Editorial Note On The Review Process
F1000 Faculty Reviews are commissioned from members of the prestigiousF1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions .
The referees who approved this article are:
Fredric P. Manfredsson, Parkinsons Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
No competing interests were disclosed.
Tipu Z. Aziz, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
No competing interests were disclosed.
Strategies For The Treatment Of Parkinsons Disease: Beyond Dopamine
- 1Laboratorio de Neurobiología, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile
- 2Department of Biological Sciences, University of Limerick, Limerick, Ireland
- 3Health Research Institute, University of Limerick, Limerick, Ireland
- 4Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO, United States
- 5Research & Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, United States
Parkinsons disease is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal -synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.
Component #3 Some Form Of Restorative Therapy
Once the condition has been slowed/halted and a neuroprotective/nurturing environment is in place to protect the remaining cells , a curative treatment for Parkinsons will require replacing some of the cells that have been lost.
And until we have developed methods that can identify Parkinsons long before the motor features appear , some form of cell replacement therapy is required to introduce new cells to take up lost function.Cell transplantation currently represents the most straight forward method of cell replacement therapy.
Traditionally, the cell transplantation procedure for Parkinsons has involved multiple injections of developing dopamine neurons being made into an area of the brain called the putamen . These multiple sites allow for the transplanted cells to produce dopamine in the entire extent of the putamen. And ideally, the cells should remain localised to the putamen, so that they are not producing dopamine in areas of the brain where it is not desired .
Targeting transplants into the putamen. Source: Intechopen
Transplanted dopamine neurons. Source: Sciencedirect
The transplanted cells take several years to develop into mature neurons after the transplantation surgery. This means that the actually benefits of the transplantation technique will not be apparent for some time . Once mature, however, it has also been demonstrated that these transplanted cells can produce dopamine.
I think we are done.
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Why Should I Participate In A Clinical Study
We can only reach breakthroughs in treatment and care if people participate in the studies.
Participating is safe and can help you
Every clinical study is reviewed thoroughly before your doctor asks you to participate. Clinical trials carry some risks, but your doctor is required by law to explain the risks to you clearly and make sure that you understand them. If your doctor tells you about the risks of participating in the study, ask yourself, What are the risks of not participating in the study? Most of the time, if you balance the possible benefits from participating against the risks, it is about the same as the risks of not being in the study.
On the other hand, the study may be of a new drug or treatment that could help you. If you dont participate, it may be years before you have a chance to try that drug.
Some people do not participate because there is no guarantee they will get the experimental therapy they might get the placebo. Again, think carefully about the risks and benefits of entering the study and getting the new treatment, entering the study and getting the placebo or not entering the study at all.
Your participation can help others
If you have PD or any other disease, the drugs, procedures and therapies you use now were scientifically tested, likely by thousands of volunteers. Participating in a clinical trial is your way to pay it forward for people diagnosed with Parkinsons in the future.
Drug Delivery Systems For Neurotrophic Factor Therapy
Besides GDNF, other neurotrophic factor such as basic fibroblast growth factor have been evaluated. One example involves gelatin nanostructured lipid carriers encapsulating bFGF that can be targeted to the brain via nasal administration . Overall, the nanoformulation stimulated dopaminergic function in surviving synapses and played a neuroprotective role in 6-OHDA hemiparkinsonian rats. A very recent study took advantage of the neuroprotective properties of Activin B, which was administered in a parkinsonian mice using a thermosensitive injectable HG . The biomaterial allowed a sustained protein release over 5 weeks and contributed to substantial cellular protection and behavioral improvement.
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Updates On Currently Approved Pd Treatments
Table 1 Approved dopaminergic drugs
Later, DA receptor agonists, such as those shown in Table , were developed either as monotherapies or combination therapies with L-DOPA for the treatment of PD. Five types of DA receptors, D1D5, exist in the brain. The D1 and D5 receptors are grouped together as D1-like receptors based on their stimulatory effects on adenylyl cyclase , and the D2, D3, and D4 receptors are classified as D2-like receptors due to their inhibition of cAMP activity. Many synthetic DA agonists, including pramipexole and apomorphine, activate D2-like receptors, and have a lower incidence of motor fluctuations and dyskinesia .
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What Are The Different Stages Of Parkinsons Disease
Each person with Parkinsons disease experiences symptoms in in their own unique way. Not everyone experiences all symptoms of Parkinsons disease. You may not experience symptoms in the same order as others. Some people may have mild symptoms others may have intense symptoms. How quickly symptoms worsen also varies from individual to individual and is difficult to impossible to predict at the outset.
In general, the disease progresses from early stage to mid-stage to mid-late-stage to advanced stage. This is what typically occurs during each of these stages:
Early symptoms of Parkinsons disease are usually mild and typically occur slowly and do not interfere with daily activities. Sometimes early symptoms are not easy to detect or you may think early symptoms are simply normal signs of aging. You may have fatigue or a general sense of uneasiness. You may feel a slight tremor or have difficulty standing.
Often, a family member or friend notices some of the subtle signs before you do. They may notice things like body stiffness or lack of normal movement slow or small handwriting, lack of expression in your face, or difficulty getting out of a chair.
Standing and walking are becoming more difficult and may require assistance with a walker. You may need full time help to continue to live at home.
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Latest News In Parkinson Disease: Treatment Progress Cognition Improvements And More
An overview of the latest news in Parkinson disease reported across MJH Life Sciences.
An overview of the latest news in Parkinson disease reported across MJH Life Sciences.
FDA Approves Investigational NDA for Ketamine in Levodopa-Induced Dykinesia
As the gold standard of treatment for PD, levodopa effectively reduces parkinsonian symptoms, although long-term use has been linked with several adverse events. Chief among these, frequency of OFF time and abnormal involuntary movements, known as levodopa-induced dyskinesia , have been shown to significantly impact quality of life and treatment efficacy.
There are no approved treatments to address LID however, an article by NeurologyLive® indicates there may be some progress in addressing this issue. Last week, the FDA approved PharmaTher Holdings investigational new drug application for ketamine, an N-methyl-D-aspartate receptor-modulating drug, in the treatment of LID in patients with PD.
A phase 2 clinical trial evaluating the safety, efficacy, and pharmacokinetics of ketamine compared with the active control treatment of midazolam is expected to begin patient enrollment in the third quarter of this year. Pending success, the manufacturer noted that it will seek an agreement with the FDA to proceed to a phase 3 clinical study next year.
Neurological Disease Link With COVID-19 Severity, Death
The Latest In Parkinsons Medications: Taking A Personalized Approach
From renowned singer Linda Ronstadt to former NBA player Brian Grant, the faces of Parkinsons disease are as diverse as the symptoms. While there can be common themes such as slowed movement or stiffness each persons PD experience is unique, making individually tailored therapy vital. Fortunately, the list of medications and treatments that improve quality of life for people living with PD continues growing.
This article is based on a Parkinsons Foundation Expert BriefingParkinsons Disease & Medication Whats Newpresented by Vanessa K. Hinson, MD, PhD, Movement Disorders Program director, Medical University of South Carolina, a Parkinsons Foundation Center of Excellence.
Parkinsons disease can vary widely from one person to another. Whether or when someone might experience rapid, involuntary and uncontrollable body movements, called dyskinesias, as a complication of some Parkinsons medications can also fluctuate. Cognitive changes or multitasking can pose challenges for some who live with PD, while others might experience hallucinations. Optimal PD treatment and care should be based on your unique symptoms and help you to live your best life.
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The Key Is The Activation Of Ppn Neurons
In Parkinsons Disease, nerve cells that produce dopamine progressively die. Since the 1960s, doctors have relied on medication to replace the missing dopamine, but it is notoriously difficult to fully control symptoms as the disease progresses.
In many people the movement symptoms do not respond well to medical treatment in the later stages of this disease, so there has been done a lot of research into alternative treatments, including a search for optimal targets for deep brain stimulation, explains Postdoc Debora Masini, first author of the new study, which included several different strategies to substantiate their findings.
When we stimulated these specific neurons in the caudal area of the PPN, the animals were able to walk normally, across longer distances and with normal walking speed, as opposed to before the stimulation, where they would display symptoms of Parkinsons Disease, says Debora Masini.
We systematically compared stimulation of different locations and cell types in a series of complementary experiments. And they all pointed towards the same conclusion. It strongly indicates these excitatory neurons in the caudal PPN are an ideal target for recovery of movement loss, she says.
The researchers hope that the new study could aid clinicians when they pick the exact location for DBS in the brainstem.
Stem Cells For Parkinson’s Disease Are Safe And Effective
According the Venkataraman and colleagues, “A subjective improvement was found in symptoms like facial expression, gait, and freezing episodes 2 patients have significantly reduced the dosages of PD medicine. These results indicate that our protocol seems to be safe, and no serious adverse events occurred after stem-cell transplantation in PD patients.”
As stated in a 2005 study held by Brian Snyder,
Stem cells offer the potential to provide a virtually unlimited supply of optimized dopaminergic neurons that can provide enhanced benefits in comparison to fetal mesencephalic transplants. Stem cells have now been shown to be capable of differentiating into dopamine neurons that provide benefits following transplantation in animal models of Parkinson’s disease.
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New Medications For Off Time
A number of new medications approved recently are designed to reduce OFF time. These medications fall into two major categories:
- Medications that lengthen the effect of a carbidopa/levodopa dose
- Medications that are used as needed if medication effects wear off
Well give specific examples below. In general, new medications that extend the length of a carbidopa/levodopa dose are used if OFF time is somewhat predictable and occurs prior to next dose. New medications that are used as needed are most beneficial when OFF time is not predictable.
New medications that lengthen the effect of a dose of carbidopa/levodopa
- Istradefylline is an adenosine A2A receptor antagonist which was approved in the US in 2019 as an add-on therapy to levodopa for treatment of OFF time in PD. Unlike many of the other medications, it has a novel mechanism of action and is the first medication in its class to be approved for PD. It acts on the adenosine receptor, which modulates the dopaminergic system, but is not directly dopaminergic. The drug was developed in Japan and underwent clinical trials both in Japan and in the US.
- Opicapone is a catechol-O-methyltransferase inhibitor that is taken once a day. It was approved in the US in 2020 as an add-on therapy to levodopa for motor fluctuations.
New formulations of levodopa designed to be used as needed if medication effects wear off
Other medications used as needed if medication effects wear off
How Do I Take Care Of Myself
If you have Parkinsons disease, the best thing you can do is follow the guidance of your healthcare provider on how to take care of yourself.
- Take your medication as prescribed. Taking your medications can make a huge difference in the symptoms of Parkinsons disease. You should take your medications as prescribed and talk to your provider if you notice side effects or start to feel like your medications arent as effective.
- See your provider as recommended. Your healthcare provider will set up a schedule for you to see them. These visits are especially important to help with managing your conditions and finding the right medications and dosages.
- Dont ignore or avoid symptoms. Parkinsons disease can cause a wide range of symptoms, many of which are treatable by treating the condition or the symptoms themselves. Treatment can make a major difference in keeping symptoms from having worse effects.
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Clinical Trial Suggests Parkinsons Drug Is Safe In Humans
A large team of researchers from Denali Therapeutics, working with colleagues from multiple entities in the U.S. and one in Canada, has found that a LRRK2 inhibitor called DNL201 showed no ill effects to volunteers in a clinical trial. In their paper published in Science Translational Medicine, the group describes their clinical trial of the Parkinsons drug and what they learned during its run. Patrick Lewis, with Royal Veterinary College London has published a Focus piece in the same journal issue outlining the work being done by the team at Denali.
Parkinsons disease is a disease that results from the destruction of neurons in the brain that produce dopamine, which is critical for motor function. Prior research has suggested it comes about most often due to environmental factors in people with a genetic risk for it. Prior research has also shown that mutated versions of a certain gene lead to overproduction of an enzyme called LRRK2, which leads to inflammation and other problems. Currently, there are no therapies available to slow its progression.
Science Translational Medicine
Currently, there are no disease modifying therapies for Parkinsons disease that can change the progression of the disease. An international team of scientists led by faculty at the University of Colorado Anschutz Medical Campus is hoping to change that.
Component #2 A Neuroprotective Agent
Once a drug or a treatment has been determined to slow down the progression of Parkinsons, it will be necessary to protect the remaining cells and provide a nurturing environment for the third part of the cure .
Neuroprotection is the area of research that has had the most attention over the years. Drug companies have employed vast resources in this area in the hope of discovering a treatment which will work across conditions , and thus provide them with tremendous profits. Unfortunately, conditions of the brain have proven to be a lot more complicated than first perceived and cross-condition therapies seem unlikely as we move towards greater stratification and personalisation of disease and treatment, respectively.
But there has been the hint of a potential neuroprotective effect in one class of drugs for Parkinsons: GLP-1R agonists.
Neuroprotective approach: GLP-1R agonists
Exenatide is a glucagon like peptide-1 receptor agonist. This is a class of drug that has traditionally been used for treating diabetes, but has recently been repurposed for Parkinsons.
After multiple studies suggested neuroprotective properties in models of Parkinsons, a clinical trial program was intiated, and in 2017, a Phase II Exenatide trial reported the stablisation of Parkinsons motor features over the course of the 48 week trial .
Reduction in motor scores in Exenatide group. Source: Lancet
In late 2019, we saw the initiation of a Phase III clinical trial for .
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Link Could Play Role In Pd Development
To investigate the mechanism of Syn-induced immune responses to viral infections in the brain, the researchers challenged Syn knock-out mice and human Syn KO dopaminergic neurons with RNA virus infection. They discovered that Syn is required for neuronal expression of interferon-stimulated genes . They then found that following any stimulus that triggers interferon signals, a type of immune response, Syn interacts with signaling proteins in neurons to trigger expression of ISGs.
This work provides the first clear mechanism that links inflammation and aSyn, a protein that is closely associated with the development of Parkinsons disease.
The authors mention that this data confirms that Syn responds to infection and inflammatory pathways and suggests that this interaction may play an important role in the development of Parkinsons disease. The next important step is to determine if the interactions between interferon and Syn trigger the formation of the toxic forms of misfolded Syn, called fibrils, that have been found in Parkinsons disease.
The researchers suggest future studies are needed to look into the interactions between type 1 interferon signals in neurons and misfolded Syn to determine if drugs that inhibit these interactions can prevent the formation of misfolded Syn. This would result in a potential disease-modifying therapeutic approach that is needed for patients.