

It’s an exciting time for PD drug advances. While gene therapy benefits are still being studied, many new medications are on the market or are soon to be. These new treatments are designed to tackle Parkinson’s disease challenges, including:

• Psychosis – hallucinations and delusions.
• Orthostatic hypotension – a blood pressure drop when rising or standing.
• “Off” time – when symptoms and movement difficulties increase.
• Dyskinesia – abnormal, involuntary muscle movement.
• Dementia – memory and thinking declines.
• Falls – PD can cause slowness of movements, increasing falling and other risks.

Current Treatments

Parkinson's Disease Psychosis

PD-associated psychosis can be caused by the disease itself or PD medications. Challenging for people with PD and caregivers, symptoms include confusion, delusions and hallucinations. Report any changes to your medical team.

Pimavanserin (Nuplazid®), newer to the market, is the only approved treatment for PD psychosis. It does not block dopamine or worsen motor symptoms. It can improve hallucinations, delusions, night-time sleep and daytime sleepiness. Side effects include nausea, confusion and hallucinations.

Orthosstatic Hypotension

From 20 to 50 percent of people living with PD experience a significant blood pressure drop upon standing, known as orthostatic hypotension; certain medications can worsen this. This drop can cause lightheadedness or fainting, and other symptoms.

Droxidopa (NORTHERA®) treats lightheadedness. It should not be taken within five hours of bedtime. Side effects include headache, dizziness, nausea, fatigue and high blood pressure when lying down.

"Off"-Time Advancements

Levodopa is synthesized in the brain into dopamine, making it key to PD symptom management. But several factors can interfere with steady, accurate dose delivery. When medication is not taken on time, or absorption is delayed, freezing and other sudden and debilitating motor symptoms can occur. These newer medications can help tackle “off” periods.

Carbidopa/Levodopa Enteral Suspension (Duopa™)

Duopa™ therapy, a newer carbidopa/levodopa treatment, can benefit people with advanced PD who respond well to levodopa and experience three or more “off” hours daily. It’s delivered in gel form (called enteral suspension). Duopa™ users must first have surgery to place a tube in their intestine that is later connected to a pump that delivers Duopa™.

Safinamide (XADAGO®)

Safinamide tablets (XADAGO®) are an add-on treatment for people with Parkinson’s taking carbidopa/levodopa and experiencing “off” times. Safinamide is a monoamine oxidase B (MAO-B) inhibitor that can reduce “off” times up to 55 minutes a day, without dyskinesia. Interactions include other MAO-B class drugs, certain antidepressants and the cold medicine dextromethorphan. Anyone taking a PD medication should talk to their doctor and pharmacist about potential drug interactions.

On-Demand Therapy

Levodopa Inhalation (INBRIJA™)

The levodopa inhalation powder INBRIJA™ is an add-on drug for “off” periods in people taking carbidopa/levodopa. Administered via inhaler, it can be used up to five times a day, improving “off” symptoms as soon as 10 minutes and lasting up to 60 minutes. This can improve symptoms for people with decreased gut motility while waiting for oral carbidopa/levodopa to take effect.

Amantadine ER capsules (GOCOVRI®)

This is the only medication to treat dyskinesia and “off” time in people with PD taking carbidopa/levodopa. It must be taken before bedtime and provides control of dyskinesia upon awakening and throughout the day. It can cause hallucinations and lightheadedness. This medication is different from immediate-release amantadine and amantadine ER tablets (OSMOLEX ER™) which are not approved for dyskinesia or “off” time.

IncobotulinumtoxinA (XEOMIN)

More than 50 percent of people with PD can have excessive drooling, causing skin breakdown around the mouth, odors, embarrassment or choking. Two injections on the face, every 3-4 months of XEOMIN, can manage symptoms.

Future Therapies

Sublingual Apomorphine

Apomorphine is administered through injections under the skin. Sublingual apomorphine, dissolved under the tongue, can relieve “wearing off” episodes for people with Parkinson’s disease in 15 minutes and lasts up to 90 minutes. Side effects can include nausea, sleepiness, and dizziness.

Rimabotulinumtoxin B (MYOBLOC®)

Rimabotulinumtoxin B is currently approved for dystonia and used off-label for drooling. It is undergoing trials to treat drooling. Side effects include dry mouth, mild swallowing difficulty, mild chewing weakness and saliva thickness changes.

Adenosine A2 Antagonist: Istradefylline

A group of brain circuits called the basal ganglia play a role in causing PD symptoms. The basal ganglia have adenosine A2A receptors that are located next to dopamine receptors. Scientists believe that activating the dopamine receptor or blocking the adenosine A2 receptor can improve PD symptoms.

Istradefylline, an adenosine A2A receptor antagonist shows mild motor symptom fluctuation improvements. Approved for use in Japan, Istradefylline has also received U.S. FDA approval.

Subcutaneous Apomorphine Infusion

Available in Europe, subcutaneous apomorphine treatment offers a less invasive motor fluctuation treatment option. A small delivery tube placed under the skin is connected to an apomorphine-filled pumping device. It can reduce daily “off” time and possibly dyskinesia by reducing needed levodopa dose. Those with hallucinations and dementia might not be candidates.

Subcutaneous Carbidopa/Levodopa Pump

Two companies are currently developing pumps for continuous under-skin carbidopa/levodopa therapy to reduce “off” times and motor symptom fluctuations. The pumps can be used around the clock and don’t require surgery.

Carbidopa/levodopa extended release

New tests are underway for extended-release carbidopa/levodopa therapy to reduce “off” times and motor symptom fluctuations.

• Accordion Pill™, Carbidopa/Levodopa (AP-CD/LD) maker, will begin its Phase 3 clinical trial of new delivery technology. The Accordion Pill slowly releases treatment in the stomach for more steady absorption.
• IPX203, an investigational extended-release oral carbidopa/levodopa formulation that increases “on” time, is currently enrolling participants in its Phase 3 clinical study.

Opicapone

Experimental opicapone is a COMT (catechol-o-methyl transferase) inhibitor. This drug class can extend levodopa benefits. Available in Europe, opicapone reduces “off” time for people with PD experiencing levodopa effectiveness fluctuations.

If you have any questions about managing Parkinson’s, PD medications or caregiving, call our Helpline at 1-800-4PD-INFO (473-4636) on weekdays from 9 a.m. to 8 p.m. You can also check out these resources:

• Prescription Medications
• For Caregivers
• Episode 6: New Levodopa Delivery Methods for Parkinson’s
• Parkinson’s Treatment

Many people with advanced Parkinson’s disease (PD) suffer from gait (walking) dysfunction, freezing of gait and postural instability. These symptoms can cause falling, resulting in a multitude of injuries, a loss of personal freedom, caregiver stress and a reduction in the quality of life (Pirker & Katzenschlager, 2017; Samotus, Parrent, & Jog, 2018). Medications, such as levodopa, rarely helps with these specific motor symptoms, while deep brain stimulation (DBS) results are limited and unpredictable for these particular symptoms. The fact is, current PD medications, therapies or surgical procedures do not effectively address this debilitating unmet need. This lack of options might be changing, due to an intervention called spinal cord stimulation (SCS).

Surgically implanted, SCS is a device that alters nerve activity by sending a low-voltage electrical current to select areas of the spinal cord. These voltage settings are adjustable post-implantation, which allows for personalized optimization. SCS is currently used to treat people with chronic back and nerve pain, as well as for neuropathic pain, such as diabetic neuropathy, and chemotherapy or radiation induced neuropathy. Exploring its usefulness for people with PD has just begun.

Recently published in the journal of Movement Disorders, a study titled, “Spinal Cord Stimulation Therapy for Gait Dysfunction in Advanced Parkinson's Disease Patients” (Samotus et al., 2018), a six-month pilot study recruited five PD participants with advanced PD. These participants were chosen based on convenience. Participants were an average age of 71 with average disease duration of 14 years. Participants who had a stroke (or any other neurological diseases) and moderately severe parkinsonism in the context of unstable medication treatment (Samotus et al., 2018) were not included in the study. All five participants underwent mid-thoracic spinal cord stimulation surgery and a dorsal spinal cord stimulator was implanted in the epidural space (near the lower back).

This study evaluated SCS efficacy by clinical evaluation and objective gait analysis before and after surgery. A 20-foot gait detection mat equipped with pressure sensors — a relatively new technology (Muro-de-la-Herran, Garcia-Zapirain, & Mendez-Zorrilla, 2014) — was used to measure various features of gait such as step length, stride width, stride velocity, step time, stance, swing, and percentage of time one or two feet are on the ground. To measure freezing of gait, a timed sit-to-stand test was used, as well as an automated freezing detection program that measured changes in foot pressure.

The study also evaluated different frequency and pulse width combinations via gait analysis multiple times 1-4 months after surgery. Eleven frequency and pulse width SCS combinations were tested. Of note, the freezing questionnaire, the Unified Parkinson’s Disease Rating Scale (UPDRS) motor items, Activities-specific Balance Confidence Scale (ABC), and Parkinson’s Disease Questionnaire (PDQ-8) were given to all five participants at every visit.

Results

• Six months post-implantation, there was an average improvement of 33.5%, in the UPDRS motor score, 26.8% in the FOG questionnaire and 71.4%, in the ABC score.
• Significant improvement in all participants’ confidence to complete daily activities, especially around and outside the house, occurred in week six and improvements were maintained following week 10, resulting in an average improvement of 71.4% in week 24 compared to before the SCS implantation.
• The number of freezing episodes captured on the gait mat dropped quickly from an average of 16 before surgery to zero six months after surgery, per study participant, on levodopa and off stimulation.
• Stride velocity significantly improved by 42.3%, mean step length improved by 38.8% and the time in seconds for a participant to arise from a chair to a standing position improved by 50.3%.
• By week 24, two of the five participants were able to walk without assistance whereas they needed it before surgery, and three of the five participants reported that their activities of daily living were now only moderately affected by gait dysfunction, whereas they were severely affected before surgery.
• One participant reported no longer needing to use his wheelchair and was solely using a walker by the end of the study,
• No adverse effects were reported.

What Does This Mean?

First presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders, this is the first study to use objective gait technology to assess SCS efficacy for people with advanced PD.

Ranging from significant improvement in all study participants’ confidence in performing activities of daily living, to one of the participants no longer needing a wheelchair, to sustained improvements in gait, the pilot study results are encouraging. Stride velocity improved by 42.3%, average step length improved by 38.8% and the time in seconds for a participant to stand up from a chair improved by 50.3%. Perhaps most impressive was the reporting of zero freezing episodes six months after SCS surgical implantation with no adverse effects.

Further, SCS technology proved to be personalized, as doctors were able to adjust technology after implantation in order to provide the optimal therapeutic value. Unlike most surgical procedures, SCS is reversible. Also, important to note, SCS runs on batteries — some are rechargeable, and others last up to 5 years (NIH, 2019).

Although it is a small pilot study, it nonetheless demonstrated that SCS may offer some significant therapeutic value for people with advanced PD. A larger and longer clinical study is warranted to see if these rather remarkable preliminary results can be replicated.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about freezing, balance, gait and falls and Parkinson’s in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).
• Walking with Parkinson’s: Freezing, Balance and Falls
• Expert Briefings: Gait, Balance and Falls in Parkinson's Disease
• Podcast Episode 18: Stall the Fall

Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

Much of our understanding of Parkinson’s disease comes from genetic studies. The most common genetic changes linked to Parkinson’s occur in the GBA gene. The role of GBA in cells is to break down complex lipids in the cell’s “recycling bin,” the lysosome.

Roy N. Alcalay, MD, MS,  is a Stanley Fahn Junior Faculty Awardee at Columbia University Medical Center who received a Parkinson’s Foundation grant to identify the parts of lipid metabolism that are most affected by Parkinson’s and to find potential drug targets to correct them. With cutting-edge technology, Dr. Alcalay’s research will measure 520 lipids in blood samples from people with Parkinson’s and from people without the disease. In people who carry Parkinson’s-related mutations in the GBA or alpha-synuclein genes, we will test if altered lipid levels are linked to Parkinson’s diagnosis.

Dr. Alcalay’s research will also analyze 600 people with Parkinson’s and 400 without the disease, testing for genetic changes in 32 genes involved with lipid metabolism. His team will look at the relationship between lipid levels and the activities of lysosome enzymes, also assessing genetic changes in the enzymes’ genes. Our hope is that Dr. Alcalay’s and his team can identify novel drug targets and biomarkers for Parkinson’s that will improve diagnosis and treatment of the disease.

The Parkinson's Foundation Stanley Fahn Junior Faculty Award helps ensure promising early career scientists stay in the PD research field. This award provides junior investigators the support they need to develop their own independent funding source.

What's Next: Reporting Our Findings

Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. Scientists submit yearly progress reports to the Parkinson’s Foundation, and we report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.

Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

Alpha-synuclein (αSyn)is a protein central to Parkinson’s. In Parkinson’s, this protein misfolds, forming a clump in the brain. Large clumps are known as “Lewy bodies” and disrupt the brain’s normal functioning in people with PD.

Alpha-synuclein is also involved in the regulation of lipids and fatty acids, which help to prevent disease-associated changes in the brain. In Parkinson’s, alpha-synuclein is destabilized. This makes the protein more likely to break down and clump together. What triggers the destabilization of alpha-synuclein in the human brain remains one of the most critical questions in the study of Parkinson’s.

Tim Bartels, MSc, PhD, from Brigham and Women's Hospital Inc., received a Parkinson’s Foundation research grant to gain a better understating of alpha-synuclein in Parkinson’s. He and his research team will analyze the interactions of lipids with different forms of alpha-synuclein in human brain samples. Dr. Bartels hopes to discover which lipids and fatty acids prevent alpha-synuclein aggregation and which ones promote aggregation.

He will also investigate the normal interaction of alpha-synuclein with fatty acids and lipids. Together, these approaches should suggest how to develop drugs that stabilize alpha-synuclein by mimicking the beneficial lipids and fatty acids.

Dr. Bartels team may also find a signature of specific lipids and fatty acids that are associated with PD. This could be an easily accessible biomarker — a biological molecule that is a sign of disease — for Parkinson’s. Having a biomarker for Parkinson’s could lead to earlier diagnosis of the disease. This can improve outcomes for people living with PD.

The Parkinson’s Foundation Stanley Fahn Junior Faculty Award helps ensure promising early career scientists stay in the PD research field. This award provides junior investigators the support they need to develop their own independent funding source.

What’s Next: Reporting Our Findings
Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. Scientists submit yearly progress reports to the Parkinson’s Foundation, and we report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.

First described as a common symptom of Parkinson’s disease (PD) more than 20 years ago, PD-related fatigue remains an under-recognized, clinically significant, disabling symptom that can diminish quality of life (Herlofson et al., 2018; Kluger et al., 2016). Often occurring prior to movement symptoms of PD — tremor, rigidity and bradykinesia — (Chong, Albor, Wakade, & Morgan, 2018), PD-related fatigue doesn’t go away over time and getting more rest does not help (APDA, 2017).

The 2014 Parkinson’s Foundation Conference on Fatigue found that half of all people with PD reported fatigue as a major problem, and one-third shared that fatigue is their single most disabling symptom. The conference brought together a multidisciplinary group of experts, including a scientist studying fatigue in breast cancer. Research in breast cancer has shown that inflammation plays a large role in fatigue, even years after treatment when patients are in remission. One of the questions that came out of the 2014 conference was whether inflammation also plays a role in fatigue in PD.

Recently published in the journal, Acta Neurologica Scandinavica, a study titled, “Inflammation and fatigue in early, untreated Parkinson’s” (Herlofson et al., 2018) sought to explore the possible association of proinflammatory cytokines (a type of substance released by a cell that promotes inflammation) and fatigue in PD. Considered the boss of the immune system, cytokines are chemical messengers responsible for up-regulating (initiating), as well as down-regulating (turning off) the immune response. Studies have found that proinflammatory cytokines may play a role in PD and have been proposed to be part of an immune response to tissue damage (Williams-Gray et al., 2016)

Funded by the Parkinson’s Foundation, Karen Herlofson, MD, led a study measuring 13 different inflammatory markers and adhesion molecules (helps cells stick to one another), obtained with a simple blood-draw in people with PD who had also been assessed for fatigue levels.

The study recruited 212 participants who were newly diagnosed with PD and untreated. They were initially recruited from the Norwegian ParkWest Project — a population-based prospective longitudinal cohort study of newly diagnosed, untreated people with PD. However, after excluding those with decreased cognitive function, symptoms of depression, excessive daytime sleepiness, apathy, other diseases or relevant medications, a total of 47 participated in this study; 24 had low fatigue scores and 23 had high fatigue scores.

Demographic data (age, years of education, weight, and height) were collected during a semi-structured interview. Disease severity was assessed by the Unified Parkinson’s Disease rating Scale part III (UPDRS III). Fatigue was assessed by the Fatigue Severity Scale (FSS), a self-administered questionnaire, which focuses upon the physical social, and mental aspects of fatigue. All 47 participants had their blood drawn the same day as the clinical assessment and all fasted the night before. The blood draw occurred between 8 and 10 a.m., to minimize confounding factors caused by circadian rhythm.

Results

Compared to the study participants without fatigue, participants with fatigue:

• Had significantly higher levels of the cytokine IL1-Ra and the adhesion molecule VCAM-1
• Had more advanced disease, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score.
• Had lower cognitive function, as measured by the MMSE (Mini-Mental State Examination).
• Had more depression, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Had less excessive daytime sleepiness, as measured by the Epworth Sleepiness Scale (ESS), showed no correlations between IL1-Ra or VCAM-1 with age, sex, years of education, BMI, UPDRS, MADRS, MMSE, apathy, or ESS.

What Does This Mean?

PD-associated fatigue can have a detrimental impact on quality of life; yet, the underlying biological cause remains unknown. This study found that having higher blood levels of the inflammatory markers IL1-Ra and VCAM-1 were associated with higher fatigue levels in newly diagnosed, untreated participants with PD. If true, and an altered immune response is indeed a factor, this finding may offer new targets to explore for future treatment — as the immune system is a promising therapeutic target for disease modification.

Additionally, these findings may, if correct, offer some future early PD diagnostic potential — as fatigue commonly presents before the classic hallmark symptoms of PD. We know that inflammation contributes to neurodegeneration in the brain. Whether or not cytokines are increased as a result of the stress and tissue damage that are a consequence of PD — or whether the inflammation happens prior to the fatigue — is a question that must be answered. This study brings us one step closer

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about the connection between fatigue and Parkinson’s in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).

• Fatigue
• Fatigue & Parkinson's

Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

A key feature of Parkinson’s disease is abnormal protein clumping within nerve cells or neurons. These protein clumps, called aggregates, spread throughout the nervous system as Parkinson’s progresses. How this occurs remains unclear. Mutations in the GBA1 gene are a strong genetic risk factor for developing Parkinson’s. They are also linked with faster progression of motor and cognitive symptoms.

Marie Ynez Davis, MD, PhD, is a Parkinson’s Foundation Clinical Research Awardee of VA Puget Sound, is investigating a potential new role for the gene GBA1 in speeding the spread of protein aggregates through exosomes. These are small bubble-like structures released by neurons and other cells. They contain proteins and other material that can travel and be received by other neurons and cells.

Dr. Davis’ goal is to find out whether a lack of GBA1 influences the development of Parkinson’s by increasing the number of exosomes and the proteins inside them that can be delivered to other neurons. This could promote clumping in the receiving neurons throughout the nervous system.

To achieve this goal, she will study human neurons from people with GBA1 mutations and Parkinson’s. She will examine the development and structure of exosomes. She will also look at their ability to promote protein aggregation.

Our hope is that results from this work will improve our understanding of how Parkinson’s occurs. It may also reveal new targets for therapies that could halt or slow progression of the disease.

Parkinson’s Foundation Clinical Research Awards help facilitate the development of clinician scientists, ensuring that promising early career scientists stay in the PD research to help us solve, treat and end this disease. These scientists are vital, as they apply research to the real-world as well as applying real-world issues to research. 

What’s Next: Reporting Our Findings

Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. Scientists submit yearly progress reports to the Parkinson’s Foundation, and we report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.

Levodopa-induced dyskinesias (LIDs) are a debilitating side effect of long-term use of levodopa therapy that negatively impacts the quality of life for upwards of 90% of people with Parkinson’s disease (PD). From the Greek word, dys, meaning ill or bad, and kīnēsia, meaning movement or muscular activity, dyskinesias are abnormal, involuntary muscle movements, often presenting as erratic writhing movements of the face, arms, legs or trunk.

This side effect is caused by the loss of dopamine in the striatum (a structure in the brain). That loss of dopamine causes the calcium channels in the brain to not function properly.

Why do calcium channels matter?

The human brain has roughly 100 billion interconnected cells. A calcium channel lets calcium into each cell, allowing it to function normally. Previous studies in rats have shown that calcium activity in the brain plays an important role in the onset of Parkinson’s. These channels are also believed to contribute to levodopa-induced dyskinesias.

Evidence suggests that silencing one specific type of these calcium channels might hold some therapeutic promise. The Ca_v1.3 channel is the calcium channel found in the striatum and is made by the human CACNA1D gene. There are existing drugs that can inhibit these calcium channels. However, these drugs are not very potent. For people with PD, they only partially help with levodopa-induced dyskinesias and the relief only lasts a short time, but hope may be on the horizon.

Gene Expression and Gene Silencing

Genes tell cells how to make proteins. This instruction process is called gene expression. Like a dimmer switch, gene silencing is the regulation of gene expression in a cell that prevents or reduces that expression. Figuring out how to identify and silence certain genes is being increasingly studied to help find new therapeutic avenues to combat diseases.

Funded by the Parkinson’s Foundation and the National Institute of Neurological Disorders and Stroke, the study “Genetic Silencing of Striatal CaV1.3 Prevents and Ameliorates Levodopa Dyskinesia” (Steece-Collier et al., 2019) investigated whether silencing of striatal CaV1.3 channels genetically ― as opposed to using medications ― might have the potential to transform Parkinson’s treatments. If successful, this approach could lead to the development of new highly targeted drugs that would allow people with PD to enjoy the motor benefits of levodopa, without the debilitating LID side effects.

To validate the CaV1.3 as a potential target for drugs that might reduce the LID, Kathy Steece-Collier, PhD, and her research team created a virus in their lab that delivers genetic material into cells to target the CaV1.3 channel and prevent it from being made. This virus is a stripped-down version of a normal virus, with all the harmful viral information removed, and is called a viral vector. They injected the viral vector into severely parkinsonian rats to see if that would reduce expression of CaV1.3 channels and thereby impact LIDs.

This was a two-month study that included a control group of severely parkinsonian rats for comparison (that would not receive the genetic treatment). Both groups of rats received increasing doses of Levodopa over time. All rats were regularly tested both prior to and after introducing levodopa therapy.

Results

• If the CaV1.3 channels are silenced in severely parkinsonian rats prior to giving them levodopa therapy, this was able to completely prevent LID symptoms from forming.
• Even with very high doses of daily levodopa, the prevention of LIDs remained and did so, long-term.
• This experimental approach was capable of even partially reversing the LID in rats with established, preexisting severe LID behavior. Current calcium channel drugs are not able to do this.
• The positive therapeutic (motor) benefits of levodopa remained throughout gene silencing.
• As expected, in group of rats who did not receive the genetic treatment, LID worsened severely as the levodopa dose was increased.

What Does This Mean?

This study suggests that reducing the number of CaV1.3 calcium channels has the potential to transform the treatment of individuals with PD by allowing maintenance of the motor benefit of levodopa without the debilitating side effect of LIDs. Further, this study demonstrated it was possible to reverse preexisting, severe levodopa-induced dyskinesias. So, not only did the experimental approach have a protective/preventative effect, it helped the rats that were already severely impaired.

What we don’t know, yet, is whether or not reducing striatal CaV1.3 expression will work in people. However, the authors of this article stated that if the findings of this study can be validated clinically in people, this would be “a much-needed breakthrough in the treatment of individuals with PD and has the potential to allow the most powerful antiparkinsonian therapy identified (i.e., levodopa) to work unabated through the duration of the disease.”

In short, though there is much more work that lies ahead, this preclinical data suggests it may indeed be possible to prevent, and even reverse LIDs, which would be an extraordinary finding for the PD community.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about the Parkinson’s and LID in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).

• New Drug Shows Promise for Levodopa-Induced Dyskinesia
• Dyskinesia

Parkinson’s disease (PD) results in the loss of dopamine-producing cells in the brain. Because dopamine cannot cross the blood-brain barrier (a safety feature of the brain), people cannot simply take dopamine pills. The drug levodopa (L-dopa) — a precursor to dopamine and the gold standard for treating PD — does have the ability to cross the blood-brain barrier, where it successfully converts into the much-needed dopamine.

Since 1971, scientists were aware that one or more of the many microorganisms living in the human gastrointestinal tract prematurely convert the L-dopa into dopamine before it gets into the brain― but they didn’t know which ones. To combat some of this loss, L-dopa is usually combined with carbidopa to help block the premature metabolism, as well as help with the common side effects of nausea and vomiting.

Only about 44% of the L-dopa makes it to the brain. There are many different types of microorganisms, such as bacteria, viruses and fungi. Understanding which ones may affect this process could help improve the efficiency of levodopa as a treatment for PD.

A study titled, “Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism” (Maini Rekdal, Bess, Bisanz, Turnbaugh, & Balskus, 2019), sought to decipher the molecular mechanisms by which gut bacteria might be responsible for this degradation of L-dopa en route to the brain. A complex undertaking, researchers used several, highly sophisticated methods, from running tests on the microbiome (trillions of microorganisms that help keep the body running smoothly) to evaluating inhibitors and testing the gut microbiota of people with and without PD.

Results

• In the gut, some of the L-dopa was converted into dopamine by an enzyme from the common gut bacteria (Enterococcus faecalis).
• Then, the dopamine (still in the gut) was further metabolized into a compound called m-tyramine, by an enzyme from a second bacterium (called Eggerthella lenta).
• The enzymes from these two bacteria (Enterococcus faecalis and Eggerthella lenta) appear to be responsible for L-dopa metabolizing first into dopamine and then into m- tyramine, prior to reaching to blood-brain barrier, thereby diminishing how much L-dopa and the dopamine treatment successfully makes it to the brain.
• Carbidopa is successful in inhibiting the metabolism of L-dopa by human enzymes, but not by the bacterial enzymes in the human gut.
• When L-dopa was given to lab rodents orally along with a bacterial enzyme inhibitor called AFMT, this prevented metabolism of L-dopa and resulted in improved bioavailability of the drug in the animals’ blood stream.  

What Does This Mean?

Using a complex set of steps, this study identified two enzymes in human gut microbiota (called  Enterococcus faecalis and Eggerthella lenta) that are key to impeding a significant portion of the L-dopa from reaching the brain.

Further, in lab rodents, researchers increased the amount of L-dopa reaching the brain, by manipulating the activity of these enzymes in the gut with a drug, AFMT. This suggests that this approach (inhibiting bacterial enzymes) could possibly be developed for human use. In short, they may have found a drug that can reduce the premature metabolism of L-dopa into dopamine in the human gut, ultimately improving the efficiency of L-dopa treatment.

Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

Many cellular components are involved in the development and progression of Parkinson’s disease. One component is the “energy factory” of the cell, called mitochondria. Certain genetic changes are known to impair the function of mitochondria.

Jannik Prasuhn, MD, of the Institute of Neurogenetics, University of Luebeck in Germany, has received a Clinical Research Award from the Parkinson’s Foundation to investigate the use of vitamin K2 in people with Parkinson’s whose disease is caused by genetic mutations that affect the mitochondria.

Vitamin K2 has been shown to be safe in previous studies of people with PD with osteoporosis. The vitamin is known to play a role in supplying cells with energy.

Dr. Prasuhn’s goal is to determine if vitamin K2 can increase energy levels and improve symptoms in people with mitochondrial-related Parkinson’s.

To achieve this goal, he will study 130 people: 26 people with PD who have mitochondrial mutations; 52 people with PD with idiopathic PD, and 52 people without Parkinson’s. They will be randomly assigned to receive vitamin K2 or a placebo for six months. All participants will undergo brain imaging before and after the study, and they will undergo medical exams five times throughout the study.

If this research suggests K2 could be helpful to people with Parkinson’s who have mitochondrial mutations, our hope is that larger, longer-term studies will be conducted that could ultimately lead to using K2 as a PD treatment.

Parkinson’s Foundation Clinical Research Awards help facilitate the development of clinician scientists, ensuring that promising early career scientists stay in the PD research to help us solve, treat and end this disease. These scientists are vital, as they apply research to the real-world as well as applying real-world issues to research. 

What’s Next: Reporting Our Findings

Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. We report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.