Parkinson’s disease (PD) progression occurs in part because of a misfolded protein called alpha-synuclein that spreads in the brain. Alpha-synuclein forms clumps that clog brain cells (including neurons), leading to their eventual deterioration. Over time, the clumping kills neurons and impairs the brain’s ability to produce dopamine, leading to Parkinson’s symptoms.

Sunil Kumar, PhD, a recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, is working on a new way to stop this spread using foldamers, which mimic the chemical and structural fingerprints of clumping alpha-synuclein and prevent this toxic process.

Foldamers are bioengineered compounds designed to fold into specific shapes, similar to how proteins, like alpha synuclein, fold and behave in the body. Understanding how foldamers fold and their unique structures could lead to the development of new therapeutics.

Dr. Kumar explained that while there is other research being done to prevent alpha-synuclein clumping, his lab’s approach at the University of Denver is unique because they are using foldamer molecules. Many other approaches use either antibodies, which are effective, but large, and have difficulty crossing the blood-brain barrier, or small molecules that are not very specific and therefore not effective in targeting alpha-synuclein.

“We came up with this idea of foldamer molecules, which are as specific as antibodies but they are much smaller in size, allowing them to cross the blood-brain barrier efficiently, which is essential when making a drug for Parkinson’s,” said Dr. Kumar.

“With this foldamer strategy, our lab has identified two or three lead compounds that have advanced through the initial pre-clinical stages,” he said. “We have optimized their activity all the way up to mouse models and they have shown very nice activity to rescue all the Parkinson’s disease phenotypes. We are now in the second phase where we are optimizing their pharmaceutical properties.”

So far, his lab has seen success with this strategy, and he hopes it will lead to a new treatment for people with PD in the future.

“We are very hopeful that once we pass the current testing stage, we can move to the clinical phase and find a drug to stop the progression of the disease or slow it down,” Dr. Kumar said. “This would increase the lifespan of people with Parkinson’s disease, as well as their quality of life.”

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.

Un ensayo clínico demuestra que un tratamiento con ultrasonido puede ayudar a controlar los movimientos involuntarios alterados de las personas con Parkinson.

Las personas con la enfermedad de Parkinson (EP) experimentaron una mejoría significativa en el temblor, la movilidad y otros síntomas motores tras someterse a un procedimiento mínimamente invasivo con ultrasonido focalizado, muestra un estudio publicado en el New England Journal of Medicine.

La estimulación cerebral profunda (ECP) se ha convertido en el principal tratamiento quirúrgico para las personas con EP que no tienen una buena respuesta a la levodopa. Consiste en la colocación quirúrgica invasiva de minúsculos cables en la zona cerebral deseada, que es estimulada mediante el envío de señales eléctricas a través de los cables. El ultrasonido focalizado es un tratamiento que emite ondas sonoras de alta intensidad en el cerebro, guiadas por resonancia magnética (RM). Donde se cruzan estas ondas, crean una alta energía, que genera calor, destruyendo una zona específica del cerebro relacionada con el temblor. Se considera no invasivo porque no implica incisiones ni agujeros en el cráneo.

Ambos tratamientos tienen pros y contras.

• El ultrasonido focalizado no es invasivo. No requiere ajustes adicionales y crea un cambio permanente.
• La ECP es una cirugía invasiva que permite ajustes a medida que los síntomas del movimiento empeoran en el transcurso del Parkinson, incluso años después de la cirugía. La ECP puede seguir siendo una opción para quienes se realizan el ultrasonido focalizado si la enfermedad sigue progresando.

La Administración de Alimentos y Medicamentos de los EE.UU. o Food and Drug Administration (FDA, por sus siglas en inglés) aprobó el ultrasonido focalizado como tratamiento para el Parkinson para quienes presentan síntomas motores principalmente en un lado del cuerpo. Sin embargo, la mayoría de las personas con Parkinson presentan síntomas motores en ambos lados del cuerpo. En este estudio participaron personas con síntomas en ambos lados del cuerpo.

Acerca del estudio y los resultados

El ultrasonido focalizado se dirige a una parte del cerebro llamada globo pálido interno (GPi), que forma parte de los ganglios basales, una red de estructuras cerebrales que controla el movimiento. En el Parkinson, la pérdida de neuronas productoras de dopamina altera el funcionamiento normal de los ganglios basales. Esto puede conducir finalmente a una actividad anormal en el GPi y puede contribuir a los síntomas motores del Parkinson.

Este estudio examinó la seguridad y eficacia del ultrasonido focalizado en el GPi en un ensayo aleatorio de 94 participantes con síntomas motores de la EP. Sólo se trató el lado del cerebro opuesto al lado más sintomático del participante. De los 94 participantes, 69 fueron asignados aleatoriamente al grupo de ultrasonido focalizado y 25 al grupo de control, donde recibieron un tratamiento simulado  (sin activación del ultrasonido).

Cada participante recibió una evaluación clínica de la gravedad y progresión de su Parkinson antes y después del tratamiento. Casi un 70% de los participantes del grupo de tratamiento presentaron mejorías en los síntomas tras tres meses de seguimiento, en comparación con un 32% del grupo de control, que se sometió a un procedimiento inactivo sin ultrasonidos focalizados.

Un año más tarde, se realizó una evaluación de seguimiento a 60 de los 69 participantes originales y se descubrió que un 66% de los que recibieron tratamiento y que tuvieron una mejoría inicial de los síntomas seguían teniendo una respuesta positiva al tratamiento. Asimismo, de los 25 participantes que recibieron inicialmente un tratamiento placebo, 20 optaron por someterse al tratamiento real tres meses después. De los 20 que eligieron el tratamiento, un 70% tuvo una respuesta positiva a los tres meses y un 57% siguió teniendo éxito un año después.

Un tercio de los participantes no tuvo efectos secundarios. Entre los que sí los tuvieron, la mayoría de los participantes sólo experimentaron algunos síntomas leves o moderados, como dolores de cabeza, mareos y náuseas. Sin embargo, un individuo experimentó una complicación grave relacionada con el procedimiento: una embolia pulmonar no fatal. En el control realizado a los tres meses, las reacciones adversas fueron de leves a moderadas e incluyeron dificultad para hablar, trastornos de la marcha, pérdida del gusto, trastornos visuales y debilidad facial. 

Sobresalientes

• El ensayo clínico utilizó ultrasonido focalizado para tratar los síntomas motores de los participantes con Parkinson con el objetivo de mejorarlos.
• Casi un 70% de los participantes del grupo de tratamiento respondieron satisfactoriamente al tratamiento tras tres meses de seguimiento, en comparación con un 32% del grupo de control que no se sometió al ultrasonido focalizado.
• Alrededor de un 66% de los participantes en el grupo de tratamiento que tuvieron éxito inicial siguieron teniendo una respuesta positiva al tratamiento un año después.

¿Qué significa esto?

Este tratamiento puede ser eficaz para mejorar los síntomas físicos del Parkinson. Sin embargo, aún se desconocen sus efectos a largo plazo. Todos los participantes en el estudio serán objeto de seguimiento durante cinco años para evaluar los efectos y la seguridad del procedimiento a largo plazo.

¿Qué significan estos hallazgos para las personas con EP en este momento?

Aunque está aprobado por la Administración de Alimentos y Medicamentos (FDA, por sus siglas en inglés), pasarán años antes de que conozcamos la eficacia y los efectos a largo plazo del ultrasonido focalizado como tratamiento de la EP. La Parkinson's Foundation invita a las personas con EP a trabajar con un especialista en trastornos del movimiento para asegurarse de que el ultrasonido focalizado sea una buena opción.

Cada vez hay más centros que ofrecen ultrasonido focalizado para el Parkinson en todo el país. Para obtener una lista de sitios que ofrecen el tratamiento, visite el sitio web de la Focused Ultrasound Foundation. Asegúrese de preguntar por la experiencia que tiene el centro en el tratamiento de la enfermedad de Parkinson, en concreto.

Hay que tener en cuenta que el ultrasonido focalizado no está cubierto universalmente por Medicare: la elegibilidad y la región varían en lo que respecta al reembolso de Medicare. El procedimiento tardará en generalizarse y estar cubierto por los seguros. Póngase en contacto directamente con el centro que ofrece el ultrasonido focalizado en su zona para obtener información específica acerca de la cobertura de seguros.

Aprenda más

La Parkinson’s Foundation cree en el empoderamiento de la comunidad de Parkinson a través de la educación. Aprenda más acerca de la EP y de los temas en estos recursos a continuación o llame gratis a nuestra Línea de Ayuda al 1-800-4PD-INFO (1- 800- 473-4636), opción 3 para español, para obtener respuestas a sus preguntas acerca del Parkinson.

• Podcast: Opciones quirúrgicas en el tratamiento de la enfermedad de Parkinson
• Opciones quirúrgicas:Una guía de tratamiento para el Parkinson - Actualizada
• ¿Debería Considerar la Estimulación Cerebral Profunda?

Though there is still a lot we don’t know about Parkinson’s disease (PD), therapies aimed at modifying disease progression are poised for major breakthroughs. Researchers are excited about the potential of current studies to improve, slow or someday stop PD.

This article is based on Research Update: Working to Halt PD, a Parkinson’s Foundation Expert Briefing webinar presented by Lorraine Kalia, MD, PhD, FRCPC, assistant professor in the Division of Neurology, Department of Medicine at the University of Toronto and scientist at Toronto Western Research Institute and Tanz Centre for Research in Neurodegenerative Disease.

Understanding PD Progression

Parkinson’s is not a static condition — it's an intricate, progressive disease that evolves over time. Uncovering its many complexities is one of the challenges PD researchers face as they work toward halting its progression.

As people age, the loss of some brain cells is expected. In Parkinson’s this loss happens at a much faster rate. Neurodegeneration, the progressive loss of neurons that produce dopamine — a feel-good chemical related to movement, mood and more — is tied to movement and non-movement symptoms that develop in PD. As time progresses, new symptoms may develop or worsen.

Right now, we have therapies that can treat Parkinson’s symptoms — lessening tremor, easing mobility, improving mood and more — but we can’t stop the disease. Research is at the beginning stages of discovering disease-modifying therapies that might slow or stop the loss of dopamine-producing neurons.

Exploring Disease-Modifying Therapies

Therapies that can potentially change the course of Parkinson’s are rapidly evolving. A 2023 analysis of 139 PD drug therapy clinical trials registered as active on the ClinicalTrials.gov website showed 76 were investigating symptomatic treatments and another 63 were exploring disease-modifying therapies.

Though these therapies are still on the horizon for use in PD, the first drug to change the course of multiple sclerosis (MS) — a condition that affects a person’s spinal cord and brain and spine — was discovered in 1993. Now, there are more than 20 disease-modifying therapies for MS. One reason medications to slow MS progression have been so successful is that scientists have a way to identify the disease and observe its response to therapies. This is known as a biomarker.

Researchers are beginning to discover possible biomarkers related to Parkinson's. PD is tied to the abnormal clumping of a protein called alpha-synuclein in the brain. Alpha-synuclein can act as a biomarker in PD. Reliable biomarkers can potentially lead to the ability to diagnose Parkinson’ sooner, track disease progression and help researchers design and test therapies that might change the course of the disease.

Changing the Course of PD

Neurodegeneration in Parkinson’s — progressive damage to normal, healthy brain cells — can cause cell dysfunction and death. This process may be reversible. Cell protection is an approach that seeks to slow or prevent this process.

Areas of research that focus on cell protection are expected to show the most progress in the near future. They include:

Exercise

One of the most important PD symptom management tools, it improves heart, muscle and bone health, lung function, as well as cognitive and mental health. Exercise can also reduce the risk of fractures and falls. Research shows it can also help maintain movement in Parkinson’s, slow disease progression and improve symptoms; it may also provide cell protection.

Studies suggest exercise might reduce inflammation in PD and increase growth factors — proteins that stimulate cell growth and influence how a cell functions.

Alpha-synuclein

This protein is abundant in the brain. Though it’s unclear why, alpha-synuclein malfunctions in PD and the proteins start to misfold and stick together, forming increasing buildups. These ultimately form Lewy bodies.

Brain cells are complex and require several healthy components to function. Researchers think malformed alpha-synuclein can disrupt these cell functions and can impact nearby brain cells. Targeting misfolded alpha-synuclein may protect brain cells from dying. There are many potential ways to do this. Researchers are currently exploring prescription therapies that could:

• Reduce alpha-synuclein production in the cell (Buntanetap ION464.)
• Degrade corrupt alpha-synuclein (Minzasolmin.)
• Reduce or prevent problematic alpha-synuclein moving from one cell to another (Prasinezumab ACI-7104.056 and UB-312.)

GBA1 and LRRK2 Genes

There is a connection between genetics and Parkinson’s. GBA is the most common Parkinson's-related gene, occurring in 5 to 10% of people with PD. Carriers may experience PD symptoms at an earlier age compared to those who do not have a genetic form of PD. LRRK2 is involved in about 5% of people with a family history of Parkinson’s. Carriers may have milder symptoms of dementia and depression. 

Lysosome, one of the disposal systems of the cell, is an enzyme that breaks down and gets rid of waste. One thing it may get rid of is alpha-synuclein. GBA lives within the lysosome. In people with a GBA gene mutation, the lysosome enzyme may be underactive. Researchers are currently exploring prescription therapies that could enhance lysosome activity and make it work better.

In Parkinson’s, a LRRK2 mutation impacts the autophagy lysosomal pathway, another cell waste disposal system, causing overactivity. Slowing this activity might reduce neurodegeneration. BIIB094 and BIIB122, intended to curb this excess activity, are currently in clinical trial.

Repurposing Existing Drugs

Therapies already approved for other diseases may hold great potential in Parkinson’s. If proven effective, they can be fast-tracked to begin treating people with PD because they have already gone through clinical trials to demonstrate their safety.

More than one-third of the drugs in current PD clinical trials being tested as potential disease-modifying therapies are repurposed drugs.

Amantadine is an example of drug repurposing in Parkinson’s as it was originally developed as a flu treatment. In the 1960s, a woman with PD taking amantadine for the flu told her doctor her Parkinson’s symptoms felt much better. Subsequent clinical trials confirmed the benefits of amantadine on some PD symptoms. The medication was initially prescribed for movement symptoms, before levodopa became the most effective, widely available Parkinson’s drug. Today, amantadine is primarily used to treat dyskinesia.

Ambroxol is currently approved as a cough suppressant and is in clinical trial to enhance GBA activity. It has quickly moved from Phase II onto Phase III clinical trials.

GLP-1 receptor activators are another category of medications that may hold major disease-modifying potential, are currently making headlines. These drugs were primarily developed for diabetes (one of the most familiar brand names in the category is Ozempic).

GLP-1 receptor activators bind to a receptor on the outside of a cell, causing a chain of activities that can potentially improve memory, cell survival and effects of mitochondria, while reducing inflammation and alpha-synuclein. Exenatide is the first of these to be tested. Various versions of it, NLY01 (slow-release) and PT320 (pegylated), have been or are in clinical trials.

Two related medications, Liraglutide and Lixisenatide, have been or are also in clinical trials. The results of a phase II trial of Lixisenatide published in the April 3, 2024 New England Journal of Medicine are causing a lot of excitement. Lixisenatide therapy in participants with early PD resulted in less motor disability progression than placebo at 12 months. The study is poised to move on to a phase III trial.

Cell Replacement

Early studies to investigate whether brain cells could be replaced in Parkinson's isolated and removed dopamine-making stem cells from human fetal tissue and grafted them into the brains of research participants with PD. While the research showed promise, nuances and complications limited long-term research.

Remarkable advances in stem cell technology over the past decade have led to the ability to make dopamine-producing cells from a person’s blood or skin cells or from embryonic stem cells, unlocking a new generation of stem cell research. There are ongoing clinical trials in countries around the world, including the U.S., investigating potential benefits in Parkinson's.

Cautious Optimism

Parkinson's disease looks different for different people. Different causes may spur its development. Multifaceted research is essential to moving forward.

Science must keep an open mind, follow the evidence and — when disease-modifying treatments become available — target people with the right treatments at the most impactful stages of the disease.

Ultimately, Parkinson’s is a global disease with symptoms and a rate of progression that is unique to each person living with it. It is important to pursue different avenues of research because there may be more than a single cure.

Learn More

The Parkinson’s Foundation works improve care for people with PD and advance research toward a cure.

• Discover how we are working to close gaps in knowledge about PD: Advancing Research
• Explore ongoing Parkinson’s research studies: Join A Study

Learn about PD GENEration — a global genetics study that provides genetic testing and counseling at no cost for people with Parkinson’s.

New research indicates that a skin biopsy could possibly lead to accurate diagnosis of Parkinson’s and other neurodegenerative diseases.

Currently, there is no single test to diagnose Parkinson’s disease (PD). Doctors rely on symptoms, which can mean a delay in diagnosis as early symptoms can be hard to distinguish from other common ailments. A new study in the Journal of the American Medical Association (JAMA) shows that a skin biopsy test can reliably detect Parkinson’s and other related diseases.

Parkinson’s, along with dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF) are four diseases characterized by progressive neurodegeneration and disability. Together this group of diseases are called synucleinopathies because the nerve cells accumulate an abnormal version of the protein alpha-synuclein, which is also referred to as phosphorylated alpha-synuclein (P-SYN).

Previous research indicated that P-SYN could also be found in nerve cells present in the skin. The new JAMA study shows that small amounts of skin taken from the leg, thigh and back of the neck can be analyzed to detect P-SYN in people who have synucleinopathies.

A similar study published last year detected alpha-synuclein in a slightly different test referred to as a seed amplification assay (SAA) analysis . In that study, investigators collected spinal fluid from people with early Parkinson’s. A skin biopsy is considerably less invasive than a lumbar puncture (also known as a spinal tap), which is why this study has generated a lot of interest.

About the Study & Results

The study enrolled 428 participants; 277 were diagnosed with Parkinson’s or another synucleinopathy (DLB, MSA or PAF), along with 151 people who had no history of neurodegenerative disease. Each participant had three skin biopsies that were analyzed in the laboratory.

Of those confirmed to have a synucleinopathy, the biopsies tested positive for P-SYN 92.7% of the time with Parkinson’s, 98.2% with MSA, 96% with DLB, and 100% with PAF. For people who did not have a diagnosis, only 3.3% of the biopsies tested positive for P-SYN.

The researchers also found a correlation between the amount of P-SYN in the biopsies and the severity of the participants’ symptoms.

Biopsy detection of P-SYN was the lowest among those with Parkinson’s (at the rate of 92.7% positive), potentially because there are different subtypes of Parkinson’s or because some genetic causes of Parkinson’s, there may be less P-SYN accumulation. However, study results did not address genetic variations associated with the diagnosis of PD.

However, it’s possible that skin biopsies could detect many cases of Parkinson’s before hallmark symptoms appear — such as tremor and trouble walking. Researchers suspect that P-SYN begins to accumulate in the nerve cells before there are noticeable changes to a person's movement. More research will be needed to confirm this suspicion.

The authors of the study speculated that the 3.3% of the biopsies that tested positive for P-SYN among those who did not have a neurodegenerative disease diagnosis, may indicate the potential for a future synucleinopathy diagnosis. However, longer-term follow-up is needed for confirmation.

More research is needed to determine when P-SYN can be detected in the progression of these diseases, and in those who don’t have symptoms, whether P-SYN detection is always predictive of future disease.

Highlights

• The study looked for a skin biopsy marker of Parkinson’s and other related neurodegenerative diseases, called phosphorylated alpha-synuclein (P-SYN).
• Among those confirmed to have Parkinson’s, 92.7% of the skin biopsies tested positive for P-SYN.
• Among those who did not have a neurodegenerative diagnosis, only 3.3% of the skin biopsies were positive for P-SYN.
• The amount of P-SYN in the biopsies correlated with the severity of the participants’ symptoms.

What does this mean?

This skin test method could be used to detect Parkinson’s and related diseases before symptoms appear. By identifying the disease before symptoms manifest there is a possibility of developing treatments before the condition progresses. With a reliable way to identify these diseases at their earliest stages, researchers could more effectively evaluate potential treatments and hopefully bring them to people living with PD sooner.

Additionally, because the researchers found a correlation between the amount of P-SYN in the biopsies and the severity of symptoms, the test might be used to test whether potential treatments are working. For example, if a drug treatment reduces P-SYN, it could indicate that the treatment is having an effect.

More research is needed before a skin biopsy would be considered useful for someone who does not have symptoms, as we don’t yet know how early the test could detect whether they will likely have Parkinson’s or other related diseases. We also do not know if some people could have P-SYN in their skin, but never develop symptoms.

What do these findings mean to the people with PD right now?

The skin biopsy test is commercially available today. It is called the Syn-One Test® and doctors may use it to confirm a synucleinopathy, which may lead to a Parkinson’s diagnosis. A doctor assesses test results alongside other in-office tests and present symptoms to confirm a Parkinson’s diagnosis. If you are already diagnosed with Parkinson’s disease and respond to levodopa treatment, the skin biopsy will likely not add anything to your current management and would not be necessary.

According to the Syn-One Test® manufacturer, Medicare typically covers 80% of the total fee. Insurance may cover all or some of the test fee.

When diagnosing possible Parkinsonism, instead of the Syn-One Test, a doctor may order a DaT scan. Similarly, a DaT scan does not differentiate between the various forms of parkinsonism. Usually if a doctor orders a test to help confirm a Parkinson’s diagnosis, the test is either the skin biopsy test or a DaT scan — not both.

Talk to your Parkinson’s doctor about the Syn-One Test®. If you have already been diagnosed with Parkinson’s and you are responding to therapy, your doctor will most likely not recommend the test. If you are in the process of being diagnosed or confirming a diagnosis, a neurologist or a neurologist with specialty training in movement disorders if available in your region, may consider this test to confirm a diagnosis of a synucleinopathy. Remember that this test is relatively new, so not all Parkinson’s doctors are utilizing it.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about PD and the topics in this article through our below resources, or by calling our free Helpline at 1-800-4PD-INFO (1-800-473-4636) for answers to your Parkinson’s questions.

• Getting Diagnosed
• Neuro Talk: Why Are More People Getting Diagnosed with Parkinson’s?
• Detecting Early Parkinson’s with a Wearable Movement-Tracking Device